The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development.
Mycolic acids are very long-chain fatty acids representing essential components of the mycobacterial cell wall. Considering their importance, characterization of key enzymes participating in mycolic acid biosynthesis not only allows an understanding of their role in the physiology of mycobacteria, but also might lead to the identification of new drug targets. Mycolates are synthesized by at least two discrete elongation systems, the type I and type II fatty acid synthases (FAS-I and FAS-II respectively). Among the FAS-II components, the condensing enzymes that catalyse the formation of carbon-carbon bonds have received considerable interest. Four condensases participate in initiation (mtFabH), elongation (KasA and KasB) and termination (Pks13) steps, leading to full-length mycolates. We present the recent biochemical and structural data for these important enzymes. Special emphasis is given to their role in growth, intracellular survival, biofilm formation, as well as in the physiopathology of tuberculosis. Recent studies demonstrated that phosphorylation of these enzymes by mycobacterial kinases affects their activities. We propose here a model in which kinases that sense environmental changes can phosphorylate the condensing enzymes, thus representing a novel mechanism of regulating mycolic acid biosynthesis. Finally, we discuss the attractiveness of these enzymes as valid targets for future antituberculosis drug development.
Bhatt
Apoorva
A
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Molle
Virginie
V
Besra
Gurdyal S
GS
Jacobs
William R
WR
Kremer
Laurent
L
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000472:pathogenicity*; D009171:Mycolic Acids / Q000378:metabolism*; D014376:Tuberculosis / Q000382:microbiology / Q000503:physiopathology; D014774:Virulence
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D064429:Fatty Acid Synthases