ArticleJournal of the American Chemical Society2016
Spectroscopic Evidence for the Two C-H-Cleaving Intermediates of Aspergillus nidulans Isopenicillin N Synthase.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed.
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- Electronic Structure Contributions to the Reactivity of Mononuclear FeAccounts of chemical research · 2026Article
- Enzymatic Synthesis of β-lactam Antibiotics: From Enzyme Dataset Construction to Action Mechanism and Semi-Rational Design.Current protein & peptide science · 2026Review
- Heme Oxygenase-Like Metalloenzymes.Annual review of biochemistry · 2025Review
- Mechanism of OACS central science · 2025Article
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- New Frontiers in Nonheme Enzymatic Oxyferryl Species.Chembiochem : a European journal of chemical biology · 2024Review
- Exploring the influence of H-bonding and ligand constraints on thiolate ligated non-heme iron mediated dioxygen activation.Chemical science · 2024Article
- An Unusual Ferryl Intermediate and Its Implications for the Mechanism of Oxacyclization by the Loline-Producing Iron(II)- and 2-Oxoglutarate-Dependent Oxygenase, LolO.Biochemistry · 2024Article
- Multinuclear non-heme iron dependent oxidative enzymes (MNIOs) involved in unusual peptide modifications.Current opinion in chemical biology · 2024Review
- Unusual cysteine modifications in natural product biosynthesis.RSC chemical biology · 2024Review
- A Nonheme Iron(III) Superoxide Complex Leads to Sulfur Oxygenation.Journal of the American Chemical Society · 2024Article
- Selective Radical Transfer in a Series of Nonheme Iron(III) Complexes.Inorganic chemistry · 2023Article
- An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C-S Bond Formation.Angewandte Chemie (International ed. in English) · 2023Article
- Structures of the holoenzyme TglHI required for 3-thiaglutamate biosynthesis.Structure (London, England : 1993) · 2023Article
- Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692.ACS central science · 2023Article
- Oxygen versus Sulfur Coordination in Cobalt Superoxo Complexes: Spectroscopic Properties, OInorganic chemistry · 2023Article
- Article
- Electronic Structure and Reactivity of Dioxygen-Derived Aliphatic Thiolate-Ligated Fe-Peroxo and Fe(IV) Oxo Compounds.Journal of the American Chemical Society · 2022Article
14 more citing papers are in PubMed but not listed here.
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11 authors.
Funding
Abstract
The enzyme isopenicillin N synthase (IPNS) installs the β-lactam and thiazolidine rings of the penicillin core into the linear tripeptide l-δ-aminoadipoyl-l-Cys-d-Val (ACV) on the pathways to a number of important antibacterial drugs. A classic set of enzymological and crystallographic studies by Baldwin and co-workers established that this overall four-electron oxidation occurs by a sequence of two oxidative cyclizations, with the β-lactam ring being installed first and the thiazolidine ring second. Each phase requires cleavage of an aliphatic C-H bond of the substrate: the pro-S-CCys,β-H bond for closure of the β-lactam ring, and the CVal,β-H bond for installation of the thiazolidine ring. IPNS uses a mononuclear non-heme-iron(II) cofactor and dioxygen as cosubstrate to cleave these C-H bonds and direct the ring closures. Despite the intense scrutiny to which the enzyme has been subjected, the identities of the oxidized iron intermediates that cleave the C-H bonds have been addressed only computationally; no experimental insight into their geometric or electronic structures has been reported. In this work, we have employed a combination of transient-state-kinetic and spectroscopic methods, together with the specifically deuterium-labeled substrates, A[d2-C]V and AC[d8-V], to identify both C-H-cleaving intermediates. The results show that they are high-spin Fe(III)-superoxo and high-spin Fe(IV)-oxo complexes, respectively, in agreement with published mechanistic proposals derived computationally from Baldwin's founding work.
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