Biosynthesis of mycobacterial lipids by polyketide synthases and beyond

Over a decade ago, the analysis of the complete sequence of the genome of the human pathogen Mycobacterium tuberculosis revealed an unexpectedly high number of open reading frames encoding proteins with homology to polyketide synthases (PKSs). PKSs form a large family of fascinating multifunctional enzymes best known for their involvement in the biosynthesis of hundreds of polyketide natural products with diverse biological activities. The surprising polyketide biosynthesis capacity of M. tuberculosis has been investigated since its initial inference from genome analysis. This investigation has been based on the genes found in M. tuberculosis or their orthologs found in other Mycobacterium species. Today, the majority of the PKS-encoding genes of M. tuberculosis have been linked to specific biosynthetic pathways required for the production of unique lipids or glycolipid conjugates that are critical for virulence and/or components of the extraordinarily complex mycobacterial cell envelope. This review provides a synopsis of the most relevant studies in the field and an overview of our current understanding of the involvement of PKSs and several other polyketide production pathway-associated proteins in critical biosynthetic pathways of M. tuberculosis and other mycobacteria. In addition, the most relevant studies on PKS-containing biosynthetic pathways leading to production of metabolites from mycobacteria other than M. tuberculosis are reviewed.