Probing the selectivity of β-hydroxylation reactions in non-ribosomal peptide synthesis using analytical ultracentrifugation

Kokona, Bashkim; Winesett, Emily S.; Krusenstiern, A. Nikolai von; Cryle, Max J.; Fairman, Robert; Charkoudian, Louise K.

doi:10.1016/j.ab.2015.11.011

Cited by 12 publications

(26 citation statements)

References 38 publications

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“…Structures of holo‐PCPs in multidomain environments revealed that Ppant arm loading strengthens domain interactions 24, 26, 36. This appears to be especially crucial for PCP interactions in trans, for example with P450 enzymes 11, 12…”

Section: Pcp Domain Interactions With Nrps Catalytic Domainsmentioning

confidence: 99%

“…Further diversity can be achieved through additional cis domains, such as formylation, oxidation, and methylation domains,3 or through interaction with enzymes that act in trans to the main NRPS machinery 11, 12, 13. In both cases, these interactions occur on PCP‐bound substrates, with PCP domains playing a major role in the recruitment of enzymes in trans 11, 12, 13.…”

Section: Nrps Assembly Linesmentioning

confidence: 99%

“…[3] Further diversity can be achieved through additional cis domains,s uch as formylation, oxidation, and methylation domains, [3] or through interaction with enzymes that act in trans to the main NRPS machinery. [11][12][13] In both cases,these interactions occur on PCP-bound substrates,with PCP domains playing am ajor role in the recruitment of enzymes in trans. [11][12][13] An exception to PCP-driven recruitment is the Xdomain (an additional C/E-type domain) from glycopeptide antibiotic biosynthesis,w hich is required to recruit cytochrome P450s to the PCP-bound substrate to perform crosslinking of aromatic side chains.…”

Section: Nrps Assembly Linesmentioning

confidence: 99%

“…[11][12][13] In both cases,these interactions occur on PCP-bound substrates,with PCP domains playing am ajor role in the recruitment of enzymes in trans. [11][12][13] An exception to PCP-driven recruitment is the Xdomain (an additional C/E-type domain) from glycopeptide antibiotic biosynthesis,w hich is required to recruit cytochrome P450s to the PCP-bound substrate to perform crosslinking of aromatic side chains. [14,15] Diversification of "standard" domain chemistry is also increasingly being observed in NRPS assembly lines:r ecent discoveries include b-lactam formation, [16] and TE-catalyzed epimerization [17] in norcardicin biosynthesis,a nd transesterification in salinamide biosynthesis.…”

Section: Nrps Assembly Linesmentioning

confidence: 99%

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New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis

et al. 2016

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The nonribosomal peptide synthetases (NRPSs) are one of the most promising resources for the production of new bioactive molecules. The mechanism of NRPS catalysis is based around sequential catalytic domains: these are organized into modules, where each module selects, modifies, and incorporates an amino acid into the growing peptide. The intermediates formed during NRPS catalysis are delivered between enzyme centers by peptidyl carrier protein (PCP) domains, which makes PCP interactions and movements crucial to NRPS mechanism. PCP movement has been linked to the domain alternation cycle of adenylation (A) domains, and recent complete NRPS module structures provide support for this hypothesis. However, it appears as though the A domain alternation alone is insufficient to account for the complete NRPS catalytic cycle and that the loaded state of the PCP must also play a role in choreographing catalysis in these complex and fascinating molecular machines.

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Section: Pcp Domain Interactions With Nrps Catalytic Domainsmentioning

confidence: 99%

Section: Nrps Assembly Linesmentioning

confidence: 99%

Section: Nrps Assembly Linesmentioning

confidence: 99%

Section: Nrps Assembly Linesmentioning

confidence: 99%

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New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis

et al. 2016

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“…[234][235][236] A further example of this amino acid hydroxylation strategy has been identied in telomycin biosynthesis, in which the P450 enzyme Tem23 hydroxylates the Leu-10 residue during NRPS-mediated biosynthesis of the peptide. 237 A related strategy to this has also been invoked in hydroxylation of a PCP-bound threonine residue during actinomycin G biosynthesis, although in this case it appears as though there is a relationship between the P450 (AcmG8) and a halogenase that modies the same position (AcmG9) that needs further clarication.…”

