气候变化领域集成服务门户(CCPortal): Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, D-amino acid, and dehydroamino acid synthesis

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DOI	10.1073/pnas.2026017118
	Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, D-amino acid, and dehydroamino acid synthesis
	Wheadon M.J.; Townsend C.A.
发表日期	2021
ISSN	00278424
卷号	118 期号:17
英文摘要	Nonribosomal peptide synthetases (NRPSs) are large, multidomain biosynthetic enzymes involved in the assembly-line–like synthesis of numerous peptide natural products. Among these are clinically useful antibiotics including three classes of β-lactams: the penicillins/cephalosporins, the monobactams, and the monocyclic nocardicins, as well as the vancomycin family of glycopeptides and the depsipeptide daptomycin. During NRPS synthesis, peptide bond formation is catalyzed by condensation (C) domains, which couple the nascent peptide with the next programmed amino acid of the sequence. A growing number of additional functions are linked to the activity of C domains. In the biosynthesis of the nocardicins, a specialized C domain prepares the embedded β-lactam ring from a serine residue. Here, we examine the evolutionary descent of this unique β-lactam–synthesizing C domain. Guided by its ancestry, we predict and demonstrate in vitro that this C domain alternatively performs peptide bond formation when a single stereochemical change is introduced into its peptide starting material. Remarkably, the function of the downstream thioesterase (TE) domain also changes. Natively, the TE directs C terminus epimerization prior to hydrolysis when the β-lactam is made but catalyzes immediate release of the alternative peptide. In addition, we investigate the roles of C-domain histidine residues in light of clade-specific sequence motifs, refining earlier mechanistic proposals of both β-lactam formation and canonical peptide synthesis. Finally, expanded phylogenetic analysis reveals unifying connections between β-lactam synthesis and allied C domains associated with the appearance of D-amino acid and dehydroamino acid residues in other NRPS-derived natural products. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Condensation domain; Evolution; Nocardicin; Nonribosomal peptide synthetase; β-lactam
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179730
作者单位	Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, United States
推荐引用方式 GB/T 7714	Wheadon M.J.,Townsend C.A.. Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, D-amino acid, and dehydroamino acid synthesis[J],2021,118(17).
APA	Wheadon M.J.,&Townsend C.A..(2021).Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, D-amino acid, and dehydroamino acid synthesis.Proceedings of the National Academy of Sciences of the United States of America,118(17).
MLA	Wheadon M.J.,et al."Evolutionary and functional analysis of an NRPS condensation domain integrates β-lactam, D-amino acid, and dehydroamino acid synthesis".Proceedings of the National Academy of Sciences of the United States of America 118.17(2021).