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Repurposing the GNAT fold in the initiation of polyketide biosynthesis

TitleRepurposing the GNAT fold in the initiation of polyketide biosynthesis
Publication TypeJournal Article
Year of Publication2020
AuthorsSkiba M.A, Tran C.L, Dan Q.Y, Sikkema A.P, Klaver Z., Gerwick WH, Sherman D.H, Smith J.L
Date Published2020/01
Type of ArticleArticle
ISBN Number0969-2126
Accession NumberWOS:000505976100007
Keywordsbacterial; Biochemistry & Molecular Biology; Biophysics; Cell Biology; crystal-structure; gcn5-related n-acetyltransferases; gene-cluster; malonyl-coa decarboxylase; mycobacterium-tuberculosis; natural-product; peptide synthetase; provide insights; structural basis; symbiont

Natural product biosynthetic pathways are replete with enzymes repurposed for new catalytic functions. In some modular polyketide synthase (PKS) pathways, a GCN5-related N-acetyltransferase (GNAT)-like enzyme with an additional decarboxylation function initiates biosynthesis. Here, we probe two PKS GNAT-like domains for the dual activities of S-acyl transfer from coenzyme A (CoA) to an acyl carrier protein (ACP) and decarboxylation. The GphF and CurA GNAT-like domains selectively decarboxylate substrates that yield the anticipated pathway starter units. The GphF enzyme lacks detectable acyl transfer activity, and a crystal structure with an isobutyryl-CoA product analog reveals a partially occluded acyltransfer acceptor site. Further analysis indicates that the CurA GNAT-like domain also catalyzes only decarboxylation, and the initial acyl transfer is catalyzed by an unidentified enzyme. Thus, PKS GNAT-like domains are re-classified as GNAT-like decarboxylases. Two other decarboxylases, malonyl-CoA decarboxylase and EryM, reside on distant nodes of the superfamily, illustrating the adaptability of the GNAT fold.

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