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TitleMenaquinone-specific turnover by Mycobacterium tuberculosis cytochrome bd is redox regulated by the Q-loop disulfide bond.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 2, Page 108094, Year 2025
Publish dateDec 18, 2024
AuthorsTijn T van der Velden / Kanwal Kayastha / Caspar Y J Waterham / Steffen Brünle / Lars J C Jeuken /
PubMed AbstractCytochrome bd from Mycobacterium tuberculosis (Mtbd) is a menaquinol oxidase that has gained interest as an antibiotic target because of its importance in survival under infectious conditions. Mtbd ...Cytochrome bd from Mycobacterium tuberculosis (Mtbd) is a menaquinol oxidase that has gained interest as an antibiotic target because of its importance in survival under infectious conditions. Mtbd contains a characteristic disulfide bond that has been hypothesized to allow for Mtbd activity regulation at the enzymatic level, possibly helping M. tuberculosis to rapidly adapt to the hostile environment of the phagosome. Here, the role of the disulfide bond and quinone specificity have been determined by reconstitution of a minimal respiratory chain and the single-particle cryo-EM structure in the disulfide-reduced form. Mtbd was shown to be specific for menaquinone, while regulation by reduction of the Q-loop disulfide bond decreased oxidase activity up to 90%. Structural analysis shows that a salt bridge unique to Mtbd keeps the Q-loop partially structured in its disulfide-reduced form, which could facilitate the rapid activation of Mtbd upon exposure to reactive oxygen species. We signify Mtbd as the first redox sensory terminal oxidase and propose that this helps M. tuberculosis in the defense against reactive oxygen species encountered during infection.
External linksJ Biol Chem / PubMed:39706268 / PubMed Central
MethodsEM (single particle)
Resolution2.96 Å
Structure data

50520

9fka

EMDB-50520, PDB-9fka:
Cryo-EM structure of the reduced cytochrome bd oxidase from M. tuberculosis
Method: EM (single particle) / Resolution: 2.96 Å

Chemicals

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

ChemComp-MQ9:
MENAQUINONE-9

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-HDD:
CIS-HEME D HYDROXYCHLORIN GAMMA-SPIROLACTONE

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

ChemComp-CD4:
(2R,5R,11R,14R)-5,8,11-trihydroxy-5,11-dioxido-17-oxo-2,14-bis(tetradecanoyloxy)-4,6,10,12,16-pentaoxa-5,11-diphosphatriacont-1-yl tetradecanoate

Source
  • Mycobacterium tuberculosis (bacteria)
  • mycobacterium tuberculosis h37rv (bacteria)
KeywordsOXIDOREDUCTASE / Ubiquinone / Demethylmenaquinone / Cryo-EM / Respiration / Substrate specificity / Disulfide regulation

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