Menaquinone-specific oxidation byM. tuberculosiscytochromebdis redox regulated by the Q-loop disulfide bond

Author:

van der Velden Tijn T.ORCID,Waterham Caspar Y. J.,Jeuken Lars J. C.ORCID

Abstract

AbstractCytochromebdfromMycobacterium tuberculosis(Mtbd) is a menaquinol oxidase that has gained considerable interest as an antibiotic target due to its importance in survival under infectious conditions.Mtbdcontains a characteristic disulfide bond that has been hypothesized to confer a redox regulatory role during infection by constraining the movement of the menaquinone-binding Q-loop. Interference of reductants used in the standard activity assay of quinol oxidases has prevented testing of this hypothesis. Here, the role of the disulfide bond and quinone specificity ofMtbdhas been determined by the reconstitution of a minimal respiratory chain consisting of a NADH dehydrogenase andMtbd, both in detergent and native-like lipid environments. Comparison to cytochromebdfromEscherichia coli(Ecbd) confirms thatMtbdis under tight redox regulation and is selective for menaquinol, unable to oxidize either ubiquinol or demethylmenaquinol. Reduction of theMtbddisulfide bond resulted in a decrease in oxidase activity up to 90%, depending on menaquinol concentrations. In addition, the catalytic rates ofEcbdandMtbdare over 10 times lower with the natural lipophilic quinones in comparison to their often-used hydrophilic analogs. Additionally, unlikeEcbd, the activity ofMtbdis substrate inhibited at physiologically relevant menaquinol concentrations. We signifyMtbdas the first redox sensory terminal oxidase and propose that this enablesMtbdto adapt its activity in defence against reactive oxygen species encountered during infection byM. tuberculosis.

Publisher

Cold Spring Harbor Laboratory

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