Sandbox Reserved 1625: Difference between revisions

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OCA, Emily Neal, Grace A. Bassler, Marisa Villarreal

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 Three <scene name='83/832931/Heme/6'>hemes</scene> are present in the <scene name='83/832924/Cyda_subunit/6'>CydA subunit</scene>. These three hemes form a triangle to maximize subunit stability<ref name="Safarian">PMID:31604309</ref><ref name="Alexander">PMID:31723136</ref><ref name="Safarian2">PMID:27126043</ref>, which is an evolutionary conserved feature across bd oxidases<ref name="Safarian">PMID:31604309</ref>.  Heme b<sub>558</sub> acts as the primary [https://en.wikipedia.org/wiki/Electron_acceptor electron acceptor] by [https://en.wikipedia.org/wiki/Catalysis catalyzing] the [https://en.wikipedia.org/wiki/Hydroquinone#Redox oxidation of quinol]<ref name="Alexander">PMID:31723136</ref>. Conserved <scene name='83/832931/Met393/1'>His186 and Met393</scene> help to stabilize heme b558<ref name="Alexander">PMID:31723136</ref>. Heme b<sub>558</sub> [https://en.wikipedia.org/wiki/Electron_transfer transfers] the electrons to heme b595, which transfers them to the active site heme d<ref name= "Safarian">PMID:31604309</ref>.  Multiple residues help stabilzie this electron trasnfer including a conserved <scene name='83/832931/Trp441/6'>Trp441</scene> that assists heme b<sub>595</sub> in transferring electrons to heme d<ref name="Safarian2">PMID:27126043</ref>.  A conserved <scene name='83/832931/Hemeb595/2'>Glu445</scene> is also essential for charge stabilization of heme b<sub>595</sub><ref name="Alexander">PMID:31723136</ref>, while <scene name='83/832931/Hemeh19/3'>His19</scene> stabilizes heme d<ref name="Safarian2">PMID:27126043</ref>. As heme d collects the electrons from heme b<sub>595</sub>, <scene name='83/832931/Heme_d/3'>Glu99</scene> in the O-channel facilities the binding of oxygen to heme d, and <scene name='83/832931/Heme_d/3'>Ser108, Glu107, and Ser140</scene> in the H-channel facilitate proton transfer to heme d<ref name="Safarian">PMID:31604309</ref>. Similar to the three hemes, the <scene name='83/832931/Uq8/3'>ubiquinone-8</scene> (UQ-8) molecule found in the <scene name='83/832924/Cydb_subunit/2'>CydB subunit</scene> mimics the triangular formation to stabilize the subunit<ref name="Safarian">PMID:31604309</ref>.
 ===Mechanism===
-Quinol transfers two electrons to heme b<sub>558</sub> and releases two protons into the periplasmic space as the initial [https://en.wikipedia.org/wiki/Electron_donor electron donor].  <scene name='83/832931/Heme/6'>Heme b558</scene> transfers the electrons to <scene name='83/832931/Heme/6'>heme b595</scene>, which transfers the electrons to <scene name='83/832931/Heme/6'>heme d</scene>.  Concurrently, the <scene name='83/832931/Overall_h_channel/2'>H-channel</scene> collects protons from the cytoplasmic side using the proton gradient generating by quinol and the <scene name='83/832931/O_channel_overall/3'>O-channel</scene> collects oxygen atoms.  The protons and oxygen flow to the active site heme d (Fig. 3).  With electrons, oxygen, and protons available, heme d can successfully reduce dioxygen to water (Fig. 2, 4).  [[Image:mech4.png|500 px|center|thumb|''Figure 4''. General mechanism of cytochrome bd-oxidase in ''E. coli''. Electrons are passed from quinol to heme b<sub>558</sub> to heme b<sub>595</sub> to heme d. Protons and oxygen atoms flow into the H-channel and O-channel to heme d. Heme d catalzyes the reduction of oxygen to water.]]
