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===
-A reduced quinol with two electrons received from NADH, pyruvate, D-lactate, or acyl coenzyme A transfers these 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 and the <scene name='83/832931/O_channel_overall/3'>O-channel</scene> collects oxygen atoms from 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).  This exergonic reaction is coupled with the movement of protons against their gradient when quinol releases two protons into the periplasmic space and when the H-channel uptakes protons from the cytoplasmic side and transfers then to heme d.  [[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.]]
+A reduced quinol with two electrons received from NADH, pyruvate, D-lactate, or acyl coenzyme A transfers these 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 and the <scene name='83/832931/O_channel_overall/3'>O-channel</scene> collects oxygen atoms from 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).  This exergonic reaction is coupled with the movement of protons against their gradient when quinol releases two protons into the periplasmic space and when the H-channel uptakes protons from the cytoplasmic side and transfers them to heme d.  [[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>.