Reconstitution of the Final Steps in the Biosynthesis of Valanimycin Reveals the Origin of Its Characteristic Azoxy Moiety DOI
Ziyang Zheng, Jin Xiong,

Junling Bu

et al.

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 136(1)

Published: Nov. 15, 2023

Abstract Valanimycin is an azoxy‐containing natural product isolated from the fermentation broth of Streptomyces viridifaciens MG456‐hF10. While biosynthesis valanimycin has been partially characterized, how azoxy group constructed remains obscure. Herein, membrane protein VlmO and putative hydrazine synthetase ForJ formycin biosynthetic pathway are demonstrated to catalyze N−N bond formation converting O ‐( l ‐seryl)‐isobutyl hydroxylamine into N ‐(isobutylamino)‐ ‐serine. Subsequent installation shown be catalyzed by non‐heme diiron enzyme VlmB in a reaction which single VlmO/ForJ oxidized four electrons yield group. The catalytic cycle appears begin with resting μ‐oxo diferric complex VlmB, as supported Mössbauer spectroscopy. This study also identifies d ‐serine alternative substrate for leading two regioisomers. reactions kinase VlmJ lyase VlmK during final steps established well. was thus fully reconstituted vitro using enzymes VlmO/ForJ, VlmK. Importantly, VlmB‐catalyzed represents first example enzyme‐catalyzed expected proceed atypical mechanism.

Language: Английский

Carrier Protein Mediated Formation of the Dihydropyridazinone Ring in Actinopyridazinone Biosynthesis DOI Creative Commons
Kuga Arima,

Satoko Akiyama,

Kazuo Shin‐ya

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(29)

Published: May 17, 2023

Heterocycles with nitrogen-nitrogen (N-N) bonds are privileged building blocks of synthetic drugs. They also found in natural products, although the biosynthetic logic behind them is poorly understood. Actinopyridazinones produced by Streptomyces sp. MSD090630SC-05 possess unique dihydropyridazinone rings that have been studied as core nuclei several approved therapeutics. Herein, we performed gene knockouts and vitro biochemical experiments to elucidate major steps actinopyridazinone biosynthesis, including unprecedented carrier protein mediated machinery for formation.

Language: Английский

Citations

5
O-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis DOI Creative Commons

Yuchun Zhao,

Xiangyang Liu,

Zhihong Xiao

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 4, 2023

Abstract Diazo compounds are rare natural products possessing various biological activities. Kinamycin and lomaiviticin, two diazo featured by the diazobenzofluorene core, exhibit exceptional potency as chemotherapeutic agents. Despite extensive studies on their biosynthetic gene clusters assembly of polyketide scaffolds, formation characteristic group remains elusive. l -Glutamylhydrazine was recently shown to be hydrazine donor in kinamycin biosynthesis, however, mechanism for installation onto scaffold is still unclear. Here we describe an O -methyltransferase-like protein, AlpH, which responsible incorporation biosynthesis. AlpH catalyses a unique SAM-independent coupling -glutamylhydrazine intermediate via Mannich reaction Our discovery expands catalytic diversity enzymes lays strong foundation development novel through genome mining synthetic biology.

Language: Английский

Citations

5
Novel Biocatalysts from Specialized Metabolism DOI Creative Commons
Hajo Kries, Felix Trottmann, Christian Hertweck

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 63(4)

Published: Sept. 22, 2023

Abstract Enzymes are increasingly recognized as valuable (bio)catalysts that complement existing synthetic methods. However, the range of biotransformations used in laboratory is limited. Here we give an overview on biosynthesis‐inspired discovery novel biocatalysts address various challenges. Prominent examples from this dynamic field highlight remarkable enzymes for protecting‐group‐free amide formation and modification, control pericyclic reactions, stereoselective hetero‐ polycyclizations, atroposelective aryl couplings, site‐selective C−H activations, introduction ring strain, N−N bond formation. We also explore unusual functions cytochrome P450 monooxygenases, radical SAM‐dependent enzymes, flavoproteins, recruited primary metabolism, which offer opportunities biology, enzyme engineering, directed evolution, catalyst design.

Language: Английский

Citations

5
Double Bond Geometric Isomers of Pentaketide Ansamycins from Streptomyces sp. S008 DOI
Shengliang Zhao, Chunhua Lu, Haoxin Wang

et al.

Organic Letters, Journal Year: 2023, Volume and Issue: 25(38), P. 6954 - 6958

Published: Sept. 14, 2023

Six new pentaketide ansamycins, namely, shengliangmycins A-F (1-6, respectively), were obtained from the fermentation products of Streptomyces sp. S008OEslmR2 that was derived by constitutive expression LAL regulator gene slmR2. The structures 1-6 determined through comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Compound 1 has a cis-C6═C7 bond, which is different compounds 2-5. Compounds 3-6 feature morpholinone structural moiety, whereas 5 characterized pyrazoline ring, rare in natural products.

