Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

Friedrich, Thorsten; Wohlwend, Daniel; Borisov, Vitaliy B.

doi:10.3390/ijms23063166

Cited by 29 publications

(29 citation statements)

References 124 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A supercomplex composed of cytochrome bc 1 and aa 3 -type cytochrome c oxidase was also identified in Rhodobacter sphaeroides [38]. Figure 1 shows examples of three different types of branched bacterial respiratory chains in which the complex III is absent (E. coli [34]), present as a separate enzyme (Pseudomonas aeruginosa [29]), or forms a tight supercomplex with the aa 3 -type cytochrome c oxidase (M. tuberculosis [39,40]). The membrane-bound terminal oxidases are divided into two superfamilies: hemecopper oxidases and bd-type cytochromes [41][42][43].…”

Section: Bacterial Aerobic Respiratory Chainsmentioning

confidence: 98%

See 1 more Smart Citation

Bioenergetics and Reactive Nitrogen Species in Bacteria

Borisov

Forte

2022

IJMS

Self Cite

View full text Add to dashboard Cite

The production of reactive nitrogen species (RNS) by the innate immune system is part of the host's defense against invading pathogenic bacteria. In this review, we summarize recent studies on the molecular basis of the effects of nitric oxide and peroxynitrite on microbial respiration and energy conservation. We discuss possible molecular mechanisms underlying RNS resistance in bacteria mediated by unique respiratory oxygen reductases, the mycobacterial bcc-aa3 supercomplex, and bd-type cytochromes. A complete picture of the impact of RNS on microbial bioenergetics is not yet available. However, this research area is developing very rapidly, and the knowledge gained should help us develop new methods of treating infectious diseases.

show abstract

Section: Bacterial Aerobic Respiratory Chainsmentioning

confidence: 98%

“…The active site of cytochrome bd contains a high-spin heme d but not a copper ion [39,[63][64][65][66][67][68][69]. There are data that one more high-spin heme, b 595 , could perform some of the functions of Cu B [70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86].…”

Section: Bacterial Aerobic Respiratory Chainsmentioning

confidence: 99%

Bioenergetics and Reactive Nitrogen Species in Bacteria

Borisov

Forte

2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Canonical cytochrome bd oxidases share a common core architecture of two subunits, denoted CydA and CydB, which may be accompanied by up to two additional single-transmembrane helix subunits ( Miller and Gennis, 1983 ; VanOrsdel et al, 2013 ; Hoeser et al, 2014 ; Safarian et al, 2016 ; Safarian et al, 2019 ; Theßeling et al, 2019 ; Grund et al, 2021 ; Safarian et al, 2021 ; Wang et al, 2021 ; Friedrich et al, 2022 ). As implied by designation, cytochromes bd contain two b -type hemes (low-spin b 558 , high-spin b 595 ) and one d -type heme involved in quinol oxidation, electron transfer and oxygen reduction.…”

Section: Introductionmentioning

confidence: 99%

The cryoEM structure of cytochrome bd from C. glutamicum provides novel insights into structural properties of actinobacterial terminal oxidases

et al. 2023

View full text Add to dashboard Cite

Cytochromes bd are essential for microaerobic respiration of many prokaryotes including a number of human pathogens. These enzymes catalyze the reduction of molecular oxygen to water using quinols as electron donors. Their importance for prokaryotic survival and the absence of eukaryotic homologs make these enzyme ideal targets for antimicrobial drugs. Here, we determined the cryoEM structure of the menaquinol-oxidizing cytochrome bd-type oxygen reductase of the facultative anaerobic Actinobacterium Corynebacterium glutamicum at a resolution of 2.7 Å. The obtained structure adopts the signature pseudosymmetrical heterodimeric architecture of canonical cytochrome bd oxidases formed by the core subunits CydA and CydB. No accessory subunits were identified for this cytochrome bd homolog. The two b-type hemes and the oxygen binding heme d are organized in a triangular geometry with a protein environment around these redox cofactors similar to that of the closely related cytochrome bd from M. tuberculosis. We identified oxygen and a proton conducting channels emerging from the membrane space and the cytoplasm, respectively. Compared to the prototypical enzyme homolog from the E. coli, the most apparent difference is found in the location and size of the proton channel entry site. In canonical cytochrome bd oxidases quinol oxidation occurs at the highly flexible periplasmic Q-loop located in the loop region between TMHs six and seven. An alternative quinol-binding site near heme b595 was previously identified for cytochrome bd from M. tuberculosis. We discuss the relevance of the two quinol oxidation sites in actinobacterial bd-type oxidases and highlight important differences that may explain functional and electrochemical differences between C. glutamicum and M. tuberculosis. This study expands our current understanding of the structural diversity of actinobacterial and proteobacterial cytochrome bd oxygen reductases and provides deeper insights into the unique structural and functional properties of various cytochrome bd variants from different phylae.

show abstract

“…Comparison to homologous terminal oxidases in Escherichia coli suggests that cytochrome bcc - aa 3 represents an energy-efficient terminal oxidase with low affinity for oxygen, whereas cytochrome bd is less energy-efficient but shows higher oxygen affinity and lower sensitivity to inhibitors such as nitric oxide and cyanide [ 9 , 10 , 11 , 12 ]. Targeting these terminal oxidases currently is regarded as a viable therapeutic strategy and has attracted strong attention in the TB drug discovery field [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

Chauhan

Meulen

Caetano

et al. 2022

IJMS

View full text Add to dashboard Cite

For the design of next-generation tuberculosis chemotherapy, insight into bacterial defence against drugs is required. Currently, targeting respiration has attracted strong attention for combatting drug-resistant mycobacteria. Q203 (telacebec), an inhibitor of the cytochrome bcc complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against M. tuberculosis, which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome bd. In contrast, non-tuberculous mycobacteria, such as Mycobacterium smegmatis, show only very little sensitivity to Q203. In this report, we investigated factors that M. smegmatis employs to adapt to Q203 in the presence or absence of a functional cytochrome bd, especially regarding its terminal oxidases. In the presence of a functional cytochrome bd, M. smegmatis responds to Q203 by increasing the expression of cytochrome bcc as well as of cytochrome bd, whereas a M. smegmatisbd-KO strain adapted to Q203 by increasing the expression of cytochrome bcc. Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome bd isoform postulated for M. smegmatis. Although this putative isoform showed differential expression in response to Q203 in the M. smegmatisbd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant.

show abstract

Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

Cited by 29 publications

References 124 publications

Bioenergetics and Reactive Nitrogen Species in Bacteria

Bioenergetics and Reactive Nitrogen Species in Bacteria

The cryoEM structure of cytochrome bd from C. glutamicum provides novel insights into structural properties of actinobacterial terminal oxidases

Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

Contact Info

Product

Resources

About