https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Ilan+SamishProteopedia - User contributions [en]2026-10-03T15:50:51ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=956062Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-12T21:24:55Z<p>Ilan Samish: /* Amantadine and Rimantadine - M2 Proton Channel Inhibitors */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>. The influenza virus includes only eight proteins. Sequences of these proteins as obtained from numerous strains are available in the [http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/select.cgi?go=1 NCBI Influenza Virus Resource]. For more about the structure and biology, including references for the points made here, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
For more about neuraminidase, including references for the points made in this paragraph, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
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<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
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===Neuraminidase Structure and Conserved Amino Acids===<br />
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*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
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*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
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*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
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==Pandemic Influenza==<br />
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[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
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===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
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==Prophylaxis and Treatment of Influenza==<br />
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'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
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'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
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===Amantadine and Rimantadine - M2 Proton Channel Inhibitors===<br />
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[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the [http://www.proteopedia.org/wiki/index.php/Proton_Channels M2 proton-channel] ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
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===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
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[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
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[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
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'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
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====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
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====Tamiflu Binds to N1 by Induced Fit====<br />
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<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
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The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
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===Cavity in N1: An Opportunity for Drug Design===<br />
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<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
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N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
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<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
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==Links==<br />
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*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
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*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
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*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
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*[http://tamiflu.com Tamiflu] official website by Roche.<br />
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*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
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==Notes and Literature References==<br />
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<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=955942Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-08T17:46:41Z<p>Ilan Samish: /* Amantadine and Rimantadine */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>. The influenza virus includes only eight proteins. Sequences of these proteins as obtained from numerous strains are available in the [http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/select.cgi?go=1 NCBI Influenza Virus Resource]. For more about the structure and biology, including references for the points made here, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
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<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
<br />
===Neuraminidase Structure and Conserved Amino Acids===<br />
<br />
*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
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*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
<br />
{{Clear}}<br />
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==Pandemic Influenza==<br />
<br />
[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
<br />
===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
<br />
==Prophylaxis and Treatment of Influenza==<br />
<br />
'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
<br />
'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
<br />
===Amantadine and Rimantadine - M2 Proton Channel Inhibitors===<br />
<br />
[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the M2 proton-channel ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
<br />
===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
<br />
[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
<br />
[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
<br />
'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
<br />
====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
{{Clear}}<br />
<br />
====Tamiflu Binds to N1 by Induced Fit====<br />
<br />
<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
<br />
The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
<br />
===Cavity in N1: An Opportunity for Drug Design===<br />
<br />
<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
<br />
N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
<br />
<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
{{Clear}}<br />
<br />
==Links==<br />
<br />
*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
<br />
*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
<br />