+Quinol transfers two electrons to heme b<sub>558</sub> and releases two protons into the periplasmic space as the initial [https://en.wikipedia.org/wiki/Electron_donor electron donor].  <scene name='83/832931/Heme/6'>Heme b558</scene> transfers the electrons to <scene name='83/832931/Heme/6'>heme b595</scene>, which transfers the electrons to <scene name='83/832931/Heme/6'>heme d</scene>.  Concurrently, the <scene name='83/832931/Overall_h_channel/2'>H-channel</scene> collects protons <scene name='83/832931/O_channel_overall/3'>O-channel</scene> collects oxygen atoms the cytoplasmic side.  The protons and oxygen flow to the active site heme d (Fig. 3).  With electrons, oxygen, and protons available, heme d can successfully reduce dioxygen to water (Fig. 2, 4).  [[Image:mech4.png|500 px|center|thumb|''Figure 4''. General mechanism of cytochrome bd-oxidase in ''E. coli''. Electrons are passed from quinol to heme b<sub>558</sub> to heme b<sub>595</sub> to heme d. Protons and oxygen atoms flow into the H-channel and O-channel to heme d. Heme d catalzyes the reduction of oxygen to water.]]
 == Relevance ==
 The cytochrome ''bd'' oxidase is essential for [https://en.wikipedia.org/wiki/Pathogenic_bacteria pathogenic bacteria] to thrive in the human body because it enhances bacterial growth and [https://en.wikipedia.org/wiki/Bacterial_growth colonization].  Any alteration of the ''bd'' oxidase Cyd subunits will most likely produce a nonfunctional [https://en.wikipedia.org/wiki/Mutant mutant] cytochrome ''bd'' oxidase<ref name="Moosa">PMID: 28760899</ref>, which inhibits bacterial growth.  If ''E. coli'' are missing or possess ineffective CydA and B subunits, bacterial growth ceases.<ref name="Hughes">PMID: 28182951</ref>.  With [https://en.wikipedia.org/wiki/Colitis colitis], ''E. coli'' mutants that were missing CydAB colonized poorly in comparison to the [https://en.wikipedia.org/wiki/Wild_type wild type] levels of colonization<ref name="Hughes">PMID: 28182951</ref>.  The cytochrome ''bd'' oxidase is the main component in [https://en.wikipedia.org/wiki/Biological_functions_of_nitric_oxide#Effects_in_bacteria nitric oxide] (NO) tolerance in bacteria, which is released by [https://en.wikipedia.org/wiki/Neutrophil neutrophils] and [https://en.wikipedia.org/wiki/Macrophage macrophages] when the [https://en.wikipedia.org/wiki/Host_(biology) host] is infected<ref name="Shepherd">PMID: 27767067</ref>. ''E. coli'' growth seen in [https://en.wikipedia.org/wiki/Urinary_tract_infection urinary tract infections] is mainly due to the NO resistant ''bd'' oxidase. Without the CydA  and CydB subunits, bacteria could not colonize in high NO conditions<ref name="Shepherd">PMID: 27767067</ref>.  Cytochrome ''bd'' oxidases are essential for life in other pathogenic bacteria such as [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis ''M. tuberculosis''].  Deletion of the CydA and CydB subunits dramatically decreased the growth of ''M. tb'' compared to the wild type when exposed to [https://en.wikipedia.org/wiki/Imidazopyridine imidazo[1,2-]][https://en.wikipedia.org/wiki/Imidazopyridine pyridine], a known [https://en.wikipedia.org/wiki/Enzyme_inhibitor inhibitor] of respiratory enzymes<ref name="Arora">PMID:25155596</ref>.  [https://en.wikipedia.org/wiki/Downregulation_and_upregulation Upregulation] of the cytochrome ''bd'' oxidase Cyd genes resulted in a mutant strain of ''M. tb'' that was [https://en.wikipedia.org/wiki/Antimicrobial_resistance resistant] to imidazo[1,2-α]pyridine<ref name="Arora">PMID:25155596</ref>.