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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="Rajendran">PMID:27126043</ref>.  The <scene name='83/832931/Cyds/1'>CydS</scene> 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>.
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="Rajendran">PMID:27126043</ref>.  The <scene name='83/832931/Cyds/1'>CydS</scene> 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 ===
=== 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:31604309</ref><ref name="Theßeling">PMID:31723136</ref><ref name="Rajendran">PMID:27126043</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/Hemeb558/4'>His186 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/Trp441/4'>Trp441</scene> assists heme b<sub>595</sub> in transferring electrons to heme d<ref name="Rajendran">PMID:27126043</ref>.  A conserved <scene name='83/832931/Hemeb558/5'>Glu445</scene> is essential for charge stabilization of heme b<sub>595</sub><ref name="Theßeling">PMID:31723136</ref>, while <scene name='83/832931/Hemeh19/1'>His19</scene> stabilizes heme d<ref name="Rajendran">PMID:27126043</ref>. As heme d collects the electrons from heme b<sub>595</sub>, <scene name='83/832931/Heme_d/1'>Glu99</scene> in the o-channel facilities the binding of oxygen to heme d, and <scene name='83/832931/Heme_d/1'>Ser109, 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.
There are three <scene name='83/832931/Heme/6'>heme</scene> molecules present in the CydA subunit that form a triangle to maximize subunit stability<ref name="Safarian">PMID:31604309</ref><ref name="Theßeling">PMID:31723136</ref><ref name="Rajendran">PMID:27126043</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/Uq8/3'>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/Hemeb558/4'>His186 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/Trp441/4'>Trp441</scene> assists heme b<sub>595</sub> in transferring electrons to heme d<ref name="Rajendran">PMID:27126043</ref>.  A conserved <scene name='83/832931/Hemeb558/5'>Glu445</scene> is essential for charge stabilization of heme b<sub>595</sub><ref name="Theßeling">PMID:31723136</ref>, while <scene name='83/832931/Hemeh19/1'>His19</scene> stabilizes heme d<ref name="Rajendran">PMID:27126043</ref>. As heme d collects the electrons from heme b<sub>595</sub>, <scene name='83/832931/Heme_d/1'>Glu99</scene> in the o-channel facilities the binding of oxygen to heme d, and <scene name='83/832931/Heme_d/1'>Ser109, 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 ==
== 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>.   
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>.   

Revision as of 02:24, 6 April 2020

This Sandbox is Reserved from Jan 13 through September 1, 2020 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1598 through Sandbox Reserved 1627.
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Cytochrome bd-1 oxidase in Escherichia coliCytochrome bd-1 oxidase in Escherichia coli

IntroductionIntroduction

test</scene’>


Function

The allows bacteria to be resistant to hypoxia, cyanide, nitric oxide, and H2O2[1]

Disease

Relevance

Molecular Function

H and O channels

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+ and O2 molecules to reach the active site of cytochrome bd oxidase. A proton motive force generated by the oxidase[2] allows protons from the cytoplasm to flow through a hydrophilic full of water (pink dots), entering at and moving past [3] where they can be transferred to the active site with the help of the conserved residues [2]. A smaller 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 in CydB and passing by [2], which assists with the binding of oxygen to the active site. The o-channel channel is approximately 1.5 Å in diameter[3], which may help with selectivity.

Interestingly, the o-channel does not exist in the cytochromebd oxidase of Geobacillus Thermodenitrificans; instead, oxygen binds directly to the active site[4]. The subunit found in E. coli blocks this alternate oxygen entry site, which allows oxygen to travel through the o-channel[2][3]. 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[3].

Hemes

There are three molecules present in the CydA subunit that form a triangle to maximize subunit stability[2][3][4], which is an evolutionary conserved feature across bd oxidases[2]. Similar to the hemes, the (UQ-8) molecule found in CydB mimics the triangular formation to stabilize the subunit[2]. Heme b558 acts as the primary electron acceptor by catalyzing the oxidation of quinol[3]. Conserved help to stabilize heme b558[3]. Heme b558 transfers the electrons to heme b595, which transfers them to the active site heme d[2]. A conserved assists heme b595 in transferring electrons to heme d[4]. A conserved is essential for charge stabilization of heme b595[3], while stabilizes heme d[4]. As heme d collects the electrons from heme b595, in the o-channel facilities the binding of oxygen to heme d, and in the h-channel facilitate proton transfer to heme d[2]. 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[5]. Specifically with colitis, E. coli mutants that were missing CydAB colonized quite poorly, while the wild type colonized at high levels[5]. 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[6]. 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[6]. Cytochrome bd oxidases are essential in other bacteria, specifically in 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[7].