*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
<br />
*[http://tamiflu.com Tamiflu] official website by Roche.<br />
<br />
*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
<br />
==Notes and Literature References==<br />
<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=955941Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-08T17:45:29Z<p>Ilan Samish: /* Influenza */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>. The influenza virus includes only eight proteins. Sequences of these proteins as obtained from numerous strains are available in the [http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/select.cgi?go=1 NCBI Influenza Virus Resource]. For more about the structure and biology, including references for the points made here, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
{{Clear}}<br />
<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
<br />
===Neuraminidase Structure and Conserved Amino Acids===<br />
<br />
*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
<br />
*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
<br />
{{Clear}}<br />
<br />
==Pandemic Influenza==<br />
<br />
[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
<br />
===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
<br />
==Prophylaxis and Treatment of Influenza==<br />
<br />
'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
<br />
'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
<br />
===Amantadine and Rimantadine===<br />
<br />
[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the M2 proton-channel ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
<br />
===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
<br />
[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
<br />
[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
<br />
'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
<br />
====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
{{Clear}}<br />
<br />
====Tamiflu Binds to N1 by Induced Fit====<br />
<br />
<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
<br />
The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
<br />
===Cavity in N1: An Opportunity for Drug Design===<br />
<br />
<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
<br />
N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
<br />
<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
{{Clear}}<br />
<br />
==Links==<br />
<br />
*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
<br />
*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
<br />
*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
<br />
*[http://tamiflu.com Tamiflu] official website by Roche.<br />
<br />
*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
<br />
==Notes and Literature References==<br />
<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=955940Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-08T17:45:04Z<p>Ilan Samish: /* Influenza Virus Neuraminidase */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>. The influenza virus includes only eight proteins. Sequences of these proteins as obtained from numerous strains are available in the [http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/select.cgi?go=1 NCBI Influenza Virus Resource].<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
{{Clear}}<br />
<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
<br />
===Neuraminidase Structure and Conserved Amino Acids===<br />
<br />
*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
<br />
*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
<br />
{{Clear}}<br />
<br />
==Pandemic Influenza==<br />
<br />
[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
<br />
===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
<br />
==Prophylaxis and Treatment of Influenza==<br />
<br />
'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
<br />
'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
<br />
===Amantadine and Rimantadine===<br />
<br />
[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the M2 proton-channel ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
<br />
===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
<br />
[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
<br />
[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
<br />
'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
<br />
====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
{{Clear}}<br />
<br />
====Tamiflu Binds to N1 by Induced Fit====<br />
<br />
<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
<br />
The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
<br />
===Cavity in N1: An Opportunity for Drug Design===<br />
<br />
<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
<br />
N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
<br />
<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
{{Clear}}<br />
<br />
==Links==<br />
<br />
*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
<br />
*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
<br />
*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
<br />
*[http://tamiflu.com Tamiflu] official website by Roche.<br />
<br />
*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
<br />
==Notes and Literature References==<br />
<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=955939Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-08T17:34:33Z<p>Ilan Samish: /* Influenza */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>. The influenza virus includes only eight proteins. Sequences of these proteins as obtained from numerous strains are available in the [http://www.ncbi.nlm.nih.gov/genomes/FLU/Database/select.cgi?go=1 NCBI Influenza Virus Resource].<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
For more about the structure and biology, including references for the points made here, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
{{Clear}}<br />
<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
<br />
===Neuraminidase Structure and Conserved Amino Acids===<br />
<br />
*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
<br />
*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
<br />
{{Clear}}<br />
<br />
==Pandemic Influenza==<br />
<br />
[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
<br />
===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
<br />
==Prophylaxis and Treatment of Influenza==<br />
<br />
'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
<br />
'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
<br />
===Amantadine and Rimantadine===<br />
<br />
[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the M2 proton-channel ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
<br />
===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
<br />
[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
<br />
[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
<br />
'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
<br />
