Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase

Hoffart, Lee M.; Barr, Eric W.; Guyer, Robert B.; Bollinger, J. Martin; Krebs, Carsten

doi:10.1073/pnas.0604005103

Cited by 299 publications

(393 citation statements)

References 54 publications

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“…Halogenation was shown to follow a similar mechanism to the Fe 2þ /αKG-dependent oxygenases (13). Following dioxygencatalyzed decarboxylation of αKG, a reactive O ¼ Fe 4þ intermediate abstracts a hydrogen atom from the C-H bond of the substrate, yielding a Fe 3þ -OH and a substrate radical (13,14). The substrate radical is halogenated by "rebound" of the chlorine atom, similar to rebound of hydroxyl in the Fe 2þ /αKG-dependent hydroxylases.…”

Section: Cryptic Chlorination | Natural Products | Polyketide Synthasesmentioning

confidence: 92%

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Khare¹,

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The CurA halogenase (Hal) catalyzes a cryptic chlorination leading to cyclopropane ring formation in the synthesis of the natural product curacin A. Hal belongs to a family of enzymes that use Fe 2þ , O 2 and α-ketoglutarate (αKG) to perform a variety of halogenation reactions in natural product biosynthesis. Crystal structures of the enzyme in five ligand states reveal strikingly different open and closed conformations dependent on αKG binding. The open form represents ligand-free enzyme, preventing substrate from entering the active site until both αKG and chloride are bound, while the closed form represents the holoenzyme with αKG and chloride coordinated to iron. Candidate amino acid residues involved in substrate recognition were identified by site-directed mutagenesis. These new structures provide direct evidence of a conformational switch driven by αKG leading to chlorination of an early pathway intermediate.cryptic chlorination | natural products | polyketide synthases

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Section: Cryptic Chlorination | Natural Products | Polyketide Synthasesmentioning

confidence: 92%

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Khare¹,

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Many inorganic and enzymatic reactions involving HAA exhibit a large primary kinetic isotope effect (KIE > ~10), such as KIE = 35 observed in NHFe taurine dioxygenase,[185] KIE = 60 in NHFe prolyl-4-hydroxylase, [ 186 ] that usually indicates significant tunneling effects on reaction dynamics.…”

Section: Kinetic Isotope Effectmentioning

confidence: 99%

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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In this minireview, we provide an account of the current state-of-the-art developments in the area of mono-and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represent a challenge for both experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems.After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods.

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“…Notably, the Fe(IV)=O species has been trapped and characterized by spectroscopic methods for taurine 2-oxoglutarate dioxygenase and two other α-ketoacid dependent enzymes. [24][25][26] With respect to the hydroxylation reactions, for HPPD it was proposed that electrophilic attack on the aromatic ring of HPA leads to a high-spin Fe(III)/ring radical σ-complex. 8,9,14 The subsequent migration of the acetic acid side chain was found to proceed in two steps:…”

Section: Hmsmentioning

confidence: 99%

Role of Substrate Positioning in the Catalytic Reaction of 4-Hydroxyphenylpyruvate Dioxygenase—A QM/MM Study

et al. 2014

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Ring hydroxylation and coupled rearrangement reactions catalyzed by 4-hydroxyphenylpyruvate dioxygenase were studied with the QM/MM method ONIOM(B3LYP:AMBER). For electrophilic attack of the ferryl species on the aromatic ring, five channels were considered: attacks on the three ring atoms closest to the oxo ligand (C1, C2, C6) and insertion of oxygen across two bonds formed by them (C1-C2, C1-C6). For the subsequent migration of the carboxymethyl substituent, two possible directions were tested (C1→C2, C1→C6) and two different mechanisms were sought (step-wise radical, single-step heterolytic). In addition, formation of an epoxide (side)product and benzylic hydroxylation, as catalyzed by the closely related hydroxymandelate synthase, were investigated. From the computed reaction free energy profiles it follows that the most likely mechanism of 4-hydroxyphenylpyruvate dioxygenase involves electrophilic attack on the C1 carbon of the ring and subsequent singlestep heterolytic migration of the substituent. Computed values of the kinetic isotope effect for this step are inverse, consistent with available experimental data. Electronic structure arguments for the preferred mechanism of attack on the ring are also presented.

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Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase

Cited by 299 publications

References 54 publications

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Role of Substrate Positioning in the Catalytic Reaction of 4-Hydroxyphenylpyruvate Dioxygenase—A QM/MM Study

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