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| A novel tunnel in mycobacterial PKS18 reveals structural basis for generating diverse metabolites | |
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The superfamily of plant and bacterial type III polyketide synthases (PKSs)
produce 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 (CoA) starter units
(C6 to C20) to produce tri- and tetra-ketide pyrones (Saxena et al. 2003).
The protein was crystallized and the structure solved using molecular
replacement method (Rukmini, et al. 2004). 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 how delicate changes in protein
architecture can generate metabolite diversity in nature (Sankaranarayanan
et al. 2004).
1) Saxena, P., et al. J Biol Chem 278, 44780-44790 (2003).
2) Rukmini, R., et al. Acta Crystallogr D Biol Crystallogr 60, 749-751 (2004).
3) Sankaranarayanan, R. et al. Nature Struct Mol Biol (In Press) (2004).
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