====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
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<br />
====Tamiflu Binds to N1 by Induced Fit====<br />
<br />
<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
<br />
The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
<br />
===Cavity in N1: An Opportunity for Drug Design===<br />
<br />
<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
<br />
N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
<br />
<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
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<br />
==Links==<br />
<br />
*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
<br />
*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
<br />
*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
<br />
*[http://tamiflu.com Tamiflu] official website by Roche.<br />
<br />
*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
<br />
==Notes and Literature References==<br />
<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza&diff=955938Avian Influenza Neuraminidase, Tamiflu and Relenza2009-05-08T17:26:16Z<p>Ilan Samish: /* Amantadine and Rimantadine */</p>
<hr />
<div><big><br />
This article was updated April 29, 2009.<br />
</big><br />
<br />
==Influenza==<br />
<br />
Influenza <ref name="flu">[http://en.wikipedia.org/wiki/Influenza Influenza] (in Wikipedia).</ref> is a contagious disease caused by a virus. Influenza A<ref name="flu_a">See [http://en.wikipedia.org/wiki/Influenza#Types_of_influenza_virus Influenza A Types of Influenza Virus] (in Wikipedia).</ref> (one of several genera and species of influenza) is the most virulent form infecting humans. Largely by facilitating secondary bacterial pneumonias, influenza kills 500,000 people worldwide annually (including about 36,000 in the USA), mostly during seasonal [http://en.wikipedia.org/wiki/Epidemic epidemics] each year. Most people killed in the annual influenza epidemics are people whose immune defenses are weak, including the very young and the old. Influenza also kills large numbers of animals and birds, both domestic and wild<ref name="animals">[http://www.fao.org/avianflu/en/clinical.html Epidemiology of Avian Influenza] at the [http://fao.org Food and Agriculture Organization of the United Nations].</ref>.<br />
<br />
==Influenza Virus Neuraminidase==<br />
<br />
[[Image:3D_Influenza_virus.png|frame|Structure of an influenza virus <ref>[http://en.wikipedia.org/wiki/Image:3D_Influenza_virus.png Image of influenza virus structure] was obtained from Wikipedia.</ref>.]]<br />
<br />
The surfaces of influenza viruses include, among other molecules, two glycoproteins named '''hemagglutinin (H)''' and '''neuraminidase (N)''', coded for by the viral segmented RNA genome. Each of these molecules is required for successful infection and spread in a host animal. The hemagglutinin attaches influenza to sialic acid on the surfaces of cells, enabling them to enter and infect cells. After the virus has replicated, neuraminidase (also called sialidase) removes sialic acid from the cell, enabling the newly assembled virions to be released in order to spread and infect other cells.<br />
The hemagglutinin ('''H''') and neuraminidase ('''N''') of influenza A are classified into various numbered serotypes or subtypes, such as H1N1, H2N2, H3N2, H5N1, and so forth<ref name="fluwikipedia">[http://en.wikipedia.org/wiki/Influenza Influenza] at Wikipedia.</ref>.<br />
For more about the structure and biology, including references for the points made here, please see [http://en.wikipedia.org/wiki/Influenza Influenza at Wikipedia].<br />
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<applet load='2hu4_1.pdb' size='500' frame='true' align='right' caption='Influenza Neuraminidase N1 (2hu4).' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1' /><br />
<br />
===Neuraminidase Structure and Conserved Amino Acids===<br />
<br />
*Influenza neuraminidase is a homotetramer<ref>The tetramer is one of two [[Biological Unit|biological units]] in the [[Asymmetric Unit|asymmetric unit]] of [[2hu4]].</ref> (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/1'>restore initial scene</scene>). <br />
<br />
*Each of the four protein chains in the tetramer has a catalytic site, indicated in <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/3'>this scene</scene> by the positions of the bound <font color='red'>'''Tamiflu'''</font> inhibitors.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/5'>substrate binding site</scene> involves only a single protein chain, being distant from neighboring chains.<br />
<br />
*The <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/6'>secondary structure</scene> is mostly beta, consisting of several beta sheets with three short alpha helices ({{Template:ColorKey_Strand}}, {{Template:ColorKey_Helix}}).<br />
<br />
*The residues contacting the <font color='red'>'''Tamiflu inhibitory substrate analog'''</font> are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/7'>highly conserved</scene><ref>See [[Evolutionary Conservation]]. Coloring by ConSurf on chain A of 2hu4 based on 100 unique homologs using default conditions, done on September 23, 2008.</ref>.<br />
<center>{{Template:ColorKey_ConSurf}}</center><br />
<br />
*These highly conserved residues include some known to be crucial to binding sialic acid substrate: Arg 118, Arg 292 and Arg 371 bind the carboxylate; Arg 152 interacts with the acetamido substituent; and Glu 276 forms hydrogen bonds with the 8- and 9-hydroxyl groups of the substrate. These residues are <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_tetramer/8'>highlighted here</scene> in contact with the sialic acid substrate analog Tamiflu. In this scene, atoms and bonds in Tamiflu and the highlighted residues are colored by element: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
<br />
{{Clear}}<br />
<br />
==Pandemic Influenza==<br />
<br />
[http://en.wikipedia.org/wiki/Pandemic Pandemics] occur when localized [http://en.wikipedia.org/wiki/Epidemic epidemics] spread through large regions of the world.<br />
<br />
===Past Influenza Pandemics===<br />
<br />
For the meaning of &quot;H1N1&quot;, &quot;H2N2&quot;, etc. see [[#Influenza Virus Neuraminidase|above]].<br />
<br />
* '''H1N1 1918-20''': The [http://en.wikipedia.org/wiki/Spanish_flu Spanish Flu] pandemic killed tens of millions of people worldwide (about twice as many as were killed in World War I). One in five suffered with this disease, and about one in 30 died. This pandemic may have killed more people than did the [http://en.wikipedia.org/wiki/Black_Death Black Plague]. Spanish Flu was caused by a particularly virulent form of [http://en.wikipedia.org/wiki/H1N1 H1N1] believed to be derived from influenza A viruses in the natural reservoir of wild birds.<br />
<br />
