The primary step of biotin synthesis in mycobacteria

Abstract

Biotin plays an essential role in growth of mycobacteria. Synthesis of the cofactor is essential forMycobacterium tuberculosisto establish and maintain chronic infections in a murine model of tuberculosis. Although the late steps of mycobacterial biotin synthesis, assembly of the heterocyclic rings, are thought to follow the canonical pathway, the mechanism of synthesis of the pimelic acid moiety that contributes most of the biotin carbon atoms is unknown. We report that theMycobacterium smegmatisgene annotated as encoding Tam, anO-methyltransferase that monomethylates and detoxifiestrans-aconitate, instead encodes a protein having the activity of BioC, anO-methyltransferase that methylates the free carboxyl of malonyl-ACP. TheM. smegmatisTam functionally replacedEscherichia coliBioC both in vivo and in vitro. Moreover, deletion of theM. smegmatis tamgene resulted in biotin auxotrophy, and addition of biotin toM. smegmatiscultures repressedtamgene transcription. Although its pathogenicity precluded in vivo studies, theM. tuberculosisTam also replacedE. coliBioC both in vivo and in vitro and complemented biotin-independent growth of theM. smegmatis tamdeletion mutant strain. Based on these data, we propose that the highly conserved mycobacterial tamgenes be renamedbioC.M. tuberculosisBioC presents a target for antituberculosis drugs which thus far have been directed at late reactions in the pathway with some success.