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confidence: 99%

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

et al. 2018

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The cytochromes P450 (P450s) are a superfamily of heme-containing monooxygenases that perform diverse catalytic roles in many species, including bacteria. The P450 superfamily is widely known for the hydroxylation of unactivated C-H bonds, but the diversity of reactions that P450s can perform vastly exceeds this undoubtedly impressive chemical transformation. Within bacteria, P450s play important roles in many biosynthetic and biodegradative processes that span a wide range of secondary metabolite pathways and present diverse chemical transformations. In this review, we aim to provide an overview of the range of chemical transformations that P450 enzymes can catalyse within bacterial secondary metabolism, with the intention to provide an important resource to aid in understanding of the potential roles of P450 enzymes within newly identified bacterial biosynthetic pathways. 1.Introduction to P450s 2.Chemistry of P450 enzymes 3.Bacterial biosynthesis pathways involving P450s 3.1Terpene metabolism 3.1. Battersby (1925Battersby ( -2018 to the molecular understanding of biosynthesis over the course of their careers.

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Neue Strukturdaten geben Einblick in die Bewegungen von Transportproteinen in der nicht‐ribosomalen Peptidsynthese

et al. 2016

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Mohamed Marahiel gewidmetBiosynthese ·Enzyme ·Nicht-ribosomale Peptidsynthetasen ·Peptidyl-Transportprotein ·P roteinstrukturen 1. Strukturelle und biologische Diversität nicht-ribosomaler Peptide Sekundärmetabolite weisen eine große Vielfalt an medizinisch bedeutsamen Aktivitäten auf.S ie wirken beispielsweise krebshemmend (Bleomycin), antibiotisch (Vancomy-cin), antimykotisch (Echinocandin) oder immunsuppressiv (Ciclosporin; Abbildung 1A). [1] Nicht-ribosomale Peptide (NRPs) stellen eine besonders reichhaltige Quelle an antimikrobiellen Wirkstoffen dar [2] und werden unabhängig vom Ribosom durch Enzym-Komplexe,d en sogenannten nichtribosomalen Peptidsynthetasen (NRPS), produziert. [3] Da dieser Vorgang nicht den Einschränkungen der ribosombasierten Synthese unterliegt, kçnnen NRPs aus weit mehr Monomeren als dem Standardsatz proteinogener Aminosäuren gebildet werden:B is heute wurden mehr als 500 verschiedene Monomere in NRPs identifiziert. Dadurch bedingt sich die enorme strukturelle und biologische Vielfalt dieser Verbindungen. [4] Nicht-ribosomale Peptidsynthetasen (NRPS) gehçren zu den vielversprechendsten Ressourcen bei der Herstellung neuer biologisch aktiver Moleküle.D er Mechanismus der NRPS-Katalyse beruht auf sequentiell angeordneten katalytischen Domänen. Diese sind modular organisiert, wobei jedes Modul jeweils eine Aminosäure auswählt, modifiziert und in das wachsende Peptid einbaut. Die während der NRPS-Katalyse gebildeten Zwischenprodukte werden von Peptidyltransportprotein(PCP)-Domänen von einem Enzymzentrum zum nächsten weitergereicht. Daher sind die Wechselwirkungen und Bewegungen der PCPs von entscheidender Bedeutung für den NRPS-Mechanismus.PCP-Bewegungen wurden mit den alternierenden Zyklen der Adenylierungsdomänen (A-Domänen) in Zusammenhang gebracht,und kürzlichverçffentlichteStrukturen vollständiger NRPS-Module stützen diese Hypothese.E sscheint allerdings,d ass das Alternieren der A-Domänen allein nicht zur Beschreibung des vollständigen NRPS-Katalysezyklus ausreicht und dass der Beladungszustand des PCP für die Abfolge der Katalyseereignisse in diesen komplexen und faszinierenden molekularen Maschinen ebenfalls eine Rolle spielt.

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Probing the selectivity of β-hydroxylation reactions in non-ribosomal peptide synthesis using analytical ultracentrifugation

Cited by 12 publications

References 38 publications

New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis

New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

Neue Strukturdaten geben Einblick in die Bewegungen von Transportproteinen in der nicht‐ribosomalen Peptidsynthese

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