Sandbox Reserved 1625: Difference between revisions
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<StructureSection load='6rx4' size='350' frame='true' side='right' caption='Cartoon representation of E. coli cytochrome bd-1 oxidase designed from [https://www.rcsb.org/structure/6RX4 PDB: 6RX4]. Blue= CydA; green= CydB; yellow= CydX; pink= CydS; gray = hemes and UQ-8.' scene='83/832931/Full/3'> | <StructureSection load='6rx4' size='350' frame='true' side='right' caption='Cartoon representation of E. coli cytochrome bd-1 oxidase designed from [https://www.rcsb.org/structure/6RX4 PDB: 6RX4]. Blue= CydA; green= CydB; yellow= CydX; pink= CydS; gray = hemes and UQ-8.' scene='83/832931/Full/3'> | ||
==Introduction== | ==Introduction== | ||
<scene name='83/832931/Full/4'>Cytochrome bd oxidase</scene> is a type of quinol-dependent transmembrane (Fig. 1) terminal [https://en.wikipedia.org/wiki/Oxidase oxidase] found exclusively in prokaryotes.<ref name="Safarian">PMID: 27126043</ref> With a very high oxygen affinity, bd oxidases play a vital role in the [https://en.wikipedia.org/wiki/Oxidative_phosphorylation oxidative phosphorylation] pathway in both gram-positive and gram-negative bacteria. Cytochrome ''bd'' oxidase's responsibility in the oxidative phosphorylation pathway also allows it to act as a key survival factor in the bacterial stress response against antibacterial drugs <ref name="Safarian">PMID: 31604309</ref>, hypoxia, cyanide, nitric oxide, and H<sub>2</sub>O<sub>2</sub><ref name="Harikishore">PMID: 31939065</ref>. Given this knowledge, ''bd'' oxidases have become an area of scientific research worth pursuing as they could serve as an ideal target for antimicrobial drug development. <ref name="Boot">PMID: 28878275</ref> | <scene name='83/832931/Full/4'>Cytochrome bd oxidase</scene> is a type of quinol-dependent transmembrane (Fig. 1) terminal [https://en.wikipedia.org/wiki/Oxidase oxidase] found exclusively in prokaryotes.<ref name="Safarian">PMID: 27126043</ref> With a very high oxygen affinity, bd oxidases play a vital role in the [https://en.wikipedia.org/wiki/Oxidative_phosphorylation oxidative phosphorylation] pathway in both gram-positive and gram-negative bacteria. Cytochrome ''bd'' oxidase's responsibility in the oxidative phosphorylation pathway also allows it to act as a key survival factor in the bacterial stress response against antibacterial drugs <ref name="Safarian">PMID: 31604309</ref>, hypoxia, cyanide, [https://en.wikipedia.org/wiki/Nitric_oxide nitric oxide], and H<sub>2</sub>O<sub>2</sub><ref name="Harikishore">PMID: 31939065</ref>. Given this knowledge, ''bd'' oxidases have become an area of scientific research worth pursuing as they could serve as an ideal target for antimicrobial drug development. <ref name="Boot">PMID: 28878275</ref> | ||
[[Image:Pp_and_cp_of_oxdiase.png|550 px|center|thumb|''Figure 1''. Cartoon model of cytochrome bd-oxidase in ''E. coli''. Dashed lines represent borders of cytoplasmic and periplasmic regions. A bound quinol between transmembrane helices 6 and 7 undergoes oxidation and releases protons into the periplasmic space, generating a proton gradient. Protons and oxygen atoms from the cytoplasmic side enter cytochrome ''bd'' oxidase through specific channels. Oxygen is reduced to water, which is released into the cytoplasmic space. Blue = CydA; green = CydB; yellow = CydX; pink = CydS. [[https://www.rcsb.org/structure/6RX4 PDB: 6RX4]]]] | [[Image:Pp_and_cp_of_oxdiase.png|550 px|center|thumb|''Figure 1''. Cartoon model of cytochrome bd-oxidase in ''E. coli''. Dashed lines represent borders of cytoplasmic and periplasmic regions. A bound quinol between transmembrane helices 6 and 7 undergoes oxidation and releases protons into the periplasmic space, generating a proton gradient. Protons and oxygen atoms from the cytoplasmic side enter cytochrome ''bd'' oxidase through specific channels. Oxygen is reduced to water, which is released into the cytoplasmic space. Blue = CydA; green = CydB; yellow = CydX; pink = CydS. [[https://www.rcsb.org/structure/6RX4 PDB: 6RX4]]]] | ||
