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{{Sandbox_Reserved_CH462_Biochemistry_II}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | {{Sandbox_Reserved_CH462_Biochemistry_II}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
= | = Cytochrome ''bd''-1 oxidase in ''Escherichia coli'' = | ||
<StructureSection load=' | ==Introduction== | ||
<StructureSection load='6rx4' size='350' frame='true' side='right' caption='E. coli cytochrome bd-1 oxidase. Blue= CydA; green= CydB; yellow= CydX; pink= CydS; gray = hemes and UQ-8.' scene='83/832931/Full/3'>test</scene’> | |||
== Function == | == Function == | ||
The cytochrome ''bd'' oxidase allows bacteria to be resistant to hypoxia, cyanide, nitric oxide, and H<sub>2</sub>O<sub>2</sub><ref name="Harikishore">PMID: 31939065</ref> | |||
== Disease == | == Disease == | ||
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== Structural highlights == | == Structural highlights == | ||
=== H and O channels === | |||
[[Image:O-h channel.png|300 px|right|thumb|'''Figure 3'''. H and o-channels of cytochrome bd-oxidase in ''E. coli''. Channels are outlined in gray, water is shown as spheres, and various amino acids are labeled above.]] | |||
The hydrogen and oxygen channels (Fig. 3) are essential for H<sup>+</sup> and O<sub>2</sub> molecules to reach the active site of cytochrome ''bd'' oxidase. A proton motive force generated by the oxidase<ref name= "Safarian">PMID:31604309</ref> allows protons from the cytoplasm flow through a water-filled hydrophilic H-channel entering at Asp119<sup>A</sup> and moving past Lys57<sup>A</sup>, Lys109<sup>B</sup>, Asp105<sup>B</sup>, Tyr379<sup>B</sup>, and Asp58<sup>B</sup><ref name="Theßeling">PMID:31723136</ref> where they can be transferred to the active site with the help of the conserved residues Ser108<sup>A</sup>, Glu107<sup>A</sup>, and Ser140<sup>A</sup><ref name= "Safarian">PMID:31604309</ref>. A smaller o-channel also exists that transitions from hydrophobic to hydrophilic as it gets closer to the active site. This channel allows oxygen to reach the active site, starting near Trp63 in CydB and passing by Leu101<sup>B</sup>, Ile114<sup>A</sup>, and Glu99<sup>A</sup><ref name= "Safarian">PMID:31604309</ref>, which assists with the binding of oxygen to the active site. The o-channel channel is approximately 1.5 Å in diameter<ref name="Theßeling">PMID:31723136</ref>, which may help with selectivity. | |||
Interestingly, the o-channel does not exist in the cytochrome''bd'' oxidase of [https://en.wikipedia.org/wiki/Geobacillus_thermoglucosidasius ''Geobacillus Thermodenitrificans'']; instead, oxygen binds directly to the active site<ref name="Safarian">PMID:27126043</ref>. The CydS subunit found in E. coli blocks this alternate oxygen entry site, which allows oxygen to travel through the o-channel<ref name="Safarian">PMID:31604309</ref><ref name="Theßeling">PMID:31723136</ref>. The presence of an o-channel affects oxidase activity, as the ''E. coli'' oxidase acts as a "true" oxidase, while the ''G. th'' bd oxidase contributes more to detoxification<ref name="Theßeling">PMID:31723136</ref>. | |||
=== Hemes === | |||
There are three <scene name='83/832931/Heme/4'>heme</scene> molecules present in the CydA subunit that form a triangle to maximize subunit stability<ref name="Safarian">PMID:27126043</ref></ref><ref name="Theßeling">PMID:31723136</ref><ref name="Safarian">PMID:31604309</ref>, which is an evolutionary conserved feature across bd oxidases<ref name="Safarian">PMID:31604309</ref>. Similar to the hemes, the <scene name='83/832931/Uq8/1'>Ubiquinone-8</scene> (UQ-8) molecule found in CydB mimics the triangular formation to stabilize the subunit<ref name= "Safarian">PMID:31604309</ref>. Heme b<sub>558</sub> acts as the primary electron acceptor by catalyzing the oxidation of quinol<ref name="Theßeling">PMID:31723136</ref>. Conserved <scene name='83/832931/Hemeb558/2'>His196 and Met393</scene> help to stabilize heme b558<ref name="Theßeling">PMID:31723136</ref>. Heme b<sub>558</sub> transfers the electrons to heme b595, which transfers them to the active site heme d<ref name= "Safarian">PMID:31604309</ref>. A conserved <scene name='83/832931/Trp441/3'>Trp441</scene> assists heme b<sub>595</sub> in transferring electrons to heme d<ref name="Safarian">PMID:27126043</ref>. A conserved <scene name='83/832931/Glu445/3'>Glu445</scene> is essential for charge stabilization of heme b<sub>595</sub><ref name="Theßeling">PMID:31723136</ref>, while <scene name='83/832931/Hemed/2'>His19</scene> stabilizes heme d<ref name="Safarian">PMID:27126043</ref>. As heme d collects the electrons from heme b<sub>595</sub>, <scene name='83/832931/Glu99/5'>Glu99</scene> in the o-channel facilities the binding of oxygen to heme d, and <scene name='83/832931/Ser140_ser108_glu107/1'>Ser108, Glu107, and Ser140</scene> in the h-channel facilitate proton transfer to heme d<ref name="Safarian">PMID:31604309</ref>. With electrons, oxygen, and protons available, heme d can successfully reduce dioxygen to water. | |||
== Relevance == | |||
The cytochrome ''bd'' oxidase is essential for bacteria to thrive in the human body. Terminal oxidases in bacteria are needed for formate oxidation activity, which provides a sustainability advantage for bacterial growth. If E. coli are missing or possess ineffective CydA and B subunits, their advantage is eliminated<ref name="Hughes">PMID: 28182951</ref>. Specifically with [https://en.wikipedia.org/wiki/Colitis colitis], E. coli mutants that were missing CydAB colonized quite poorly, while the wild type colonized at high levels<ref name="Hughes">PMID: 28182951</ref>. The cytochrome ''bd'' oxidase is the main component in nitric oxide (NO) tolerance in bacteria, which is released by neutrophils and macrophages when the host is infected<ref name="Shepherd">PMID: 27767067</ref>. E. coli growth seen in urinary tract infections is mainly due to the NO resistant bd oxidase, but without the CydA A and B subunits, bacteria cannot colonize in high NO conditions<ref name="Shepherd">PMID: 27767067</ref>. Cytochrome ''bd'' oxidases are essential in other bacteria, specifically in [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis ''M. tuberculosis'']. Other known oxidases can be inhibited to prevent the spreading of ''M. tb'', however the cytochrome bd oxidase not only allows ''M. tb'' to survive, but to colonize. Without the CydAB subunits, ''M. tb'' growth dramatically decreases when exposed to imidazo[1,2-α]pyridine, a known inhibitor of ATP synthase<ref name="Arora">PMID:25155596</ref>. | |||
Due to that fact that it is only found in prokaryotes and noting its relevance in notable bacterial infections, inhibitors that target cytochrome ''bd'' oxidase are quite practical. Compounds that target heme b<sub>558</sub><ref name="Harikishore">PMID: 31939065</ref>, create unusable forms of oxygen<ref name="Galván">PMID: 30790617</ref>, and target the o-channel <ref name="Lu">PMID: 26015371 </ref> have shown tremendous potential in halting bacterial growth. | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
== Student Contributors == | |||
*Grace Bassler | |||
*Emily Neal | |||
*Marisa Villarreal | |||
