Rv0132c of Mycobacterium Tuberculosis Encodes a Coenzyme F420-dependent Hydroxymycolic Acid Dehydrogenase

PLoS One. 2013 Dec 11;8(12):e81985. doi: 10.1371/journal.pone.0081985. eCollection 2013.

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.

MeSH terms

  • Amino Acid Sequence
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Wall / enzymology*
  • Cell Wall / genetics
  • Gene Expression
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / genetics
  • Mycolic Acids / metabolism*
  • Nitroimidazoles / pharmacology
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Riboflavin / analogs & derivatives*
  • Riboflavin / chemistry
  • Riboflavin / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Substrate Specificity

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Mycolic Acids
  • Nitroimidazoles
  • pretomanid
  • coenzyme F420
  • Oxidoreductases
  • Riboflavin

Grant support

This research was supported by Virginia Bioinformatics Institute, Virginia Tech and grant 1R21AI100039 from the National Institutes of Health to BM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.