Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis

Jinyu Hu, Hang Li, Yit-Heng Choo

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Paecilomyces variotii produces the antibacterial and cytotoxic (M)-viriditoxin (1) together with a trace amount of its atropisomer (P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an alpha/beta hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.

Original languageEnglish
Pages (from-to)8068-8072
Number of pages5
JournalJournal of the American Chemical Society
Volume141
Issue number20
DOIs
Publication statusPublished - 22 May 2019

Cite this

@article{0dd1c02ca5ca45c78128686d2aae12b3,
title = "Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis",
abstract = "Paecilomyces variotii produces the antibacterial and cytotoxic (M)-viriditoxin (1) together with a trace amount of its atropisomer (P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an alpha/beta hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.",
keywords = "CELL-DIVISION, SPICARIA-DIVARICATA, SMALL-MOLECULE, MONOOXYGENASE, DISCOVERY, METABOLITE, LIGHT, FTSZ",
author = "Jinyu Hu and Hang Li and Yit-Heng Choo",
year = "2019",
month = "5",
day = "22",
doi = "10.1021/jacs.9b03354",
language = "English",
volume = "141",
pages = "8068--8072",
journal = "Journal of the Amercian Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "20",

}

TY - JOUR

T1 - Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis

AU - Hu, Jinyu

AU - Li, Hang

AU - Choo, Yit-Heng

PY - 2019/5/22

Y1 - 2019/5/22

N2 - Paecilomyces variotii produces the antibacterial and cytotoxic (M)-viriditoxin (1) together with a trace amount of its atropisomer (P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an alpha/beta hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.

AB - Paecilomyces variotii produces the antibacterial and cytotoxic (M)-viriditoxin (1) together with a trace amount of its atropisomer (P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an alpha/beta hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.

KW - CELL-DIVISION

KW - SPICARIA-DIVARICATA

KW - SMALL-MOLECULE

KW - MONOOXYGENASE

KW - DISCOVERY

KW - METABOLITE

KW - LIGHT

KW - FTSZ

U2 - 10.1021/jacs.9b03354

DO - 10.1021/jacs.9b03354

M3 - Article

VL - 141

SP - 8068

EP - 8072

JO - Journal of the Amercian Chemical Society

JF - Journal of the Amercian Chemical Society

SN - 0002-7863

IS - 20

ER -