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GNAT-like strategy for polyketide chain initiation.

Liangcai Gu1, Todd W Geders, Bo Wang

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Science (New York, N.Y.)
|November 10, 2007
PubMed
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Researchers discovered a novel biochemical pathway for initiating polyketide synthesis in curacin A. A unique GCN5-related N-acetyltransferase domain performs dual functions, enabling the creation of the anticancer compound curacin A.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Natural Product Synthesis

Background:

  • Curacin A, an anticancer agent from Lyngbya majuscula, relies on polyketide synthase (PKS) for its biosynthesis.
  • The PKS loading module's chain initiation mechanism was previously unknown.

Purpose of the Study:

  • To elucidate the biochemical strategy for polyketide chain initiation in the curacin A PKS.
  • To characterize the novel enzymatic activities within the curacin A loading module.

Main Methods:

  • Biochemical assays to assess enzymatic activities of the CurA loading tridomain.
  • X-ray crystallography to determine the structure of the GNAT(L) domain.
  • Site-directed mutagenesis and computational modeling to investigate key residues.

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Main Results:

  • A GCN5-related N-acetyltransferase (GNAT) domain (GNAT(L)) exhibits unprecedented bifunctional decarboxylase/S-acetyltransferase activity.
  • GNAT(L) catalyzes malonyl-coenzyme A decarboxylation to acetyl-CoA and subsequent S-acetyl transfer to an acyl carrier protein (ACP(L)).
  • Crystal structures reveal distinct substrate tunnels, and mutagenesis identifies key residues (His389, Thr355) involved in decarboxylation.

Conclusions:

  • The curacin A loading module employs a unique GNAT domain for chain initiation.
  • Decarboxylation of malonyl-CoA precedes acetyl-group transfer, generating the acetyl-ACP(L) starter unit.
  • This finding reveals a novel biochemical strategy within the GNAT superfamily for polyketide synthesis.