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Title: Molecular Basis for Autocatalytic Backbone N-Methylation in RiPP Natural Product Biosynthesis

Journal Article · · ACS Chemical Biology
 [1]; ORCiD logo [1]
  1. Univ. of Illinois at Urbana-Champaign, IL (United States)
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N-methylation of nucleic acids, proteins, and peptides is a chemical modification with significant impact on biological regulation. Despite the simplicity of the structural change, N-methylation can influence diverse functions including epigenetics, protein complex formation, and microtubule stability. While there are limited examples of N-methylation of the α-amino group of bacterial and eukaryotic proteins, there are no examples of catalysts that carry out post-translation methylation of backbone amides in proteins or peptides. Recent studies have identified enzymes that catalyze backbone N-methylation on a peptide substrate, a reaction with little biochemical precedent, in a family of ribosomally synthesized natural products produced in basidiomycetes. Here, we describe the crystal structures of Dendrothele bispora dbOphMA, a methyltransferase that catalyzes multiple N-methylations on the peptide backbone. We further carry out biochemical studies of this catalyst to determine the molecular details that promote this unusual chemical transformation. As a result, the structural and biochemical framework described here could facilitate biotechnological applications of catalysts for the rapid production of backbone N-methylated peptides.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health
OSTI ID:
1482230
Journal Information:
ACS Chemical Biology, Vol. 13, Issue 10; ISSN 1554-8929
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (3)

Discovery and characterization of a novel C-terminal peptide carboxyl methyltransferase in a lassomycin-like lasso peptide biosynthetic pathway journal February 2019
Discovery of novel fungal RiPP biosynthetic pathways and their application for the development of peptide therapeutics journal May 2019
Discovery of novel fungal RiPP biosynthetic pathways and their application for the development of peptide therapeutics text January 2019

Figures / Tables (7)

Figure 1(p. 24)figure Figure 1
Figure 2(p. 25)figure Figure 2
Figure 3(p. 26)figure Figure 3
Figure 4(p. 27)figure Figure 4
Figure 5(p. 28)figure Figure 5
Figure 6(p. 29)figure Figure 6
Table 1(p. 30)table Table 1

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