Structural Remodeling Creates Diversity in Lipid Repertoire of Mycobacterium tuberculosis

Kinatukara Priyadarshan, Asfarul Syed Haque, Raju Rukmini, Rajan Sankaranarayanan

Abstract


Mycobacterium tuberculosis (Mtb) cell wall houses some of the most diverse lipids known. This enormous diversity is a product of interesting evolutionary redesigning of common folds. In this review, we present three examples of changes at increasing levels of complexity in common folds to generate diversity in biochemical and biological function. PKS18, a type-III polyketide synthase, exhibits specificity for longer acyl chains due to subtle psi angle changes in a canonical thiolase fold. A small insertion in a common acetyl-CoA synthetase fold redirects transfer of activated acyl chains to polyketide biosynthesis, whereas the counterparts transfer them to Coenzyme-A for degradation. Evolution of a large hydrophobic platform in the C-terminal domain of a short-chain dehydrogenase family member and adapting reduction as a release strategy enhances the diversity of lipids manifolds. These three examples underline a general theme of divergent evolution leading to plurality of functions with different levels of changes to the existing folds in the context of complex virulent lipid synthesis in Mtb.

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