Due to that fact that it is only found in prokaryotes and considering its relevance in notable bacterial infections, inhibitors that target cytochrome bd oxidase are quite practical. Compounds that target heme b558[1], create unusable forms of oxygen[8], and target the o-channel [9] have shown tremendous potential in halting bacterial growth.

E. coli cytochrome bd-1 oxidase. Blue= CydA; green= CydB; yellow= CydX; pink= CydS; gray = hemes and UQ-8.

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ 1.0 1.1 Harikishore A, Chong SSM, Ragunathan P, Bates RW, Gruber G. Targeting the menaquinol binding loop of mycobacterial cytochrome bd oxidase. Mol Divers. 2020 Jan 14. pii: 10.1007/s11030-020-10034-0. doi:, 10.1007/s11030-020-10034-0. PMID:31939065 doi:http://dx.doi.org/10.1007/s11030-020-10034-0
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Safarian S, Hahn A, Mills DJ, Radloff M, Eisinger ML, Nikolaev A, Meier-Credo J, Melin F, Miyoshi H, Gennis RB, Sakamoto J, Langer JD, Hellwig P, Kuhlbrandt W, Michel H. Active site rearrangement and structural divergence in prokaryotic respiratory oxidases. Science. 2019 Oct 4;366(6461):100-104. doi: 10.1126/science.aay0967. PMID:31604309 doi:http://dx.doi.org/10.1126/science.aay0967
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Thesseling A, Rasmussen T, Burschel S, Wohlwend D, Kagi J, Muller R, Bottcher B, Friedrich T. Homologous bd oxidases share the same architecture but differ in mechanism. Nat Commun. 2019 Nov 13;10(1):5138. doi: 10.1038/s41467-019-13122-4. PMID:31723136 doi:http://dx.doi.org/10.1038/s41467-019-13122-4
  4. ↑ 4.0 4.1 4.2 4.3 Safarian S, Rajendran C, Muller H, Preu J, Langer JD, Ovchinnikov S, Hirose T, Kusumoto T, Sakamoto J, Michel H. Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science. 2016 Apr 29;352(6285):583-6. doi: 10.1126/science.aaf2477. PMID:27126043 doi:http://dx.doi.org/10.1126/science.aaf2477
  5. ↑ 5.0 5.1 Hughes ER, Winter MG, Duerkop BA, Spiga L, Furtado de Carvalho T, Zhu W, Gillis CC, Buttner L, Smoot MP, Behrendt CL, Cherry S, Santos RL, Hooper LV, Winter SE. Microbial Respiration and Formate Oxidation as Metabolic Signatures of Inflammation-Associated Dysbiosis. Cell Host Microbe. 2017 Feb 8;21(2):208-219. doi: 10.1016/j.chom.2017.01.005. PMID:28182951 doi:http://dx.doi.org/10.1016/j.chom.2017.01.005
  6. ↑ 6.0 6.1 Shepherd M, Achard ME, Idris A, Totsika M, Phan MD, Peters KM, Sarkar S, Ribeiro CA, Holyoake LV, Ladakis D, Ulett GC, Sweet MJ, Poole RK, McEwan AG, Schembri MA. The cytochrome bd-I respiratory oxidase augments survival of multidrug-resistant Escherichia coli during infection. Sci Rep. 2016 Oct 21;6:35285. doi: 10.1038/srep35285. PMID:27767067 doi:http://dx.doi.org/10.1038/srep35285
  7. ↑ Arora K, Ochoa-Montano B, Tsang PS, Blundell TL, Dawes SS, Mizrahi V, Bayliss T, Mackenzie CJ, Cleghorn LA, Ray PC, Wyatt PG, Uh E, Lee J, Barry CE 3rd, Boshoff HI. Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014 Nov;58(11):6962-5. doi: 10.1128/AAC.03486-14., Epub 2014 Aug 25. PMID:25155596 doi:http://dx.doi.org/10.1128/AAC.03486-14
  8. ↑ Galvan AE, Chalon MC, Rios Colombo NS, Schurig-Briccio LA, Sosa-Padilla B, Gennis RB, Bellomio A. Microcin J25 inhibits ubiquinol oxidase activity of purified cytochrome bd-I from Escherichia coli. Biochimie. 2019 May;160:141-147. doi: 10.1016/j.biochi.2019.02.007. Epub 2019 Feb, 19. PMID:30790617 doi:http://dx.doi.org/10.1016/j.biochi.2019.02.007
  9. ↑ Lu P, Heineke MH, Koul A, Andries K, Cook GM, Lill H, van Spanning R, Bald D. The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress. Sci Rep. 2015 May 27;5:10333. doi: 10.1038/srep10333. PMID:26015371 doi:http://dx.doi.org/10.1038/srep10333

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