F420-dependent hydroxymycolic acid dehydrogenase (fHMAD)

F420-dependent hydroxymycolic acid dehydrogenase (fHMAD; gene Rv0132c in M. tuberculosis) catalyzes the oxidation of hydroxymycolic acids to ketomycolic acids, key lipids of the mycobacterial cell wall. This process is dependent on the unusual deazaflavin cofactor F420, which provides reducing power for various redox reactions specific to actinobacteria. The enzyme is pharmacologically relevant because it is inhibited by PA-824 (pretomanid), an anti-tuberculosis drug candidate. Thus, fHMAD is a promising selective drug target for the treatment of tuberculosis, as its function is essential for mycobacterial survival and virulence, while being absent from humans and common commensal bacteria. The broader family of F420-dependent enzymes in mycobacteria also participate in processes such as detoxification, resistance to oxidative/nitrosative stress, and activation of prodrugs.

Other names

hydroxymycolic acid dehydrogenaseF420-dependent hydroxymycolic acid dehydrogenaseRv0132cfHMAD

Drug (PA-824) acts as a prodrug; activation depends on F420-dependent enzymes, including this one. Inhibition of F420-dependent hydroxymycolic acid dehydrogenase blocks the conversion of hydroxymycolic acids to ketomycolic acids, impacting cell wall biosynthesis and leading to bacterial death.