* '''H2N2 1957-58''': The ''Asian Flu'' pandemic originated when a virus mutation in the wild duck reservoir of influenza virus combined with a human strain. This virus, of subtype [http://en.wikipedia.org/wiki/H2N2 H2N2], killed nearly 70,000 people in the USA and infected millions worldwide. It was contained in part by a vaccine developed during the pandemic. H2N2 is also suspected of causing the ''Russian Flu'' pandemic that killed about one million people in 1889-90.<br />
<br />
* '''H3N2 1968-69''': The ''Hong Kong Flu'' pandemic was caused by an H3N2 subtype derived by genetic recombination ([http://en.wikipedia.org/wiki/Antigenic_shift antigenic shift]) between virus subtypes, believed to have occurred during co-infection of pigs by multiple virus subtypes including H2N2. Although it infected hundreds of millions of people worldwide, its modest virulence prevented the death rate from greatly exceeding that of normal flu seasons.<br />
<br />
===H1N1 "Swine Flu" Pandemic Threat in 2009===<br />
<br />
Although scientists and public health officials have been worried about an [[#Influenza Virus Neuraminidase|H5N1]] "bird flu" pandemic for many years (see next section below), the first new influenza virus to emerge in the twenty-first century<ref>Severe acute respiratory syndrome, SARS, was a near-pandemic in 2002-2003: see [http://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome Severe Acute Respiratory Syndrome] (in Wikipedia).</ref> that shows pandemic potential is an [[#Influenza Virus Neuraminidase|H1N1]] "swine flu"<ref name="swinefluoutbreak">[http://en.wikipedia.org/wiki/2009_swine_flu_outbreak 2009 Swine Flu Outbreak] (in Wikipedia).</ref> that was recognized by the US Centers for Disease Control and Prevention (CDC) in mid-April, 2009<ref name="swineflu1">[http://www.cdc.gov/swineflu/updates/investigation_042309.htm Human Swine Influenza Investigation], April 23, 2009.</ref>. &quot;The viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the U.S. or elsewhere.&quot;<ref>From the CDC: [http://cdc.gov/swineflu/pdf/HAN_042509.pdf Investigation and Interim Recommendations: Swine Influenza (H1N1)].</ref> <br />
<br />
Although, not surprisingly, this emergent flu is resistant to amantadine and rimantadine (see [[#Amantadine and Rimantadine|below]]), as of late April, 2009, it is susceptible to both Tamiflu and Relenza<ref name="anti-swine-drugs">CDC document on [http://cdc.gov/swineflu/antiviral_swine.htm Antiviral Drugs and Swine Influenza].</ref>.<br />
<br />
The majority of the approximately 500,000 fatalities worldwide during the annual seasonal influenza epidemics occur in old or very young people, or others with weak immune defenses<ref name="mortality_age">PMID:19230159</ref>. In contrast, the deaths from H1N1 "swine flu" in Mexico appear to be occurring in young, otherwise healthy people, although firm data are not yet available.<br />
<br />
On April 29, 2009, the World Health Organization (WHO) raised its pandemic alert to level five on a six point scale, indicating that a pandemic is imminent ([http://www.who.int www.who.int]). The CDC is maintaining frequent updates at [http://cdc.gov/swineflu cdc.gov/swineflu].<br />
<br />
===H5N1 "Bird Flu" Pandemic Threat===<br />
<br />
A new influenza pandemic is one of our greatest threats because it might well kill a large fraction of the human population<ref name="flu_pandemic">[http://en.wikipedia.org/wiki/Flu_pandemic Influenza Pandemic] at Wikipedia.</ref>. The subtype [http://en.wikipedia.org/wiki/H5n1 H5N1] is most feared because of the large reservoir in wild birds, and the recent emergence of strains called ''highly pathogenic avian influenza (HPAI)'' that have high virulence and mortality in birds. Hundreds of millions of domestic poultry have been culled at great economic cost in an effort to stem the spread of H5N1. Although transmission from birds to humans has apparently been very inefficient, over half of the people known to have been infected died from the disease. The emergence of a high-virulence form of H5N1 that is highly transmissable among humans seems nearly inevitable, and would cause a devastating pandemic.<br />
<br />
==Prophylaxis and Treatment of Influenza==<br />
<br />
'''Vaccines''' are effective at preventing influenza, but only if they target the relevant viral subtypes. New vaccines against the annual epidemics of influenza A and B are prepared each year, separately in the northern and southern hemispheres. These are designed to target the subtypes predicted to be prevalent in any given flu season, but sometimes those predictions are wrong, leading to that year's vaccine being ineffective. A vaccine for a pandemic strain of H5N1 could not be prepared until after the pandemic began, because only then would the relevant subtype be known<ref>[http://en.wikipedia.org/wiki/Influenza#Vaccination_and_infection_control Vaccination for Influenza] at Wikipedia</ref>.<br />
<br />
'''Drugs''' against influenza, stockpiled in advance of a panedmic, appear to be the best preparation, given the limitations of vaccines. Tens of billions of dollars have been spent on pandemic preparedness in the USA alone, and a large portion of these expenditures is for [http://en.wikipedia.org/wiki/Oseltamivir stockpiling of anti-influenza drugs]. Similar expenditures have been made in many developed countries. The World Health Organization is poised to distribute anti-influenza drugs at the first signs of an epidemic of H5N1.<br />
<br />
===Amantadine and Rimantadine===<br />
<br />
[http://en.wikipedia.org/wiki/Amantadine Amantadine] and [http://en.wikipedia.org/wiki/Rimantadine Rimantadine] are an anti-viral drugs that work by blocking the M2 proton-channel ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) that is required for viruses to infect cells. Ion-channel function appears to be required for uncoating during endocytosis. Amantadine was approved for anti-viral uses beginning in 1966 by the US FDA. Subsequent widespread use has selected amantadine-resistant influenza in humans and birds. By 2005-2006, the US CDC found 92% of H3N2 isolates were resistant, and 2 of 8 H1N1 isolates. In Asia, resistance is close to 100%. The most common mutation responsible for resistance is S31N in M2, which confers resistance to both amantadine and rimantadine<ref>[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5502a7.htm Report on amantadine resistance], CDC Morbidity and Mortality Weekly Reports, January 2006.</ref>. References for this paragraph will be found in the [http://en.wikipedia.org/wiki/Amantadine ''Amantadine'' article in Wikipedia].<br />
<br />
===Tamiflu&reg; (oseltamivir) and Relenza&reg; (zanamivir)===<br />
<br />
[http://en.wikipedia.org/wiki/Oseltamivir Tamiflu (oseltamivir)] is an inhibitor of influenza neuraminidase that binds to the enzyme active site. (''Tamiflu'' is [http://en.wikipedia.org/wiki/Hoffmann-La_Roche Roche]'s trade name; oseltamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Tamiflu is a [[Transition state analog|transition state analog]], and was the first orally active neuraminidase inhibitor commercially developed. Because neuraminidase is required for the viral life cycle, its enzymatic active site is highly conserved, and Tamflu is effective on a range of neuraminidase subtypes. It is indicated both for prophylaxis and for treatment within two days of the onset of symptoms.<br />
