Negative regulation by Ser/Thr phosphorylation of HadAB and HadBC dehydratases from Mycobacterium tuberculosis type II fatty acid synthase system

The type II fatty acid synthase system of mycobacteria is involved in the biosynthesis of major and essential lipids, mycolic acids, key-factors of Mycobacterium tuberculosis pathogenicity. One reason of the remarkable survival ability of M. tuberculosis in infected hosts is partly related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate synthesis of these lipids in response to environmental changes are unknown. We demonstrate here that HadAB and HadBC dehydratases of this system are phosphorylated by Ser/Thr protein kinases, which negatively affects their enzymatic activity. The phosphorylation of HadAB/BC is growth phase-dependent, suggesting that it represents a mechanism by which mycobacteria might tightly control mycolic acid biosynthesis under non-replicating condition.

► We studied the regulation of the type II fatty acid synthase system of mycobacteria.
► We could demonstrate that HadAB and HadBC dehydratases of this system are phosphorylated by Ser/Thr protein kinases.
► We showed that phosphorylation negatively affects their enzymatic activity and is growth phase-dependent.
► Our results suggests that phosphorylation of HadAB/BC represents an unusual mechanism allowing Mycobacterium tuberculosis to regulate its mycolic acid content.