Rv0132c of Mycobacterium tuberculosis Encodes a Coenzyme F-420-Dependent Hydroxymycolic Acid Dehydrogenase

Abstract

The ability of Mycobacterium tuberculosis to manipulate and evade human immune system is in part due to its extraordinarily complex cell wall. One of the key components of this cell wall is a family of lipids called mycolic acids. Oxygenation of mycolic acids generating methoxy- and ketomycolic acids enhances the pathogenic attributes of M. tuberculosis. Thus, the respective enzymes are of interest in the research on mycobacteria. The generation of methoxy- and ketomycolic acids proceeds through intermediary formation of hydroxymycolic acids. While the methyl transferase that generates methoxymycolic acids from hydroxymycolic acids is known, hydroxymycolic acids dehydrogenase that oxidizes hydroxymycolic acids to ketomycolic acids has been elusive. We found that hydroxymycolic acid dehydrogenase is encoded by the rv0132c gene and the enzyme utilizes F₄₂₀, a deazaflavin coenzyme, as electron carrier, and accordingly we called it F₄₂₀-dependent hydroxymycolic acid dehydrogenase. This is the first report on the involvement of F₄₂₀ in the synthesis of a mycobacterial cell envelope. Also, F₄₂₀-dependent hydroxymycolic acid dehydrogenase was inhibited by PA-824, and therefore, it is a previously unknown target for this new tuberculosis drug.