<br />
[http://en.wikipedia.org/wiki/Zanamivir Relenza (zanamivir)] is also an inhibitor of influenze neuraminidase that binds to the enzyme active site. (''Relenza'' is [http://en.wikipedia.org/wiki/GlaxoSmithKline GlaxoSmithKline]'s trade name; zanamivir is the [http://en.wikipedia.org/wiki/International_Nonproprietary_Name generic] name.) Unlike Tamiflu, which is given orally, Relenza is usually administered by '''inhalation, or can be injected'''.<br />
<br />
'''Structure-based drug design''' was employed in the development of both Tamiflu and Relenza<ref name='Russell2006'>PMID: 16915235</ref> . A structure of N2 at 2.9 &Aring; [[resolution]] was published in 1983<ref>PMID:6843658</ref>, and a 2.2 &Aring; structure, [[1nn2]], was deposited by the same authors in the [[PDB]] in 1991. The structure of N9 was determined by the same group, e.g. [[7nn9]].<br />
<br />
====Resistance to Tamiflu and Relenza====<br />
<applet size='300' frame='true' align='right' scene='User:Eric_Martz/Sandbox_6/3ckz_relenza_tyr274/2' caption='Relenza binding to N1 mutant H274Y (3ckz).' /><br />
Because Tamiflu and Relenza closely resemble the natural sialic acid substrate of neuraminidase, it was hoped that mutations conferring resistance to these drugs would greatly lower the virulence of influenza carrying such mutations. This hope has proven false in the case of Tamiflu<ref name="collins2008">PMID:18480754</ref>. Furthermore, by early 2009, 98% of influenza A/H1N1 strains circulating in North America had become resistant to Tamiflu<ref>PMID: 19299601</ref><br />
<br />
Two common mutations that confer resistance to Tamiflu did not confer resistance to Relenza<ref name="collins2008" />. At right is Relenza binding to the H274Y mutant of N1. This suggests that it would be prudent to stockpile Relenza in addition to Tamiflu, and that combination therapy might be the most effective weapon against a new pandemic, prior to development and deployment of a vaccine.<br />
{{Clear}}<br />
<br />
====Tamiflu Binds to N1 by Induced Fit====<br />
<br />
<applet load='2hty2hu4_j.pdb' size='500' frame='true' align='right' caption='Morph of N1 alone (2hty) to N1 complexed with Tamiflu (2hu4). The position where Tamiflu will bind is shown translucent except when bound in the empirically-determined model.' scene='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/2' /><br />
Tamiflu was designed to fit N2/N9, so it is serendipitous that it works on N1. In fact, when the structure of N1 was determined<ref name='Russell2006' />, the <font color='#e07000'><b>loop comprising residues 147-152</b></font> was not in a suitable position to participate in binding Tamiflu. However, the complex of N1 with Tamiflu revealed that this loop is pulled into proper contact with the drug in an [[Induced fit|induced fit]] manner<ref name='Russell2006' />. A [[Morphs|morph]] from N1 alone ([[2hty]]) to N1 complexed with Tamiflu ([[2hu4]])<ref>Chain A from [[2hty]] was morphed to chain A of [[2hu4]] by linear interpolation, inserting 6 intermediate interpolated frames, using the freely available [http://www.umass.edu/microbio/rasmol/pdbtools.htm#martz morph2 program].</ref> shows the change in position of this loop (<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/8'>replay initial morph</scene>).<br />
<br />
The binding of Tamiflu to N1 pulls the sidechains of two conserved residues, <scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/Morph_2hty_to_2hu4/7'>Asp151, Glu119</scene>, closer to the inhibitor.<br />
<br />
===Cavity in N1: An Opportunity for Drug Design===<br />
<br />
<!--<br />
<scene name='Avian_Influenza_Neuraminidase,_Tamiflu_and_Relenza/2hu4_for_cavity/2'>larger cavity</scene><br />
See User:Eric Martz/Sandbox 4<br />
--><br />
<br />
N1 has a larger surface-accessible cavity in the substrate binding region than is present in N2/N9. The larger end of this cavity is not occupied by Tamiflu. Thus, this cavity presents an opportunity to design a drug with greater specificity and potency for N1<ref name='Russell2006' />.<br />
<br />
<blockquote><br />
For technical reasons, the cavity cannot be shown yet in Jmol in Proteopedia. (We are working to resolve this problem.) However, it may be seen in View 2 of<br />
[http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/ch_view2/chapter.htm this Chapter]<br />
of the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo Jmol Tutorial-Authoring Template (JTAT) Demonstration Tutorial].<br />
</blockquote><br />
{{Clear}}<br />
<br />
==Links==<br />
<br />
*[http://www.cdc.gov/flu cdc.gov/flu], the official influenza resource of the US Center for Disease Control.<br />
<br />
*[http://www.PandemicToolKit.com/ Pandemic Planning Toolkit] (by Roche).<br />
<br />
*[http://relenza.com Relenza] offical website by GlaxoSmithKline.<br />
<br />
*[http://tamiflu.com Tamiflu] official website by Roche.<br />
<br />
*[http://www.foreignaffairs.org/20050701faessay84401/laurie-garrett/the-next-pandemic.html The Next Pandemic?] An authoritative overview of economic and political factors written in 2005 by Laurie Garrett.<br />
<br />
==Notes and Literature References==<br />
<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Ion_channels&diff=955937Ion channels2009-05-08T17:21:44Z<p>Ilan Samish: /* Available structures */</p>
<hr />
<div>'''Ion channels''' are membrane proteins that catalyze the passive transport of ions through the cell membrane. Most ion channels are specific to an ion, like the [[natrium channels]], or the [[chloride channels]]. Some, like the [[TRP channels]], let through a bunch of cations. Another property of ion channels is that they can be either driven by voltage or concentration gradients, or they can be gated (by voltage, ligands, touch and other sensory signal). Finally, ion channels are the fastest of all membrane transporters, with 10^6 to 10^8 transported units per second versus 10^2 to 10^4 molecules per second for porters/carriers, or 10^0 to 10^3 for ATP-driven pumps.<br />
<br />
== Classification ==<br />
TCDB, the most sophisticated classification of transport proteins to date, classify ion channels as a heterogenous subset of all '''&alpha;-type channels''', whose singular property is to consist mainly of [[alpha helix|&alpha;-helices]] that span the membrane. They are distinct in this from the [[beta-barrel porins]], the [[pore-forming toxins]], but also from non-ribosomally synthesized channels like [[gramicidin]], [[polyglutamine]] or [[digitoxin]]. All these proteins are '''passive''' transport proteins.<br />
<br />
== Available structures ==<br />
Membrane transport proteins are notoriously difficult to crystallize while in a working state. So, it's no surprise that there are preciously few structure data for ion channels. At the moment, the following &alpha;-type ion channels have been at least partly resolved:<br />
