Hemoglobin: Difference between revisions

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<StructureSection load='1gzx' size='350' side='right' caption="Human Hemoglobin α chain (grey and pink) β chain (green and yellow) with bound O2 [[1gzx]]" scene="Hemoglobin/Foursubunits/5" >
<StructureSection load='1gzx' size='350' side='right' caption="Human Hemoglobin α chain (grey and pink) β chain (green and yellow) with bound O2 [[1gzx]]" scene="Hemoglobin/Foursubunits/5" >
== Function ==
== Function ==
'''Hemoglobin''' is an oxygen-transport protein.  Hemoglobin is an allosteric protein.  It is a <scene name='32/32/Subunits_1hho/1'>tetramer</scene> composed of two types of subunits designated α and β, with stoichiometry <scene name='Hemoglobin/Alpha2beta2/7'>α2β2</scene>. The  <scene name='Hemoglobin/Foursubunits/5'>four subunits</scene> of hemoglobin sit roughly at the corners of a tetrahedron, facing each other across a <scene name='Hemoglobin/Cavity/9'>cavity</scene> at the center of the molecule. Each of the subunits <scene name='Hemoglobin/Bbsubunitswithheme/5'>contains a heme</scene> prosthetic group. The <scene name='Hemoglobin/4heme/3'>heme molecules</scene> give hemoglobin its red color.
'''Hemoglobin''' is an oxygen-transport protein.  Hemoglobin is an allosteric protein.  It is a <jmol>
  <jmolLink>
    <script> script /scripts/32/32/Subunits_1hho/1.spt;
            center visible;</script>
    <text>tetramer</text>
  </jmolLink>
</jmol> composed of two types of subunits designated α and β, with stoichiometry <scene name='Hemoglobin/Alpha2beta2/7'>alpha2-beta2</scene>. The  <scene name='Hemoglobin/Foursubunits/5'>four subunits</scene> of hemoglobin sit roughly at the corners of a tetrahedron, facing each other across a <scene name='Hemoglobin/Cavity/9'>cavity</scene> at the center of the molecule. Each of the subunits <scene name='Hemoglobin/Bbsubunitswithheme/5'>contains a heme</scene> prosthetic group. The <scene name='Hemoglobin/4heme/3'>heme molecules</scene> give hemoglobin its red color.


Each individual <scene name='Hemoglobin/Deoxyheme/8'>heme</scene> molecule contains one <scene name='Hemoglobin/Deoxyheme_fe/9'>Fe<sup>2+</sup></scene> atom. In the lungs, where oxygen is abundant, an <scene name='Hemoglobin/Oxyheme_fe/7'>oxygen molecule</scene> binds to the ferrous iron atom of the heme molecule and is later released in tissues needing oxygen. The heme group binds oxygen while still attached to the <scene name='Hemoglobin/Oxysubunit/8'>hemoglobin monomer</scene>. The spacefill view of the hemoglobin polypeptide subunit with an oxygenated heme group shows how the <scene name='Hemoglobin/Oxysubunitsf/4'>oxygenated heme group is held</scene> within the polypeptide.  
Each individual <scene name='Hemoglobin/Deoxyheme/8'>heme</scene> molecule contains one <scene name='Hemoglobin/Deoxyheme_fe/9'>Fe2+</scene> atom. In the lungs, where oxygen is abundant, an <scene name='Hemoglobin/Oxyheme_fe/7'>oxygen molecule</scene> binds to the ferrous iron atom of the heme molecule and is later released in tissues needing oxygen. The heme group binds oxygen while still attached to the <scene name='Hemoglobin/Oxysubunit/8'>hemoglobin monomer</scene>. The spacefill view of the hemoglobin polypeptide subunit with an oxygenated heme group shows how the <scene name='Hemoglobin/Oxysubunitsf/4'>oxygenated heme group is held</scene> within the polypeptide.  


<scene name='Hemoglobin/Anchortrace/5'>Anchoring of the heme</scene> is facilitated by a histidine nitrogen that binds to the iron. A second histidine is near the bound oxygen. The "arms" (propanoate groups) of the heme are hydrophilic and face the surface of the protein while the hydrophobic portions of the heme are buried among the hydrophobic amino acids of the protein.
<scene name='Hemoglobin/Anchortrace/5'>Anchoring of the heme</scene> is facilitated by a histidine nitrogen that binds to the iron. A second histidine is near the bound oxygen. The "arms" (propanoate groups) of the heme are hydrophilic and face the surface of the protein while the hydrophobic portions of the heme are buried among the hydrophobic amino acids of the protein.


Perhaps the most well-known disease caused by a mutation in the hemoglobin protein is sickle-cell anemia.  It results from a mutation of the sixth residue in the β hemoglobin monomer from <scene name='32/32/Hemoglobins_1hho/9'>glutamic acid to a valine</scene>.  This hemoglobin variant is termed 'hemoglobin S' ([[2hbs]]).
Perhaps the most well-known disease caused by a mutation in the hemoglobin protein is sickle-cell anemia.  It results from a mutation of the sixth residue in the β hemoglobin monomer from <scene name='32/32/Hemoglobins_1hho/9'>glutamic acid to a valine</scene>.  This hemoglobin variant is termed 'hemoglobin S' ([[2hbs]]).
*'''mini hemoglobin''' found in neural tissue and contains 109 residues<ref>PMID:9642264</ref> .
*'''giant hemoglobin''' are sulfur-binding 400kDa hemoglobin found in mouthless and gutless marine animals which get their nutrition by symbiosis with sulfur-oxidizing bacteria<ref>PMID:16204001</ref> .
*'''truncated hemoglobin''' found in bacteria and plants.  They are 20-40 residues shorter than other Hb and have 2-on-2 alpha helical sandwich structure vs the 3-on-3 of other Hbs<ref>PMID:11696555</ref> .
*'''methemoglobin''' contains Fe+3 rather than Fe+2 can cause the lethal disease methemoglobinemia<ref>PMID:30726002</ref> .
*'''leghemoglobin''' found in roots of legumes<ref>PMID:29642729</ref> .
*'''flavohemoglobin''' is flavin-binding.  It binds NO and acts in its catabolism<ref>PMID:18379989</ref> .