Language: Английский

Citations

4
Recent Developments and Challenges in the Enzymatic Formation of Nitrogen–Nitrogen Bonds DOI Creative Commons

Charitomeni Angeli,

Sara Atienza-Sanz, Simon Schröder

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 15(1), P. 310 - 342

Published: Dec. 17, 2024

The biological formation of nitrogen–nitrogen (N–N) bonds represents intriguing reactions that have attracted much attention in the past decade. This interest has led to an increasing number N–N bond-containing natural products (NPs) and related enzymes catalyze their (referred this review as NNzymes) being elucidated studied greater detail. While more detailed information on biosynthesis NPs, which only become available recent years, provides unprecedented source biosynthetic enzymes, potential for biocatalytic applications been minimally explored. With review, we aim not provide a comprehensive overview both characterized NNzymes hypothetical biocatalysts with putative bond forming activity, but also highlight from perspective. We present compare conventional synthetic approaches linear cyclic hydrazines, hydrazides, diazo- nitroso-groups, triazenes, triazoles allow comparison enzymatic routes via these functional groups. Moreover, pathways well diversity reaction mechanisms are presented according direct groups currently accessible enzymes.

Language: Английский

Citations

1
Automated genome mining predicts combinatorial diversity and taxonomic distribution of peptide metallophore structures DOI Creative Commons
Zachary L. Reitz, Alison Butler, Marnix H. Medema

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 16, 2022

Abstract Microbial competition for trace metals shapes their communities and interactions with humans plants. Many bacteria scavenge metallophores, small molecules that chelate environmental metal ions transport them back into the cell. Our incomplete knowledge of metallophores diversity stymies our ability to fight infectious diseases harness beneficial microbiome interactions. The majority known are non-ribosomal peptides (NRPs), which feature metal-chelating moieties rarely found in other classes natural products. NRP metallophore production may be predicted by genome mining, where genomes scanned homologs biosynthetic gene clusters (BGCs). However, accurately detecting biosynthesis currently requires expert manual inspection. Here, we introduce automated identification BGCs through a comprehensive detection algorithm, newly implemented antiSMASH. Custom-designed profile hidden Markov models detect genes encoding most chelating (2,3-dihydroxybenzoate, hydroxamates, salicylate, β-hydroxyamino acids, graminine, Dmaq, pyoverdine chromophore), achieving 97% precision 78% recall against curation. We leveraged combination transporter detection, 15,562 representative bacterial predict 25% all peptide synthetases encode production. BiG-SCAPE clustering 2,562 revealed significant remains unexplored, including new combinations groups. Additionally, find Cyanobacteria severely understudied should focus more isolation efforts. inclusion antiSMASH version 7 will aid non-expert researchers facilitate large-scale investigations biology.

Language: Английский

Citations

7
New azodyrecins identified by a genome mining-directed reactivity-based screening DOI Creative Commons
Atina Rizkiya Choirunnisa, Kuga Arima, Yo Abe

et al.

Beilstein Journal of Organic Chemistry, Journal Year: 2022, Volume and Issue: 18, P. 1017 - 1025

Published: Aug. 10, 2022

Only a few azoxy natural products have been identified despite their intriguing biological activities. Azodyrecins D–G, four new analogs of aliphatic azoxides, were from two Streptomyces species by reactivity-based screening that targets bonds. A activity evaluation demonstrated the double bond in alkyl side chain is important for cytotoxicity azodyrecins. An vitro assay elucidated tailoring step azodyrecin biosynthesis, which mediated S -adenosylmethionine (SAM)-dependent methyltransferase Ady1. This study paves way targeted isolation through genome-mining approach and further investigations biosynthetic mechanisms.

Language: Английский

Citations

6
Novel Biocatalysts from Specialized Metabolism DOI Creative Commons
Hajo Kries, Felix Trottmann, Christian Hertweck

et al.

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 136(4)

Published: Sept. 22, 2023

Abstract Enzymes are increasingly recognized as valuable (bio)catalysts that complement existing synthetic methods. However, the range of biotransformations used in laboratory is limited. Here we give an overview on biosynthesis‐inspired discovery novel biocatalysts address various challenges. Prominent examples from this dynamic field highlight remarkable enzymes for protecting‐group‐free amide formation and modification, control pericyclic reactions, stereoselective hetero‐ polycyclizations, atroposelective aryl couplings, site‐selective C−H activations, introduction ring strain, N−N bond formation. We also explore unusual functions cytochrome P450 monooxygenases, radical SAM‐dependent enzymes, flavoproteins, recruited primary metabolism, which offer opportunities biology, enzyme engineering, directed evolution, catalyst design.

Language: Английский

Citations

2
The chemistry of Formycin biosynthesis DOI Creative Commons
Nigel G. J. Richards, James H. Naismith

Frontiers in Chemical Biology, Journal Year: 2024, Volume and Issue: 3

Published: July 12, 2024

Remarkable progress has been made to elucidate the structural and mechanistic enzymology of biosynthetic pathways that give rise naturally occurring C-nucleosides. These compounds are generally cytotoxic exhibit interesting antiviral, antibiotic anti-parasitic activity. Here we review current knowledge concerning formycin biosynthesis highlight deficiencies in our understanding key chemical transformations pathway.

Language: Английский

Citations

0
Pyridazine and pyridazinone compounds in crops protection: a review DOI

Xining Ma,

Ping Sun, Jiaxin Wang

et al.

Molecular Diversity, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Language: Английский

Citations

0