* the [[voltage-dependent potassium channel]] K<sub>v</sub>1 from ''Rattus norvegicus'' ([[1qrq]], [[1exb]], [[1t1d]], [[2a79]], [[2r9r]], [[3eau]], [[3eb3]], [[3eb4]])<br />
* the [[voltage-dependent calcium channel]] from ''Rattus norvegicus'' (L-type: [[1t0h]], [[1t0j]], [[1vyt]], [[1vyu]], [[1vyv]], [[2vay]], [[3bxk]], R-type: [[3bxl]])<br />
* the [[voltage-gated potassium channel]] KcsA from ''Streptomyces lividans'' and ''Mus musculus'' with the structures [[1bl8]], [[1k4c]], [[1k4d]], [[2bob]], [[2boc]], [[2hg5]],[[2h8p]], [[2hfe]], [[2itc]], [[2itd]], [[2k1e]], [[2nlj]]<br />
* the [[voltage-gated potassium channel]] K<sub>v</sub>AP from ''Aeropyrum pernix'' ([[1orq]], [[2a0l]]), and human K<sub>v</sub>7 ([[2ovc]], [[3bj4]])<br />
* the [[voltage-gated sodium channel]] Na<sub>v</sub>1.2 ([[1byy]], [[2kav]]) and Na<sub>v</sub>1.5 ([[2kbi]])<br />
* the [[calcium-gated potassium channel mthK]] from ''Methanobacterium thermoautotrophicum'' ([[1lnq]], [[2fy8]])<br />
* the hyperpolarization-activated and cyclic nucleotide-gated K+ channel [[HCN]] from ''Mus musculus'' ([[1q3e]], [[1q43]], [[1q5o]], [[2ptm]], [[2q0a]], [[3bpz]])<br />
* the [[inward rectifier potassium channels]] KirBac3.1 ([[1xl4]],[[1xl6]]) and Kir3.1 (Cyt. only: [[1n9p]], [[1u4e]], [[1u4f]], [[1p7b]], [[2e4f]])<br />
* the acid-sensitive (proton-gated) cation channel [[ASIC]] from ''Gallus gallus'' ([[2qts]])<br />
* the human [[intracellular chloride channel]] CLIC-2 ([[2per]], [[2r4v]], [[2r5g]])<br />
* the [[nicotinic acetylcholine-activated cation-selective channel]] from ''Torpedo marmorata'' ([[1oed]], [[2bg9]], [[2k58]], [[2k59]])<br />
* a [[potassium channel]] from ''Burkholderia pseudomallei'' ([[1p7b]])<br />
* the [[ammonium transporter]] from ''Archaeoglobus fulgidus'' ([[2b2f]]) and from ''Nitrosomonas europaea'' ([[3b9y]], [[3b9z]], [[3bhs]])<br />
* the small-conductance [[mechanosensitive channel]] from ''E.&nbsp;coli'' K12 ([[2oau]], [[2vv5]], see also [[2k2b]])<br />
* [[TRP channels]] ([[2rfa]], [[3e7k]])<br />
* human [[phospholamban]] ([[1zll]], [[2hyn]])<br />
* the P7 [[viroporin]] of Hepatitis C virus ([[2k8j]])<br />
* the [[M2 proton channel]] from Influenza A ([[3bkd]], [[1nyj]], [[2kad]], [[2rlf]], [[3c9j]]) <br />
* [[aquaporins]] from several species:<br />
** ''Methanobacterium thermoautotrophicum'' (aqpM, [[2evu]], [[2f2c]])<br />
** ''E.&nbsp;coli'' K12 (Aquaporin Z, [[1r2c]], [[2abm]])<br />
** the [[glycerol uptake facilitator]] from ''E.&nbsp;coli'' K12 (GlpF, [[1lda]], [[1ldf]], [[1ldi]], [[1fx8]])<br />
** ''Homo sapiens'' (AQP-1, [[1fqy]], [[1ih5]])<br />
** ''Bos taurus'' (Aquaporin-0, [[1ymg]], [[2b6p]])<br />
<br />
Additionally the following non-ribosomally synthesized channel proteins constitute ion channels, and have their structure resolved:<br />
* [[Gramicidin]] ([[1av2]], [[1c4d]], [[1mag]])<br />
* fungal [[Antiamoebin]] ([[1joh]], [[1gq0]])<br />
* fungal [[Trichotoxin]] ([[1m24]])<br />
* further [[Peptaibol]] antibiotics ([[1ob4]], [[1ob6]], [[1ob7]])<br />
<br />
We do not count ClC chloride carriers as ion channels, as they are secondary active [[carriers]].<br />
<br />
== Weblinks ==<br />
*[http://www.tcdb.org/ The TCDB database]<br />
*[http://www.tcdb.org/tcdb/subclass2.php?tc=1.A TCDB: 1.A α-Type channels]<br />
*[http://www.tcdb.org/pdb_structure.php TCDB: Transport proteins with PDB structures]</div>Ilan Samishhttps://proteopedia.org/index.php?title=Proteopedia:News&diff=762385Proteopedia:News2008-09-23T16:27:41Z<p>Ilan Samish: /* Press */</p>
<hr />
<div>==Add New Items at the Top of Each Section and Date Them, Please!==<br />
<br />
News on this page is ordered newest first, oldest last, under each subheading. Please include the <font color="red">month and year</font> at the end of each entry that you add below. Subheadings below ''Statistics'' are in alphabetical order.<br />
<br />
==Statistics==<br />
<br />
Today, Proteopedia has {{NUMBEROFUSERS}} registered users. For more information, please see [[Proteopedia:About]]. For the number of pages, page views, edits, etc. please see [[Special:Statistics]]. The number of times any page has been viewed is displayed at the bottom of the page.<br />
<br />
==Adoptions==<br />
Some bioinformatics databases and resources have ''adopted'' Proteopedia. This means that they have chosen to offer links to Proteopedia for the benefit of their users.<br />
<br />
* [http://www.cathdb.info CATH], a hierarchical classification of protein domain structures [Class (C), Architecture (A), Topology (T) and Homologous superfamily (H)], provides links on its PDB pages to Proteopedia. September, 2008.<br />
<br />
* [http://www.genecards.org GeneCards], a searchable, integrated database providing concise information on all known and predicted human genes, links relevant proteins to Proteopedia. September, 2008.<br />
<br />
* [http://bioinformatics.org/jmol-tutorials Jmol Tutorial-Authoring Template] (JTAT) automatically provides a link to Proteopedia for each [[PDB file]] illustrated in its tutorials. August, 2008. See, for example, the bottom right (''Explore further ...'' under ''How To ...'') in the [http://www.bioinformatics.org/jmol-tutorials/jtat/jtatdemo/index.htm JTAT Demo Tutorial].<br />
<br />
* [http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] by [[User:David S. Goodsell|David S. Goodsell]] provides links to Proteopedia in some recent articles. An example is linked at the end of the second page of the article on [http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb104_1.html Selenocysteine Synthase]. August, 2008. Here is the [[Teaching_Scenes%2C_Tutorials%2C_and_Educators%27_Pages|complete list]].<br />
<br />
* [http://oca.weizmann.ac.il OCA Database and Browser] for 3D macromolecular structure has a link from each [[Protein Data Bank|PDB entry]] to Proteopedia. August, 2008.<br />
<br />
* [http://www.ebi.ac.uk/pdbsum/ PDBsum] has a link to Proteopedia on every PDB entry page. August, 2008.<br />
<br />
* [http://pdbwiki.org PDBWiki] has a link to Proteopedia on every PDB entry page. August, 2008.<br />
<br />
* [http://www.pdb.org RCSB Protein Data Bank] (see Proteopedia's page on the [[Protein Data Bank]]), has a link from each [[Protein Data Bank|PDB entry]] to Proteopedia, but it can be a bit hard to find. To find it: At the ''Structure Summary'' tab/page for a given [[PDB code]], in the menu at left, click on ''External LInks''. On that page, you'll find a link to Proteopedia under ''Structure Summary''. If you think it would be useful to have a more prominent link to Proteopedia at RCSB-PDB, please email <email>info@rcsb.org</email>. In May, 2008, an international group of several structural bioinformaticians and crystallographers requested that a link to Proteopedia replace the present ''Jmol'' link under ''Display Options'' at the upper right of the main ''Structure Summary'' page for each entry, but that request was denied. [[User:Eric Martz|Eric Martz]] 03:19, 7 August 2008 (IDT)<br />
