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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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.
The authors declare that they have no competing financial interests.
Dendrogram obtained from the multiple sequence alignment of the FadDs of M. tuberculosis. (PPT 97 kb)
Exogenous incorporation of acyl-CoA. (PPT 2325 kb)
SDS-PAGE gel showing purified FadD and PKS proteins used in this study. (PPT 276 kb)
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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