==Hemoglobin subunit binding O<sub>2</sub>==
==Hemoglobin subunit binding O<sub>2</sub>==
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==Truncated hemoglobins==
==Truncated hemoglobins==
 
see [[Journal:JBIC:8]]
<!-- <StructureSection load='Jbic8.pdb' size='500' side='right' scene='Journal:JBIC:8/Cv/1' caption=''> -->
<scene name='Journal:JBIC:8/Trhb/1'>Truncated hemoglobins</scene>, also known as 2/2 hemoglobins, can be further classified into three different groups (I, II, and III). Genomic sequences of bacteria, cyanobacteria, and plants indicate that trHbs are rather common. Group I, Group II, and Group III trHbs have distinct phylogenetic trees and show different ligand-binding properties. The Group I trHb of the ciliated protozoan ''Tetrahymena pyriformis'' (''Tp'' trHb) was first discovered by Keilin and Ryley in 1953.
 
It is known that trHbs exist in ciliates of the Tetrahymena group, but trHb structure and function remain poorly understood. To investigate trHb function with respect to stability of bound oxygen and protein structure, we measured the oxygen binding kinetics of Tetrahymena pyriformis trHb, and determined the crystal structure of the protein.
 
The three-dimensional structure of an <scene name='Journal:JBIC:8/Trhb/2'>Fe(II)-O2 complex of Tp trHb</scene> was determined at 1.73 Å resolution ([[3aq9]]). <scene name='Journal:JBIC:8/Trhb/3'>Tyr25 (B10) and Gln46 (E7) were hydrogen-bonded to a heme-bound dioxygen molecule</scene>. Tyr25 donated a hydrogen bond to the terminal oxygen atom, whereas Gln46 hydrogen-bonded to the proximal oxygen atom. Furthermore, <scene name='Journal:JBIC:8/Trhb/4'>Tyr25 was hydrogen-bonded to the Gln46 and Gln50 (E11) residues</scene>.
 
The O<sub>2</sub> association and dissociation rate constants of ''T. pyriformis'' trHb were 5.5 μM<sup>-1</sup> s<sup>-1</sup>, and 0.18 s<sup>-1</sup>, respectively. The oxygen affinity was determined to be 33 nM. The autooxidation rate constant was 3.8 x 10<sup>-3</sup> h<sup>-1</sup>. These values are similar to those of <scene name='Journal:JBIC:8/Hbn/3'>HbN from Mycobacterium tuberculosis</scene>.
 
'''Mutations:'''
*Mutation at Tyr25: <scene name='43/435485/As/6'>Wildtype Y25 and mutant Y25F together</scene> and <scene name='43/435485/As/5'>animation of this scene</scene>. <jmol><jmolButton>
<script>if (_animating); anim pause;set echo bottom left; color echo white; font echo 20 sansserif;echo Animation Paused; else; anim resume; set echo off;endif;</script>
<text>Toggle Animation</text>
</jmolButton></jmol>
*Mutation at Gln46: <scene name='43/435485/Ad/4'>Wildtype Q46 and mutant Q46E together (animation)</scene> <jmol><jmolButton>
<script>if (_animating); anim pause;set echo bottom left; color echo white; font echo 20 sansserif;echo Animation Paused; else; anim resume; set echo off;endif;</script>
<text>Toggle Animation</text>
</jmolButton></jmol>
*Mutation at <scene name='Journal:JBIC:8/Trhb/11'>Gln50</scene> increased the O<sub>2</sub> dissociation and autooxidation rate constants, and partly disrupted the hydrogen-bonding network.
 
An <scene name='Journal:JBIC:8/Ag/4'>Fe(III)-H2O complex of Tp trHb was formed following reaction of the Fe(II)-O<sub>2</sub> complex of Tp trHb</scene>, in a crystal state, with nitric oxide. This suggests that ''Tp'' trHb functions in nitric oxide detoxification.


==3D Printed Physical Model of Hemoglobin at The MSOE Center for BioMolecular Modeling==
==3D Printed Physical Model of Hemoglobin at The MSOE Center for BioMolecular Modeling==
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[[Image:Cbm_hemoglobin1.jpg|450px]]
[[Image:Cbm_hemoglobin1.jpg|450px]]
[[Image:Cbm_hemoglobin2.jpg|550px]]
[[Image:Cbm_hemoglobin2.jpg|550px]]
 
[[Category:3D printer files]]
==Additional Resources==
==Additional Resources==
*[[Tutorial:How do we get the oxygen we breathe]]
*[[Tutorial:How do we get the oxygen we breathe]]
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*Squires, J.E. (2002) Artificial Blood, Science 295, 1002.
*Squires, J.E. (2002) Artificial Blood, Science 295, 1002.
*Vichinsky, E. (2002) New therapies in sickle cell disease. Lancet 24, 629.
*Vichinsky, E. (2002) New therapies in sickle cell disease. Lancet 24, 629.
<references/>


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