<br />
* [http://pfam.janelia.org/ Pfam], a large database of protein families, each represented by multiple sequence alignments and hidden Markov models, will offer links to Proteopedia beginning with Pfam release 23. August, 2008.<br />
<br />
* [http://kb.psi-structuralgenomics.org/ PSI Structural Genomics Knowledge Base] has a link to Proteopedia, on its Annotations tab, for every [[Protein Data Bank|PDB entry]]. August, 2008.<br />
<br />
==Blogs==<br />
<br />
<br />
* [http://webhosting.pl/Proteopedia..pierwsza.encyklopedia.z.trojwymiarowa.zawartoscia Proteopedia – pierwsza encyklopedia z trójwymiarową zawartością] August, 2008<br />
* [http://blog.dispatch.com/darkmatter/2008/08/ The Columbus Dispatch] August, 2008<br />
* [http://car54.wordpress.com/2008/08/22/proteopedia-3-d-encyclopedia-of-proteins-and-other-molecules/ car54.wordpress.com] August, 2008<br />
* [http://digg.com/tech_news/Proteopedia_Since_Life_Isn_t_2D_Why_Is_Your_Encyclopedia digg.com/tech_news digg/Tech News] August, 2008<br />
* [http://emmetcole.wordpress.com/2008/08/22/3d-protein-encyclopedia-aids-wikification-of-science-sort-of/#more-227 Wonder: Sci-Tech Department] August 2008<br />
* [http://esciencenews.com/articles/2008/08/22/life.isnt.2.d.so.why.should.our.encyclopedias.be e! Science News] August, 2008<br />
* [http://google-sina.com/2008/08/23/life-isnt-2-d-so-why-should-our-encyclopedias-be/ Medical Health Articles] August, 2008<br />
* [http://in.news.yahoo.com/43/20080823/982/tsc-scientific-texts-in-3d-with-interact.html YAHOO! News, India] August, 2008<br />
* [http://network.nature.com/blogs/user/rpg/2008/03/03/from-the-damn-but-thats-cool-department The Scientist -- Richard Grant's blog on Nature Network] March 2008<br />
* [http://news.webindia123.com/news/Articles/Health/20080823/1034770.html WEBINDIA123] August, 2008<br />
* [http://pda.physorg.com/lofi-news-information-structural-pages_138620877.html pda.physorg.com] August, 2008<br />
* [http://story.europesun.com/index.php/ct/9/cid/2411cd3571b4f088/id/398066/cs/1/ Europe Sun] August, 2008<br />
* [http://wwmm.ch.cam.ac.uk/blogs/murrayrust/?p=990 Peter Murray Rust's blog] March, 2008<br />
* [http://www.aecomunicacioncientifica.org/portal/index.php?option=com_content&view=article&id=19118&catid=39:alphagalileo&Itemid=75 AECC] August, 2008<br />
* [http://www.alphagalileo.org/index.cfm?_rss=1&fuseaction=readrelease&releaseid=531608 AlphaGalileo] August, 2008<br />
* [http://www.bio-medicine.org/biology-news-1/Life-isnt-2-D--so-why-should-our-encyclopedias-be-3F-4582-1/ Bio-Medicine] August, 2008<br />
* [http://www.feedzilla.com/news-archive/industry/2008-08-22-science.html FEEDZILLA] August, 2008<br />
* [http://www.eurekalert.org/pub_releases/2008-08/bc-li2082208.php EurekAlert!] August, 2008<br />
* [http://www.firstscience.com/home/news/breaking-news-all-topics/life-isn-t-2-d-so-why-should-our-encyclopedias-be-page-1-1_51454.html FirstScience News] August, 2008<br />
* [http://www.freshnews.in/scientific-texts-in-3d-with-interactive-formats-developed-57558 Latest News] August, 2008<br />
* [http://www.iconocast.com/00009/B3/News6.htm ICONOCAST] August, 2008<br />
* [http://www.iconocast.com/S00009/B3/News6.htm ICONOCAST Spanish] August, 2008<br />
* [http://www.physorg.com/news138620877.html PHYSORG.com] August, 2008<br />
* [http://www.sciencecodex.com/life_isnt_2d_so_why_should_our_encyclopedias_be Science Codex] August, 2008<br />
* [http://www.sciencedaily.com/releases/2008/08/080822120146.htm Science Daily] August, 2008<br />
* [http://www.scientificblogging.com/news_releases/proteopedia_since_life_isnt_2d_why_is_your_encyclopedia www.scientificblogging.com] August, 2008<br />
* [http://www.silobreaker.com/DocumentReader.aspx?Item=5_894191386 SILObreaker] August, 2008<br />
* [http://www.stumbleupon.com/url/www.scientificblogging.com/news_releases/proteopedia_since_life_isnt_2d_why_is_your_encyclopedia StumbleUpon] August, 2008<br />
* [http://www.thaindian.com/newsportal/uncategorized/scientific-texts-in-3d-with-interactive-formats-developed_10087726.html Thaindian News] August, 2008<br />
* [http://www.tiede.fi/keskustelut/viewtopic.php?f=3&t=32738&start=0&st=0&sk=t&sd=a&sid=3a2616e09f985ce2c5e2e7cd5657e10f TIEDE.fi] August, 2008<br />
* [http://www.toptensources.com/topteneditor.aspx?sitename=Science-News&Page=2 TopTenSources] August, 2008<br />
* [http://www.yourlabdata.com/index.php?option=com_content&task=view&id=25246&Itemid=75 Your Lab Data] August, 2008<br />
* [http://www.sciencedaily.com/releases/2008/08/080822120146.htm Science Daily] August, 2008<br />
* [http://chronicle.com/wiredcampus/article/3277/proteopedia-an-online-encyclopedia-of-interactive-3-d-macromolecules The Wired Campus] August, 2008<br />
* [http://www.polit.ru/science/2008/08/26/proteopedia.popup.html polit.ru] August, 2008<br />
* [http://infuture.ru/article/1024 infuture.ru] August, 2008<br />
<br />
==Press==<br />
* [http://www.nature.com/nrm/journal/v9/n10/full/nrm2512.html Nature Reviews Molecular Cell Biology] - October, 2008 Research highlights<br />
* [http://genomebiology.com/pressreleases/pressrelease22August08.asp GenomeBiology.com Press Release] August, 2008<br />
* [http://www.thesmarttechie.com/fullnews.php/45774 The Smart Techie] August, 2008<br />
* Scientific texts in 3D with interactive formats developed [http://www.siliconindia.com/shownews/45774 Silicon India] August, 2008<br />
* Scientific texts in 3D with interactive formats developed [http://www.newkerala.com/topstory-fullnews-14498.html newKerala.com] August, 2008<br />
* 3D interactive text formats developed, [http://www.ndtv.com/convergence/ndtv/story.aspx?Id=NEWEN20080062682&ch=633555332445438750 NDTV.com] August, 2008<br />
* [http://www.innovations-report.de/html/berichte/informationstechnologie/life_isn_039_t_2d_encyclopaedias_proteopedia_116571.html innovations report] August, 2008<br />
* [http://www.medicalnewstoday.com/articles/119088.php Medical News Today] August, 2008<br />
* Online wiki hosts interactive, 3D molecular structures, [http://www.itnews.com.au/News/83288,online-wiki-hosts-interactive-3d-molecular-structures.aspx iTnews] August, 2008<br />
* Scientific texts in 3D with interactive formats developed, [http://sify.com/news/fullstory.php?id=14745946 SiFy news] August, 2008<br />
<br />
==Talks in Meetings and Seminars==<br />
<br />
* In [http://www.sdsc.edu/pb/Talks/3Dsig.ppt I am not a PDBid I am a Biological Macromolecule], the keynote talk at [http://www.ebi.ac.uk/~rafi/3dsig08/Home.html 3DSig 2008, Structural Bioinformatics and Computational Biophysics] (an ISMB satellite meeting Toronto, 18-19 July 2008), [http://www.sdsc.edu/pb Philip E. Bourne] discussed removing the barrier between the literature and the PDB, featuring his [http://www.sdsc.edu/pb/Talks/3Dsig.ppt BioLit] project. In this context, he listed Proteopedia as Possibility 1, "a completely new beginning", and discussed its advantages (anyone can contribute leading to wiki quality) and disadvantages (reward for authoring? limitations of wiki format).<br />
