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A novel tunnel in mycobacterial type III polyketide synthase reveals the structural basis for generating diverse metabolites

Nature Structural & Molecular Biology volume 11, pages 894–900 (2004)Cite this article

Abstract

The superfamily of plant and bacterial type III polyketide synthases (PKSs) produces diverse metabolites with distinct biological functions. PKS18, a type III PKS from Mycobacterium tuberculosis, displays an unusual broad specificity for aliphatic long-chain acyl-coenzyme A (acyl-CoA) starter units (C6–C20) to produce tri- and tetraketide pyrones. The crystal structure of PKS18 reveals a 20 Å substrate binding tunnel, hitherto unidentified in this superfamily of enzymes. This remarkable tunnel extends from the active site to the surface of the protein and is primarily generated by subtle changes of backbone dihedral angles in the core of the protein. Mutagenic studies combined with structure determination provide molecular insights into the structural elements that contribute to the chain length specificity of the enzyme. This first bacterial type III PKS structure underlines a fascinating example of the way in which subtle changes in protein architecture can generate metabolite diversity in nature.

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Figure 1
Figure 2: Overall structure of PKS18.
Figure 3: Structural basis for substrate specificity.
Figure 4: Functional characterization of substrate binding tunnel.
Figure 5: C205F mutant structure.

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Acknowledgements

We thank L. Singh and S.K. Basu for helpful discussions. This work was supported by grants from the Council of Scientific and Industrial Research (CSIR), India, to the Centre for Cellular and Molecular Biology, and the Department of Biotechnology (DBT), India, to the National Institute of Immunology. R.S. and R.S.G. are Wellcome Trust International Senior Research Fellows (WTISRF) in Biomedical Science in India.

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  1. Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India

    Rajan Sankaranarayanan, Vellaiah M Shanmugam & Raju Rukmini

  2. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110 067, India

    Priti Saxena, Uttara B Marathe & Rajesh S Gokhale

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  1. Rajan Sankaranarayanan
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Correspondence to Rajan Sankaranarayanan or Rajesh S Gokhale.

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Sankaranarayanan, R., Saxena, P., Marathe, U. et al. A novel tunnel in mycobacterial type III polyketide synthase reveals the structural basis for generating diverse metabolites. Nat Struct Mol Biol 11, 894–900 (2004). https://doi.org/10.1038/nsmb809

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