Mechanistic Studies on the Radical SAM Enzyme Tryptophan Lyase (NosL)

Bhandari, Dhananjay M; Fedoseyenko, Dmytro; Begley, Tadhg P.

doi:10.1016/bs.mie.2018.06.008

Cited by 17 publications

(18 citation statements)

References 29 publications

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“…8Ba). Unusually, NosL initiates this intricate transformation by abstracting an H-atom from the α-amino group, rather than a carbon centre [148][149][150][151] . The subsequent formation of the indolic side-ring system from MIA involves the action of a novel, discrete, indoyl thiolation protein that was previously unannotated (NosJ) and a unique α/β-hydrolase fold protein (NosK) that transfers the indoyl to a linear pentathiazolyl peptide intermediate Cys residue that remains selectively unmodified [152][153][154] (FIG.…”

Section: Radical Sam Enzymesmentioning

confidence: 99%

“…Colours are used to highlight new bonds formed and/or the fate of particular atoms following (rSAM) enzyme activity. 3-Methyl-2-indolic acid (MIA) is formed by the rearrangement of L-Trp catalysed by NosL and is subsequently introduced into the nosiheptide side-ring system by NosIJK [147][148][149][150][151][152][153][154] . These enzymes transfer the MIA moiety to an unmodified Cys residue in a linear pentathiazolyl nosiheptide intermediate.…”

Section: Signature Natural Product Biosynthetic Enzymologymentioning

confidence: 99%

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The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similaritybased bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed. Bacterial natural products (NPs) are specialized metabolites that encompass an extraordinary breadth of different biological activities, many of which are of considerable value to society. NPs or NP-inspired compounds represent ~65% of all small-molecule approved drugs 1 used in medicine to treat infectious diseases, cancers or as immunosuppressants 2 , and they are also applied extensively in agriculture 3. While NPs have been an extremely productive source of new leads for the chemicals that are integral to modern life, rapid increases in resistance to antibiotics, cancer chemotherapies and pesticides pose significant threats to medicine and agriculture 4,5 .

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Section: Radical Sam Enzymesmentioning

confidence: 99%

Section: Signature Natural Product Biosynthetic Enzymologymentioning

confidence: 99%

The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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“…[ 10 ] Although NosL also produce 3‐methylindole (MI, 7 ), [ 5 ] this compound is derived from the radical intermediate 6 , not a result of the Cα—Cβ fragmentation of 3 (Figure 1A). [ 10 ] X‐ray crystallography analysis combined with hybrid quantum mechanical (QM)/molecular mechanical (MM) calculations suggested that the enzyme active site has perfectly adapted for cleaving the Cα—COO – bond and preventing Cα—Cβ cleavage. [ 34 ] The fact that NosL is unable to cleave the Cα—Cβ bond of L ‐Trp is unexpected because the L ‐Tyr lyases ThiH and HydG are phylogenetically more closely‐related to NosL compared to other L ‐Tyr lyases such as CofG (Figure 1C).…”

Section: Background and Originality Contentmentioning

confidence: 99%

“…[ 6‐8 ] Production of MIA from L ‐Trp involves a highly unusual carbon skeleton rearrangement, in which the carboxylate of L ‐Trp migrates to the indole C2 and the Cα‐N unit is released as a cyanide. [ 9‐12 ]…”

Section: Background and Originality Contentmentioning

confidence: 99%

“…unable to cleave the Cα—Cβ bond (Figure 1A). [ 10 ] Although NosL also produce 3‐methylindole (MI, 7 ), [ 5 ] this compound is derived from the radical intermediate 6 , not a result of the Cα—Cβ fragmentation of 3 (Figure 1A). [ 10 ] X‐ray crystallography analysis combined with hybrid quantum mechanical (QM)/molecular mechanical (MM) calculations suggested that the enzyme active site has perfectly adapted for cleaving the Cα—COO – bond and preventing Cα—Cβ cleavage.…”

Section: Background and Originality Contentmentioning

confidence: 99%

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The Promiscuous Activity of the Radical SAM Enzyme NosL toward Two Unnatural Substrates

Yin

Zhang

2021

Chin. J. Chem.

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Main observation and conclusion The radical S‐adenosylmethionine (SAM) enzyme NosL catalyzes the conversion of L‐tryptophan (L‐Trp, 1) to 3‐methyl‐2‐indolic acid (MIA, 2), a key intermediate in the biosynthesis of the peptide antibiotic nosiheptide. Previous study showed that this remarkable recombination reaction starts from the cleavage of the Cα—COO– bond to result in a •CO2− radical migration. In contrast to the radical SAM tyrosine lyases, NosL appears unable to cleave the Cα—Cβ bond, which is intrinsically more favorable to be cleaved than the Cα—COO– bond. In this study, we investigate the NosL activity with tryptamine (11) and tryptophol (12), two L‐Trp analogues lacking a carboxylate moiety. We showed that NosL cleaves the C1—C2 bond of these two substrates to produce 3‐methylindole (7), suggesting that the enzyme can still catalyze a β‐scission when the carboxyl group of Trp is absent. We also showed the enzyme exhibits a promiscuous activity, initiating the reaction by abstracting hydrogen atoms from two different sites to produce two sets of products.

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Revisiting the Mechanism of the Anaerobic Coproporphyrinogen III Oxidase HemN

Liu

et al. 2019

Angewandte Chemie

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Mechanistic Studies on the Radical SAM Enzyme Tryptophan Lyase (NosL)

Cited by 17 publications

References 29 publications

The hidden enzymology of bacterial natural product biosynthesis

The hidden enzymology of bacterial natural product biosynthesis

The Promiscuous Activity of the Radical SAM Enzyme NosL toward Two Unnatural Substrates

Revisiting the Mechanism of the Anaerobic Coproporphyrinogen III Oxidase HemN

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