<br />
==Training Workshops==<br />
<br />
*[http://workshops.molviz.org Short courses and one-day workshops] are taught by [[User:Eric Martz|Eric Martz]] on macromolecular structure visualization and structural bioinformatics. These now include a segment on Proteopedia, including use of Proteopedia's Scene-Authoring Tools. In 2008, these have been at the Weizmann Institute of Science in Israel, and at Osaka University and the Okinawa Institute of Science and Technology in Japan. For curricula and upcoming dates, please see [http://workshops.molviz.org Workshops.MolviZ.Org]. August, 2008.</div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752816Photosystem II2008-08-07T12:06:28Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J., "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature, Dec 15, 2005, 438(7070), 1040-4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2axt 2AXT] and [http://www.proteopedia.org/wiki/index.php/1s5l 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752815Photosystem II2008-08-07T12:03:08Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J., "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature, 2005, 438, 1040-1044. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2axt 2AXT] and [http://www.proteopedia.org/wiki/index.php/1s5l 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752814Photosystem II2008-08-07T11:56:18Z<p>Ilan Samish: /* References */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J. "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature 2005, 438: 1040-1044. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2axt 2AXT] and [http://www.proteopedia.org/wiki/index.php/1s5l 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/></div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752813Photosystem II2008-08-07T11:54:40Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J. "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature 2005, 438: 1040-1044. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2axt 2AXT] and [http://www.proteopedia.org/wiki/index.php/1s5l 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/> <br />
<br />
2. Garrett, R.H., Grisham, C.M. ''Biochemistry, 3rd Edition.'' Belmont, CA: Thomson Brooks/ Cole, 2005.</div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752812Photosystem II2008-08-07T11:53:18Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J. "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature 2005, 438: 1040-1044. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2AXT 2AXT] and [http://www.proteopedia.org/wiki/index.php/1S5L 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/> <br />
<br />
2. Garrett, R.H., Grisham, C.M. ''Biochemistry, 3rd Edition.'' Belmont, CA: Thomson Brooks/ Cole, 2005.</div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752811Photosystem II2008-08-07T11:50:52Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J. "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature 2005, 438: 1040-1044. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å (<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [http://www.proteopedia.org/wiki/index.php/2AXT 2AXT] and [http://www.proteopedia.org/wiki/index.php/1S5L 1S5L], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/> <br />
<br />
2. Garrett, R.H., Grisham, C.M. ''Biochemistry, 3rd Edition.'' Belmont, CA: Thomson Brooks/ Cole, 2005.</div>Ilan Samishhttps://proteopedia.org/index.php?title=Photosystem_II&diff=752750Photosystem II2008-08-06T21:16:33Z<p>Ilan Samish: /* Background */</p>
<hr />
<div><applet load="1s5l" size="400" frame="true" align="right" /><br />
[[Image:1s5l.gif|250px|left]]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.50 Å. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
<br />
==Photosynthesis==<br />
Photosystem II is an integral part of photosynthesis, the conversion of light energy into chemical energy by living organisms. Photosystem II is linked to a variety of other proteins, including Photosytem I. These proteins ultimately produce NADPH and ATP that power the Calvin cycle. Using this energy, glucose is synthesized from carbon dioxide and water.<br />
<br />
==Electron Transfer==<br />
<applet load="1s5l" size="400" frame="true" align="right" /><br />
<br />
[[Image:Chlorophyll_a.svg.png|thumb|170px|left|structure of chlorophyll ''a'']]<br />
<scene name='Photosystem_II/Chlorophyll_green/4'>Chlorophyll</scene> surround Photosystem II and capture energy from sunlight, exciting electrons. Chlorophyll are highly conjugated and absorb visible light, along with accessory light harvesting pigments such as <scene name='Photosystem_II/Betacarotene/3'>beta carotene</scene>. Beta carotene absorbs visible light of other wavelengths and also protects Photosystem II by destroying reactive oxygen species that result from this photoexcitation. [[Image:b-car.svg.png|b-car.svg.png|thumb|right|400px|structure of beta carotene]] Electrons are passed from chlorophyll to <scene name='Photosystem_II/Pheophytin_purple/5'>pheophytin</scene>. Pheophytin are very similar to chlorophyll except they contain 2 H<sup>+</sup> instead of a Mg<sup>2+</sup> ion. From the pheophytin, electrons transferred to <scene name='Photosystem_II/Quinone_pink/5'>plastoquinones</scene>, which are reduced. Between each pair of quinones, an iron, in red, helps to transfer the electron. These plastoquinones eventually move to a plastoquinone pool which travels to another large protein subunit, cytochrome b <sub>6</sub>/ f. Eventually these electrons reduce NADP<sup>+</sup> to NADPH. The <scene name='Photosystem_II/Electron_pathway/3'>electron pathway</scene> through Photosystem II is shown, with '''<FONT COLOR="#F87217">beta-carotenes</FONT>''', '''<FONT COLOR="#571B7e">pheophytins</FONT>''', '''<FONT COLOR="#E42217">iron</FONT>''' and '''<FONT COLOR="#F535AA">plasotoquinones</FONT>'''.<br />
[[Image:plastoquinone.jpg|thumb|300px|right|reduced plastoquinone]]<br />
<br />
==Oxygen Evolution==<br />
Another important facet of Photosystem II is its ability to oxidize water to oxygen with its <scene name='Photosystem_II/Oxygen_evolving_centers/11'>oxygen evolving centers</scene>. These centers are <scene name='Photosystem_II/Oxygen_evolving_centers/3'>cubane-like</scene> structures with 3 '''<FONT COLOR="#8D38C9">manganese</FONT>''', 4 '''<FONT COLOR="#C11B17">oxygen</FONT>''' and a '''<FONT COLOR="#59E817">calcium</FONT>''' linked to a fourth manganese.<ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref> Oxidation of water leaves 2 H <sup>+</sup> on the lumenal side of the membrane, helping to establish the proton gradient essential for ATP synthesis in the CF<sub>1</sub>CF<sub>0</sub>-ATP sythase protein.<br />
<br />
==References==<br />
<references/> <br />
<br />
2. Garrett, R.H., Grisham, C.M. ''Biochemistry, 3rd Edition.'' Belmont, CA: Thomson Brooks/ Cole, 2005.</div>Ilan Samish