A Pericyclic Reaction Cascade in Leporin Biosynthesis

Glöckle, Anna; Gulder, Tobias A. M.

doi:10.1002/anie.201800629

Cited by 10 publications

(6 citation statements)

References 25 publications

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“…On the other hand, LepI significantly changes the product distribution in favor of leporin C, thus minimizing the production of the four other isomers. Because the biosynthesis of the undesirable IMDA product cannot be suppressed completely, LepI catalyzes an additional retro‐Claisen rearrangement to convert the respective spiro‐isomer to the desired product, leporin C (Ohashi et al., 2017; Glockle & Gulder, 2018; Cai et al., 2019; Figure 13b). LepI appears to be a unique pericyclase, the first enzyme ever discovered in nature possessing a retro‐Claisen activity.…”

Section: Aspergillus Flavus Linkmentioning

confidence: 99%

Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review

Uka

Cary

Lebar

et al. 2020

Comp Rev Food Sci Food Safe

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Filamentous fungi represent a rich source of extrolites, including secondary metabolites (SMs) comprising a great variety of astonishing structures and interesting bioactivities. State-of-the-art techniques in genome mining, genetic manipulation, and secondary metabolomics have enabled the scientific community to better elucidate and more deeply appreciate the genetic and biosynthetic chemical arsenal of these microorganisms. Aspergillus flavus is best known as a contaminant of food and feed commodities and a producer of the carcinogenic family of SMs, aflatoxins. This fungus produces many SMs including polyketides, ribosomal and nonribosomal peptides, terpenoids, and other hybrid molecules. This review will discuss the chemical diversity, biosynthetic pathways, and biological/ecological role of A. flavus SMs, as well as their significance concerning food safety and security.

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Section: Aspergillus Flavus Linkmentioning

confidence: 99%

Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review

Uka

Cary

Lebar

et al. 2020

Comp Rev Food Sci Food Safe

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“…Computational analysis of their mechanisms suggests both enzymes catalyse reactions across an energy landscape featuring multiple possible mechanisms and ‘ambimodal’ transition states, in which the reaction trajectory bifurcates to two different products. However, in both cases, a single product is ultimately preferred—a phenomenon compellingly referred to as a case of “all roads lead to Rome” …”

Section: Controlling Reaction Trajectoriesmentioning

confidence: 99%

“…However,i nb othc ases,a single product is ultimately preferred-a phenomenon compellingly referredt oasac ase of "all roads lead to Rome". [59] 6.1. Spinosyn Abioynthesis SpnF,f rom spinosyn Ab iosynthesis (Scheme 4A), catalyses a transannular [4+ +2] cycloaddition, contributing ar ate enhancement of approximately 500-fold (k cat = 14 min À1 vs. k non = 0.03 min À1 ).…”

Section: Controlling Reaction Trajectoriesmentioning

confidence: 99%

Biocatalytic Strategies towards [4+2] Cycloadditions

Lichman

O’Connor

Kries

2019

Chemistry A European J

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Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understanding are underway by means of crystallography and computational modelling. This Minireview aims to shed light on the catalytic strategies that this highly diverse family of enzymes employs to accelerate and direct the course of [4+2] cycloadditions with reference to small‐molecule catalysts and designer enzymes. These catalytic strategies include oxidative or reductive triggers and lid‐like movements of enzyme domains. A precise understanding of natural cycloaddition catalysts will be instrumental for customizing them for various synthetic applications.

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“…22 LepI is considered as a SAM-dependent methyltransferase that can catalyze stereoselective dehydration via three pericyclic transformational processes: intramolecular Diels-Alder and hetero-Diels-Alder reactions and a retro-Claisen rearrangement. 22,24 The detailed mechanisms of SAM-dependent enzymatic actions are well understood, 25,26 whereas the mechanism underlying LepIcatalyzed pericyclic reactions remains unclear. 22,24 This study aimed to investigate the mechanism of LepI action.…”

Section: Introductionmentioning

confidence: 99%

“…22,24 The detailed mechanisms of SAM-dependent enzymatic actions are well understood, 25,26 whereas the mechanism underlying LepIcatalyzed pericyclic reactions remains unclear. 22,24 This study aimed to investigate the mechanism of LepI action. Herein, a series of structures, including those of SAM/5′-deoxy-5′-(methylthio) adenosine (MTA)-bound LepI, S-adenosyl-homocysteine (SAH)-bound LepI, and SAM/substrate-bound LepI, and various biochemical analyses helped elucidate the mechanisms underlying LepI activation and catalysis.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme

Sun

et al. 2019

Sig Transduct Target Ther

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S-adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5′-deoxy-5′-(methylthio) adenosine (MTA), Sadenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.

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A Pericyclic Reaction Cascade in Leporin Biosynthesis

Cited by 10 publications

References 25 publications

Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review

Chemical repertoire and biosynthetic machinery of the Aspergillus flavus secondary metabolome: A review

Biocatalytic Strategies towards [4+2] Cycloadditions

Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme

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