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The biosynthesis of mycobacterial mannose-containing lipoglycans, such as lipomannan (LM) and the immunomodulator lipoarabinomanan (LAM), is carried out by the GT-C superfamily of glycosyltransferases that require polyprenylphosphate-based mannose (PPM) as a sugar donor. The essentiality of lipoglycan synthesis for growth makes the glycosyltransferase that synthesizes PPM, a potential drug target in  Mycobacterium tuberculosis , the causative agent of tuberculosis. In  M. tuberculosis , PPM has been shown to be synthesized by Ppm1 in enzymatic assays. However, genetic evidence for its essentiality and  in vivo  role in LM/LAM and PPM biosynthesis is lacking. In this study, we demonstrate that  MSMEG3859 , a  Mycobacterium smegmatis  gene encoding the homologue of the catalytic domain of  M. tuberculosis  Ppm1, is essential for survival. Depletion of  MSMEG3859  in a conditional mutant of  M. smegmatis  resulted in the loss of higher order phosphatidyl- myo -inositol mannosides (PIMs) and lipomannan. We were also able to demonstrate that two other  M. tuberculosis  genes encoding glycosyltransferases that either had been shown to possess PPM synthase activity ( Rv3779 ), or were involved in synthesizing similar polyprenol-linked donors ( ppgS ), were unable to compensate for the loss of MSMEG3859 in the conditional mutant.

Ppm1-Encoded Polyprenyl Monophosphomannose Synthase Activity Is Essential for Lipoglycan Synthesis and Survival in Mycobacteria