Two Flavoenzymes Catalyze the Post-Translational Generation of 5-Chlorotryptophan and 2-Aminovinyl-Cysteine during NAI-107 Biosynthesis

Ortega, Manuel A.; Cogan, Dillon P.; Mukherjee, Subha; Garg, Neha; Li, Bo; Thibodeaux, Gabrielle N.; Maffioli, Sonia I.; Donadio, Stefano; Sosio, Margherita; Escano, Jerome; Smith, Leif; Nair, Satish K.; van der Donk, Wilfred A.

doi:10.1021/acschembio.6b01031

Title: Two Flavoenzymes Catalyze the Post-Translational Generation of 5-Chlorotryptophan and 2-Aminovinyl-Cysteine during NAI-107 Biosynthesis

Journal Article · Thu Dec 29 00:00:00 EST 2016 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.6b01031· OSTI ID:1356412

Ortega, Manuel A. ^[1]; Cogan, Dillon P. ^[1]; Mukherjee, Subha ^[1]; Garg, Neha ^[1]; Li, Bo ^[1]; Thibodeaux, Gabrielle N. ^[1]; Maffioli, Sonia I. ^[2]; Donadio, Stefano ^[2]; Sosio, Margherita ^[2]; Escano, Jerome ^[3];

^[3]; Nair, Satish K. ^[1];

^[1]

Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States)
NAICONS Srl, Milan (Italy)
Texas A & M Univ., College Station, TX (United States)

Lantibiotics are ribosomally synthesized and post-translationally modified antimicrobial peptides containing thioether rings. In addition to these cross-links, the clinical candidate lantibiotic NAI-107 also possesses a C-terminal S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) and a unique 5-chloro-l-tryptophan (ClTrp) moiety linked to its potent bioactivity. Bioinformatic and genetic analyses on the NAI-107 biosynthetic gene cluster identified mibH and mibD as genes encoding flavoenzymes responsible for the formation of ClTrp and AviCys, respectively. The biochemical basis for the installation of these modifications on NAI-107 and the substrate specificity of either enzyme is currently unknown. Using a combination of mass spectrometry, liquid chromatography, and bioinformatic analyses, we demonstrate that MibD is an FAD-dependent Cys decarboxylase and that MibH is an FADH2-dependent Trp halogenase. Most FADH₂-dependent Trp halogenases halogenate free Trp, but MibH was only active when Trp was embedded within its cognate peptide substrate deschloro NAI-107. Furthermore, structural comparison of the 1.88-Å resolution crystal structure of MibH with other flavin-dependent Trp halogenases revealed that subtle amino acid differences within the MibH substrate binding site generates a solvent exposed crevice presumably involved in determining the substrate specificity of this unusual peptide halogenase.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; European Commission (EC); NIGMS-NIH Chemistry–Biology Interface Training

Grant/Contract Number:: R37 GM058822; R01 GM079038; 245066; FP7-KBBE-2009-3; 5T32-GM070421; S10 RR027109 A

OSTI ID:: 1356412

Journal Information:: ACS Chemical Biology, Vol. 12, Issue 2; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 48 works

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Biosynthesis of l ‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics Luhavaya, Hanna; Sigrist, Renata; Chekan, Jonathan R. Angewandte Chemie https://doi.org/10.1002/ange.201901571	journal	May 2019
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Title: Two Flavoenzymes Catalyze the Post-Translational Generation of 5-Chlorotryptophan and 2-Aminovinyl-Cysteine during NAI-107 Biosynthesis

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