Discovery of the Lanthipeptide Curvocidin and Structural Insights into its Trifunctional Synthetase CuvL

Sigurdsson, Arnar; Martins, Berta M.; Düttmann, Simon A.; Jasyk, Martin; Dimos-Röhl, Benjamin; Schöpf, Felix; Gemander, Manuel; Knittel, Caroline H.; Schnegotzki, Romina; Schmid, Bianca; Kosol, Simone; Pommerening, Lea; González-Viegas, María; Seidel, Maria; Hügelland, Manuela; Leimkühler, Silke; Dobbek, Holger; Mainz, Andi

doi:10.1002/anie.202302490

Cited by 4 publications

(1 citation statement)

References 49 publications

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“…Critical conserved residues within the kinase domain of multiple LanKC or LanL enzymes have been identified. As exemplified by the kinase domain in CuvL, [21] residues Asn354 and Asp368 coordinate Mg 2+ , while Asp349 acts as a catalytic base to abstract the hydroxyl proton from the Ser/Thr residues (Figure 3D). The catalytic center of the lyase domain in LanKC and LanL exhibits structural homology with microbial pSer/pThr lyases such as SpvC or OspF.…”

Section: Enzymatic Formation Of Dha/dhb Residuesmentioning

confidence: 99%

Enzymatic Formation of an Aminovinyl Cysteine Residue in Ribosomal Peptide Natural Products

Cheng,

Xue,

Duan

et al. 2024

ChemPlusChem

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The carboxyl‐terminal (C‐terminal) S‐[(Z)‐2‐aminovinyl]‐cysteine (AviCys) analogs have been identified in four families of ribosomally synthesized and post‐translationally modified peptides (RiPPs): lanthipeptides, linaridins, thioamitides, and lipolanthines. Within identified biosynthetic pathways, a highly reactive enethiol intermediate, formed through an oxidative decarboxylation catalyzed by a LanD‐like flavoprotein, can undergo two types of cyclization: a Michael addition with a dehydroamino acid or a coupling reaction initiated by a radical species. The collaborative actions of LanD‐like proteins with diverse enzymes involved in dehydration, dethiolation or cyclization lead to the construction of structurally distinct peptide natural products with analogous C‐terminal macrocyclic moieties. This concept summarizes existing knowledge regarding biosynthetic pathways of AviCys analogs to emphasize the diversity of biosynthetic mechanisms that paves the way for future genome mining explorations into diverse peptide natural products.

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Section: Enzymatic Formation Of Dha/dhb Residuesmentioning

confidence: 99%

Enzymatic Formation of an Aminovinyl Cysteine Residue in Ribosomal Peptide Natural Products

Cheng,

Xue,

Duan

et al. 2024

ChemPlusChem

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Mechanistic Investigations into the Catalytic Mode of a Dehydratase Complex Involved in the Biosynthesis of Lantibiotic Cacaoidin

Xue,

Li,

et al. 2023

Chin. J. Chem.

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Comprehensive SummaryDehydration of serine/threonine residues necessitates the activity of a dehydratase enzyme (domain) during the biosynthesis of RiPP. Recently, it was reported that dehydrations in the thioviridamide pathway relies on a distinct dehydratase complex which showcases the activities of a phosphotransferase TvaC for serine/threonine phosphorylation and a lyase TvaD for subsequent phosphate elimination. Herein, we report that dehydration reactions in the pathway of lantibiotic cacaoidin involves a similar dehydratase complex, CaoK/CaoY. Remarkably, this dehydratase complex exhibits flexible enzymatic activity and tolerates significant variations in its substrate peptide sequence. By binding with the leader peptide (LP) sequence of precursor peptide CaoA, the dehydration reactions proceed directionality from the C‐terminus of the core peptide (CP) to its N‐terminus, and C‐terminally truncated variants of CP are acceptable. We show that fusing CaoK to CaoY in a 1:1 molar ratio enables the resulting enzyme CaoYK to exert enhanced dehydration activity. CaoK binds with the LP to improve its own solubility and to ensure the phosphate transfer activity, while CaoY functions in a manner independently of LP. This work advances our understanding of the dehydration process during cacaoidin formation, and provides useful enzymes and methods for the studies of the rapidly emerging RiPPs.This article is protected by copyright. All rights reserved.

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Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers

Li,

Shao,

et al. 2024

Nat Commun

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Naturally occurring lanthipeptides, peptides post-translationally modified by various enzymes, hold significant promise as antibiotics. Despite extensive biochemical and structural studies, the events preceding peptide modification remain poorly understood. Here, we identify a distinct subclass of lanthionine synthetase KC (LanKC) enzymes with distinct structural and functional characteristics. We show that PneKC, a member of this subclass, forms a dimer and possesses GTPase activity. Through three cryo-EM structures of PneKC, we illustrate different stages of peptide PneA binding, from initial recognition to full binding. Our structures show the kinase domain complexed with the PneA core peptide and GTPγS, a phosphate-bound lyase domain, and an unconventional cyclase domain. The leader peptide of PneA interact with a gate loop, transitioning from an extended to a helical conformation. We identify a dimerization hot spot and propose a “negative cooperativity” mechanism toggling the enzyme between tense and relaxed conformation. Additionally, we identify an important salt bridge in the cyclase domain, differing from those in in conventional cyclase domains. These residues are highly conserved in the LanKC subclass and are part of two signature motifs. These results unveil potential differences in lanthipeptide modification enzymes assembly and deepen our understanding of allostery in these multifunctional enzymes.

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Discovery of the Lanthipeptide Curvocidin and Structural Insights into its Trifunctional Synthetase CuvL

Cited by 4 publications

References 49 publications

Enzymatic Formation of an Aminovinyl Cysteine Residue in Ribosomal Peptide Natural Products

Enzymatic Formation of an Aminovinyl Cysteine Residue in Ribosomal Peptide Natural Products

Mechanistic Investigations into the Catalytic Mode of a Dehydratase Complex Involved in the Biosynthesis of Lantibiotic Cacaoidin

Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers

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