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Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria

A Corrigendum to this article was published on 12 August 2004

An Erratum to this article was published on 29 April 2004

Abstract

The metabolic repertoire in nature is augmented by generating hybrid metabolites from a limited set of gene products1,2,3. In mycobacteria, several unique complex lipids are produced by the combined action of fatty acid synthases and polyketide synthases (PKSs)4,5,6, although it is not clear how the covalently sequestered biosynthetic intermediates are transferred from one enzymatic complex to another. Here we show that some of the 36 annotated fadD genes, located adjacent to the PKS genes in the Mycobacterium tuberculosis genome, constitute a new class of long-chain fatty acyl-AMP ligases (FAALs). These proteins activate long-chain fatty acids as acyl-adenylates, which are then transferred to the multifunctional PKSs for further chain extension. This mode of activation and transfer of fatty acids is contrary to the previously described universal mechanism involving the formation of acyl-coenzyme A thioesters. Similar mechanisms may operate in the biosynthesis of other lipid-containing metabolites and could have implications in engineering novel hybrid products.

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Figure 1: Chemical characterization of the FadD products.
Figure 2: Activation and transfer of fatty acids on to the cognate PKS proteins.
Figure 3: Structural analysis of FAAL and FACL proteins.

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Acknowledgements

The authors thank S. K. Basu for discussions. P.A. is a Senior Research Fellow of CSIR, India. R.S.G is a Wellcome Trust International Senior Research Fellow in India. This work was also supported by grants to the National Institute of Immunology by DBT, India.

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Correspondence to Rajesh S. Gokhale.

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Supplementary information

Supplementary Figure 1

Dendrogram obtained from the multiple sequence alignment of the FadDs of M. tuberculosis. (PPT 97 kb)

Supplementary Figure 2

Exogenous incorporation of acyl-CoA. (PPT 2325 kb)

Supplementary Figure 3

SDS-PAGE gel showing purified FadD and PKS proteins used in this study. (PPT 276 kb)

Supplementary Figure Legends

SDS-PAGE gel showing purified FadD and PKS proteins used in this study. (DOC 7 kb)

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Trivedi, O., Arora, P., Sridharan, V. et al. Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428, 441–445 (2004). https://doi.org/10.1038/nature02384

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