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Streptomyces wadayamensis MppP Is a Pyridoxal 5'-Phosphate-Dependent L-Arginine α-Deaminase, γ-Hydroxylase in the Enduracididine Biosynthetic Pathway

Journal Article · · Biochemistry
 [1];  [1];  [1];  [1]
  1. Univ. of Wisconsin, Milwaukee, WI (United States)
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l-Enduracididine (l-End) is a nonproteinogenic amino acid found in a number of bioactive peptides, including the antibiotics teixobactin, enduracidin, and mannopeptimycin. The potent activity of these compounds against antibiotic-resistant pathogens like MRSA and their novel mode of action have garnered considerable interest for the development of these peptides into clinically relevant antibiotics. Here, this goal has been hampered, at least in part, by the fact that l-End is difficult to synthesize and not currently commercially available. We have begun to elucidate the biosynthetic pathway of this unusual building block. In mannopeptimycin-producing strains, like Streptomyces wadayamensis, l-End is produced from l-Arg by the action of three enzymes: MppP, MppQ, and MppR. Herein, we report the structural and functional characterization of MppP. This pyridoxal 5'-phosphate (PLP)-dependent enzyme was predicted to be a fold type I aminotransferase on the basis of sequence analysis. We show that MppP is actually the first example of a PLP-dependent hydroxylase that catalyzes a reaction of l-Arg with dioxygen to yield a mixture of 2-oxo-4-hydroxy-5-guanidinovaleric acid and 2-oxo-5-guanidinovaleric acid in a 1.7:1 ratio. The structure of MppP with PLP bound to the catalytic lysine residue (Lys221) shows that, while the tertiary structure is very similar to those of the well-studied aminotransferases, there are differences in the arrangement of active site residues around the cofactor that likely account for the unusual activity of this enzyme. The structure of MppP with the substrate analogue d-Arg bound shows how the enzyme binds its substrate and indicates why d-Arg is not a substrate. On the basis of this work and previous work with MppR, we propose a plausible biosynthetic scheme for l-End.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Michigan Economic Development Corp.; Michigan Technology Tri-Corridor; USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1233328
Journal Information:
Biochemistry, Journal Name: Biochemistry Journal Issue: 47 Vol. 54; ISSN 0006-2960
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (11)

Current Advances on Structure-Function Relationships of Pyridoxal 5′-Phosphate-Dependent Enzymes journal March 2019
Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis journal January 2016
Nicht-ribosomale Peptidsynthese - Prinzipien und Perspektiven journal March 2017
In vitro Reconstitution of the Biosynthetic Pathway to the Nitroimidazole Antibiotic Azomycin journal July 2019
Nonribosomal Peptide Synthesis-Principles and Prospects journal March 2017
In vitro Reconstitution of the Biosynthetic Pathway to the Nitroimidazole Antibiotic Azomycin journal July 2019
Chemistry and Biology of Teixobactin journal December 2017
Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights journal January 2017
Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses journal January 2018
Pyridoxal phosphate-dependent reactions in the biosynthesis of natural products journal January 2019
Characterization of three regulatory genes involved in enduracidin biosynthesis and improvement of enduracidin production in Streptomyces fungicidicus journal June 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
chemical structure
monomers
noncovalent interactions
peptides and proteins
phosphates