Fight against tuberculosis: the structure of an important target unravelled

Despite its importance as a therapeutic target against tuberculosis, the structure of Pks13 (PolyKetide Synthase 13), an enzyme involved in the last steps of acid mycolic (MA) biosynthesis, was lacking. A study published in BMC Biology reveals the first structural information on the molecular mechanism of this complex enzyme and opens up new perspectives to develop inhibitors that target the interactions with its enzymatic partners or between catalytic domains within Pks13 itself.

The biosynthesis of MAs is an Achilles’ heel of Mycobacterium tuberculosis due to the essentiality of these components among Corynebacterineae species. Pks13 is the condensase required for the final condensation step of two long acyl chains leading to MA precursors. It is a megasynthase composed of several catalytic domains on the same polypeptidic chain, post translationally modified on the two acyl carrier protein (ACP) domains, leading to an holo-form. As well as other polyketide synthases, its structural study was challenging undoubtedly due to its inherent flexibility.
In order to decipher the Pks13 molecular mechanism, scientists used small-angle X-ray scattering of the entire protein and various molecular subspecies combined with known high-resolution structures of Pks13 domains or structural homologues. Taking into account the enzyme flexibility, these high-resolution structures have been located within the entire Pks13 enzyme. As a comparison, the low-resolution structures of two other mycobacterial polyketide synthases, Mas and PpsA from Mycobacterium bovis BCG, were also challenged.