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The primary step of biotin synthesis in mycobacteria.

ABSTRACT: Biotin plays an essential role in growth of mycobacteria. Synthesis of the cofactor is essential for Mycobacterium tuberculosis to 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 the Mycobacterium smegmatis gene annotated as encoding Tam, an O-methyltransferase that monomethylates and detoxifies trans-aconitate, instead encodes a protein having the activity of BioC, an O-methyltransferase that methylates the free carboxyl of malonyl-ACP. The M. smegmatis Tam functionally replaced Escherichia coli BioC both in vivo and in vitro. Moreover, deletion of the M. smegmatis tam gene resulted in biotin auxotrophy, and addition of biotin to M. smegmatis cultures repressed tam gene transcription. Although its pathogenicity precluded in vivo studies, the M. tuberculosis Tam also replaced E. coli BioC both in vivo and in vitro and complemented biotin-independent growth of the M. smegmatis tam deletion mutant strain. Based on these data, we propose that the highly conserved mycobacterial tam genes be renamed bioC M. tuberculosis BioC presents a target for antituberculosis drugs which thus far have been directed at late reactions in the pathway with some success.

SUBMITTER: Hu Z

PROVIDER: S-EPMC7519262 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The primary step of biotin synthesis in mycobacteria.

Hu Zhe Z Cronan John E JE

Proceedings of the National Academy of Sciences of the United States of America 20200908 38

Biotin plays an essential role in growth of mycobacteria. Synthesis of the cofactor is essential for <i>Mycobacterium tuberculosis</i> to 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 the <i>Mycobact ...[more]

PMID: 32900960

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Project description:Two vitamins, biotin and lipoic acid, are essential in all three domains of life. Both coenzymes function only when covalently attached to key metabolic enzymes. There they act as "swinging arms" that shuttle intermediates between two active sites (= covalent substrate channeling) of key metabolic enzymes. Although biotin was discovered over 100 years ago and lipoic acid 60 years ago, it was not known how either coenzyme is made until recently. In Escherichia coli the synthetic pathways for both coenzymes have now been worked out for the first time. The late steps of biotin synthesis, those involved in assembling the fused rings, were well described biochemically years ago, although recent progress has been made on the BioB reaction, the last step of the pathway in which the biotin sulfur moiety is inserted. In contrast, the early steps of biotin synthesis, assembly of the fatty acid-like "arm" of biotin were unknown. It has now been demonstrated that the arm is made by using disguised substrates to gain entry into the fatty acid synthesis pathway followed by removal of the disguise when the proper chain length is attained. The BioC methyltransferase is responsible for introducing the disguise, and the BioH esterase is responsible for its removal. In contrast to biotin, which is attached to its cognate proteins as a finished molecule, lipoic acid is assembled on its cognate proteins. An octanoyl moiety is transferred from the octanoyl acyl carrier protein of fatty acid synthesis to a specific lysine residue of a cognate protein by the LipB octanoyltransferase followed by sulfur insertion at carbons C-6 and C-8 by the LipA lipoyl synthetase. Assembly on the cognate proteins regulates the amount of lipoic acid synthesized, and, thus, there is no transcriptional control of the synthetic genes. In contrast, transcriptional control of the biotin synthetic genes is wielded by a remarkably sophisticated, yet simple, system, exerted through BirA, a dual-function protein that both represses biotin operon transcription and ligates biotin to its cognate proteins.

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The primary step of biotin synthesis in mycobacteria.

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The primary step of biotin synthesis in mycobacteria.

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