6B3A

AprA Methyltransferase 1 - GNAT didomain in complex with Mn2+ and SAM

Summary for 6B3A

• Entry DOI: 10.2210/pdb6b3a/pdb
• Descriptor: AprA Methyltransferase 1, S-ADENOSYLMETHIONINE, MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: methyltransferase, apratoxin, gcn5 related n-acetyltransferase, transferase
• Biological source: Moorea bouillonii
• Total number of polymer chains: 1
• Total formula weight: 75371.30

Authors

Skiba, M.A.,Smith, J.L. (deposition date: 2017-09-21, release date: 2017-11-15, Last modification date: 2023-10-04)

Primary citation

Skiba, M.A.,Sikkema, A.P.,Moss, N.A.,Tran, C.L.,Sturgis, R.M.,Gerwick, L.,Gerwick, W.H.,Sherman, D.H.,Smith, J.L.
A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit.
ACS Chem. Biol., 12:3039-3048, 2017

PubMed Abstract: Natural product biosynthetic pathways contain a plethora of enzymatic tools to carry out difficult biosynthetic transformations. Here, we discover an unusual mononuclear iron-dependent methyltransferase that acts in the initiation steps of apratoxin A biosynthesis (AprA MT1). Fe-replete AprA MT1 catalyzes one or two methyl transfer reactions on the substrate malonyl-ACP (acyl carrier protein), whereas Co, Fe, Mn, and Ni support only a single methyl transfer. MT1 homologues exist within the "GNAT" (GCN5-related N-acetyltransferase) loading modules of several modular biosynthetic pathways with propionyl, isobutyryl, or pivaloyl starter units. GNAT domains are thought to catalyze decarboxylation of malonyl-CoA and acetyl transfer to a carrier protein. In AprA, the GNAT domain lacks both decarboxylation and acyl transfer activity. A crystal structure of the AprA MT1-GNAT di-domain with bound Mn, malonate, and the methyl donor S-adenosylmethionine (SAM) reveals that the malonyl substrate is a bidentate metal ligand, indicating that the metal acts as a Lewis acid to promote methylation of the malonyl α-carbon. The GNAT domain is truncated relative to functional homologues. These results afford an expanded understanding of MT1-GNAT structure and activity and permit the functional annotation of homologous GNAT loading modules both with and without methyltransferases, additionally revealing their rapid evolutionary adaptation in different biosynthetic contexts.

PubMed: 29096064
DOI: 10.1021/acschembio.7b00746

Experimental method

X-RAY DIFFRACTION (1.784 Å)