Characterization of SfmD as a Heme Peroxidase That Catalyzes the Regioselective Hydroxylation of 3-Methyltyrosine to 3-Hydroxy-5-methyltyrosine in Saframycin A Biosynthesis

Tang, Man-Cheng; Fu, Cheng-Yu; Tang, Gong‐Li

doi:10.1074/jbc.m111.306316

Cited by 33 publications

(33 citation statements)

References 39 publications

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“…We have been interested in the biosynthesis of these natural products for several years (16,(22)(23)(24). Recently, comparative analysis of the NDM gene cluster in S. lusitanus NRRL 8034 and the QNC gene cluster in S. melanovinaceus NRRL 12388 revealed a three-gene cassette in each, napB-napC-napD and qncN-qncM-qncL, with significant overall identify to each other ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line

Peng

Song

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Nonribosomal peptide synthetases (NRPSs) usually catalyze the biosynthesis of peptide natural products by sequential selection, activation, and condensation of amino acid precursors. It was reported that some fatty acids, α-ketoacids, and α-hydroxyacids originating from amino acid metabolism as well as polyketide-derived units can also be used by NRPS assembly lines as an alternative to amino acids. Ecteinascidin 743 (ET-743), naphthyridinomycin (NDM), and quinocarcin (QNC) are three important antitumor natural products belonging to the tetrahydroisoquinoline family. Although ET-743 has been approved as an anticancer drug, the origin of an identical two-carbon (C 2 ) fragment among these three antibiotics has not been elucidated despite much effort in the biosynthetic research in the past 30 y. Here we report that two unexpected two-component transketolases (TKases), NapB/NapD in the NDM biosynthetic pathway and QncN/QncL in QNC biosynthesis, catalyze the transfer of a glycolaldehyde unit from ketose to the lipoyl group to yield the glycolicacyl lipoic acid intermediate and then transfer the C 2 unit to an acyl carrier protein (ACP) to form glycolicacyl-S-ACP as an extender unit for NRPS. Our results demonstrate a unique NRPS extender unit directly derived from ketose phosphates through (α,β-dihydroxyethyl)-thiamin diphosphate and a lipoyl group-tethered ester intermediate catalyzed by the TKase-ACP platform in the context of NDM and QNC biosynthesis, all of which also highlights the biosynthesis of ET-743. This hybrid system and precursor are distinct from the previously described universal modes involving the NRPS machinery. They exemplify an alternate strategy in hybrid NRPS biochemistry and enrich the diversity of precursors for NRPS combinatorial biosynthesis.primary metabolism | secondary metabolism | xylulose-5-phosphate | fructose-6-phosphate

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Section: Resultsmentioning

confidence: 99%

Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line

Peng

Song

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possibly responsible for producing 3-OH-5-Me-Tyr from 3-Me-Tyr. This has significance for the biosynthesis of tetrahydroisoquinoline family members [40]. Another hemeprotein is wild-type Rhodothermus marinus (Rma) cytochrome c. The variant, Rma cytochrome c TQL, transforms alkenes to chiral 1,2-amino alcohols via direct amino-hydroxylation.…”

Section: Enzymes Applied For Oxidationmentioning

confidence: 99%

Application of Enzymes in Regioselective and Stereoselective Organic Reactions

Wang

Wamsley

et al. 2020

Catalysts

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Nowadays, biocatalysts have received much more attention in chemistry regarding their potential to enable high efficiency, high yield, and eco-friendly processes for a myriad of applications. Nature’s vast repository of catalysts has inspired synthetic chemists. Furthermore, the revolutionary technologies in bioengineering have provided the fast discovery and evolution of enzymes that empower chemical synthesis. This article attempts to deliver a comprehensive overview of the last two decades of investigation into enzymatic reactions and highlights the effective performance progress of bio-enzymes exploited in organic synthesis. Based on the types of enzymatic reactions and enzyme commission (E.C.) numbers, the enzymes discussed in the article are classified into oxidoreductases, transferases, hydrolases, and lyases. These applications should provide us with some insight into enzyme design strategies and molecular mechanisms.

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“…SfmD was characterized as a heme containing peroxidase which regioselectivly hydroxylates 3-methyltyrosine to 3-hydroxy-5-methyltyrosine ( 11 ) in the biosynthesis of saframycin A, using H 2 O 2 as oxidant [30]. SgcC is a monooxygenase involved in the biosynthesis of the antitumor enediyne C-1207 and was shown to catalyze the hydroxylation of β-Tyr in a T-domain dependent fashion [31].…”

Section: Pre-assembly Modification In Nonribosomal Peptide Biosynthesismentioning

confidence: 99%

Complexity generation during natural product biosynthesis using redox enzymes

Wang

Gao

Tang

2012

Current Opinion in Chemical Biology

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Redox enzymes such as FAD-dependent and cytochrome P450 oxygenases play indispensible roles in generating structural complexity during natural product biosynthesis. In the pre-assembly steps, redox enzymes can convert garden variety primary metabolites into unique starter and extender building blocks. In the post-assembly tailoring steps, redox cascades can transform nascent scaffolds into structurally complex final products. In this review, we will discuss several recently characterized redox enzymes in the biosynthesis of polyketides and nonribosomal peptides.

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Characterization of SfmD as a Heme Peroxidase That Catalyzes the Regioselective Hydroxylation of 3-Methyltyrosine to 3-Hydroxy-5-methyltyrosine in Saframycin A Biosynthesis

Cited by 33 publications

References 39 publications

Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line

Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line

Application of Enzymes in Regioselective and Stereoselective Organic Reactions

Complexity generation during natural product biosynthesis using redox enzymes

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