7NM8

The crystal structure of the antimycin pathway standalone ketoreductase, AntM, in complex with NADPH

This is a non-PDB format compatible entry.

Summary for 7NM8

• Entry DOI: 10.2210/pdb7nm8/pdb
• Descriptor: Antimycin pathway standalone ketoreductase, AntM, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: ketoreductase, standalone, antimycin, nadph, oxidoreductase
• Biological source: Streptomyces albus
• Total number of polymer chains: 1
• Total formula weight: 30862.19

Authors

Fazal, A.,Hemsworth, G.R.,Webb, M.E.,Seipke, R.F. (deposition date: 2021-02-23, release date: 2021-06-30, Last modification date: 2024-01-31)

Primary citation

Fazal, A.,Hemsworth, G.R.,Webb, M.E.,Seipke, R.F.
A Standalone beta-Ketoreductase Acts Concomitantly with Biosynthesis of the Antimycin Scaffold.
Acs Chem.Biol., 16:1152-1158, 2021

PubMed Abstract: Antimycins are anticancer compounds produced by a hybrid nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway. The biosynthesis of these compounds is well characterized, with the exception of the standalone β-ketoreductase enzyme AntM that is proposed to catalyze the reduction of the C8 carbonyl of the antimycin scaffold. Inactivation of and structural characterization suggested that rather than functioning as a post-PKS tailoring enzyme, AntM acts upon the terminal biosynthetic intermediate while it is tethered to the PKS acyl carrier protein. Mutational analysis identified two amino acid residues (Tyr185 and Phe223) that are proposed to serve as checkpoints controlling substrate access to the AntM active site. Aromatic checkpoint residues are conserved in uncharacterized standalone β-ketoreductases, indicating that they may also act concomitantly with synthesis of the scaffold. These data provide novel mechanistic insights into the functionality of standalone β-ketoreductases and will enable their reprogramming for combinatorial biosynthesis.

PubMed: 34151573
DOI: 10.1021/acschembio.1c00229

Experimental method

X-RAY DIFFRACTION (1.7 Å)