The overall mechanism of ''bd'' oxidases involves an exergonic [https://en.wikipedia.org/wiki/Dioxygen_in_biological_reactions reduction of molecular oxygen] into water (Fig. 2). During this reaction, a proton gradient is generated in order to assist in the conservation of energy. <ref name="Belevich">PMID: 17690093</ref> Unlike other terminal oxidases, bd oxidases do not use a proton pump. Instead, bd oxidases use a form of vectorial chemistry that releases protons from the quinol oxidation into the positive, periplasmic side of the membrane. Protons that are required for the water formation are then consumed from the negative, cytoplasmic side of the membrane, thus creating the previously mentioned proton gradient. | The overall mechanism of ''bd'' oxidases involves an exergonic [https://en.wikipedia.org/wiki/Dioxygen_in_biological_reactions reduction of molecular oxygen] into water (Fig. 2). During this reaction, a proton gradient is generated in order to assist in the conservation of energy. <ref name="Belevich">PMID: 17690093</ref> Unlike other terminal oxidases, bd oxidases do not use a proton pump. Instead, bd oxidases use a form of vectorial chemistry that releases protons from the quinol oxidation into the positive, periplasmic side of the membrane. Protons that are required for the water formation are then consumed from the negative, cytoplasmic side of the membrane, thus creating the previously mentioned proton gradient. | ||
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Quinol is used as the initial [https://en.wikipedia.org/wiki/Electron_donor electron donor] and heme b<sub>558</sub> is the initial electron acceptor. <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/1'>H-channel</scene> collects protons and <scene name='83/832931/O_channel_overall/2'>O-channel</scene> collects oxygen atoms that flow to 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''. Summarized 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 is used as the initial [https://en.wikipedia.org/wiki/Electron_donor electron donor] and heme b<sub>558</sub> is the initial electron acceptor. <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/1'>H-channel</scene> collects protons and <scene name='83/832931/O_channel_overall/2'>O-channel</scene> collects oxygen atoms that flow to 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''. Summarized 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 == | == Relevance == | ||
The cytochrome ''bd'' oxidase is essential for [https://en.wikipedia.org/wiki/Pathogenic_bacteria pathogenic bacteria] to thrive in the human body by enhancing bacterial growth and [https://en.wikipedia.org/wiki/ | The cytochrome ''bd'' oxidase is essential for [https://en.wikipedia.org/wiki/Pathogenic_bacteria pathogenic bacteria] to thrive in the human body by enhancing 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'' were missing or possessed ineffective CydA and B subunits, bacterial growth ceased.<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 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. 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 imidazo[1,2-α]pyridine, a known inhibitor of respiratory enzymes<ref name="Arora">PMID:25155596</ref>. Upregulation of the cytochrome ''bd'' oxidase Cyd genes resulted in a mutant strain of ''M. tb'' that was resistant to imidazo[1,2-α]pyridine<ref name="Arora">PMID:25155596</ref>. | ||
Since cytochrome ''bd'' oxidases are only found in prokaryotes and are required for pathogenic bacterial infections, inhibitors that target cytochrome ''bd'' oxidase are promising antibacterial agents. 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 potential in halting bacterial growth. | Since cytochrome ''bd'' oxidases are only found in prokaryotes and are required for pathogenic bacterial infections, inhibitors that target cytochrome ''bd'' oxidase are promising antibacterial agents. 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 potential in halting bacterial growth. | ||