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Publication Abstract from PubMed

The terminal reductase (R) domain from the non-ribosomal peptide synthetase (NRPS) module MxaA in Stigmatella aurantiaca Sga15 catalyzes a non-processive four-electron reduction to produce the myxalamide family of secondary metabolites. Despite widespread use in nature, a lack of structural and mechanistic information concerning reductive release from polyketide synthase (PKS) and NRPS assembly lines principally limits our ability to redesign R domains with altered or improved activity. Here we report crystal structures for MxaA R, both in the absence and, for the first time, in the presence of the NADPH cofactor. Molecular dynamics simulations were employed to provide a deeper understanding of this domain and further identify residues critical for structural integrity, substrate binding, and catalysis. Aggregate computational and structural findings provided a basis for mechanistic investigations and, in the process, delivered a rationally altered variant with improved activity toward highly reduced substrates.

Comprehensive Structural and Biochemical Analysis of the Terminal Myxalamid Reductase Domain for the Engineered Production of Primary Alcohols.,Barajas JF, Phelan RM, Schaub AJ, Kliewer JT, Kelly PJ, Jackson DR, Luo R, Keasling JD, Tsai SC Chem Biol. 2015 Jul 29. pii: S1074-5521(15)00248-3. doi:, 10.1016/j.chembiol.2015.06.022. PMID:26235055^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.