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Biotin synthesis begins by hijacking the fatty acid synthetic pathway

Nature Chemical Biology volume 6, pages 682–688 (2010)Cite this article

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Abstract

Although biotin is an essential enzyme cofactor found in all three domains of life, our knowledge of its biosynthesis remains fragmentary. Most of the carbon atoms of biotin are derived from pimelic acid, a seven-carbon dicarboxylic acid, but the mechanism whereby this intermediate is assembled remains unknown. Genetic analysis in Escherichia coli identified only two genes of unknown function required for pimelate synthesis, bioC and bioH. We report in vivo and in vitro evidence that the pimeloyl moiety is synthesized by a modified fatty acid synthetic pathway in which the ω-carboxyl group of a malonyl-thioester is methylated by BioC, which allows recognition of this atypical substrate by the fatty acid synthetic enzymes. The malonyl-thioester methyl ester enters fatty acid synthesis as the primer and undergoes two reiterations of the fatty acid elongation cycle to give pimeloyl-acyl carrier protein (ACP) methyl ester, which is hydrolyzed to pimeloyl-ACP and methanol by BioH.

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Figure 1: Scheme of the proposed biotin synthetic pathway.
Figure 2: Requirements for DTB synthesis from malonyl-CoA.
Figure 3: SAM and the methyl ester moiety are both required for synthesis of the pimeloyl moiety.
Figure 4: Inhibition of DTB synthesis by inhibitors of fatty acid synthesis and SAM-dependent methyltransferases.

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Acknowledgements

This work was supported by US National Institutes of Health grant AI15650 from the US National Institute of Allergy and Infectious Diseases.

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Authors and Affiliations

  1. Department of Microbiology, University of Illinois, Urbana, Illinois, USA

    Steven Lin, Ryan E Hanson & John E Cronan

  2. Department of Biochemistry, University of Illinois, Urbana, Illinois, USA

    John E Cronan

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  1. Steven Lin
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Contributions

S.L., R.E.H. and J.E.C. performed experiments, and S.L. and J.E.C. designed experiments and wrote the manuscript.

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Correspondence to John E Cronan.

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Lin, S., Hanson, R. & Cronan, J. Biotin synthesis begins by hijacking the fatty acid synthetic pathway. Nat Chem Biol 6, 682–688 (2010). https://doi.org/10.1038/nchembio.420

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