|Title||Repurposing the GNAT fold in the initiation of polyketide biosynthesis|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Skiba M.A, Tran C.L, Dan Q.Y, Sikkema A.P, Klaver Z., Gerwick WH, Sherman D.H, Smith J.L|
|Type of Article||Article|
|Keywords||bacterial; 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.