The Enzymology of Clavam and Carbapenem Biosynthesis

Kershaw, Nadia J.; Caines, M.E.C.; Sleeman, Mark C.; Schofield, Christopher J.

doi:10.1002/chin.200601271

Cited by 13 publications

(30 citation statements)

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“…The αKG-dependent oxygenases are the largest and functionally most diverse subgroup of mononuclear non-heme-iron enzymes. 3 They catalyze many important reactions, including steps in the biosyntheses of antibiotics 17 and collagen, 18 the sensing of oxygen, [19][20][21][22][23] the repair of akylated DNA, 24,25 and the regulation of transcription by demethylation of histones. [26][27][28] A chemical mechanism was initially proposed more than 20 years ago by Hanauske-Abel and Günzler specifically for the enzyme prolyl-4-hydroxylase (P4H), 29 but its success in accommodating ensuing experimental data for many other αKG-dependent hydroxlases led to its becoming adopted as a consensus mechanism for the sub-family (Scheme 2).…”

Section: The First Non-heme Fe(iv)-oxo Intermediatementioning

confidence: 99%

“…17 Isopenicillin N synthase (IPNS) is one of the more well-understood mononuclear non-heme-iron enzyme due to the extensive studies by Baldwin and co-workers. IPNS catalyzes the four electron oxidation of δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) tripeptide to isopenicillin N. 51 Elegant biochemical and crystallographic studies provided convincing evidence that the reaction proceeds via two successive two-electron oxidations (Scheme 6).…”

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

“…It has been proposed that a different mode of reactivity of the Fe(III)-OH/substrate radical state yields the second and third reactions. 17,66 For the dehydrogenation reaction, the Fe(III)-OH intermediate could abstract a second H-atom from the substrate radical, yielding a hexacoordinate Fe(II)-OH 2 complex and the olefinic product. 67 Similarly, the cyclization reaction could proceed by successive H-atom abstractions by the Fe(IV)-oxo and Fe(III)-OH intermediates (the latter from the hydroxyl group of the substrate) and a radical coupling step.…”

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

“…76 The Fe(III)-OH intermediate may serve as the source of the hydrogen atom to form the (3S, 5R)-carbapenam-3-carboxylate intermediate and regenerate the Fe(IV)-oxo complex. 17 The Fe(IV)-oxo intermediate may then abstract the H-atom from C3, forming a stabilized, captodative C3 radical. Subsequent desaturation across the C2-C3 linkage via Hatom abstraction from C2 by the Fe(III)-OH species would be directly analogous to the mechanisms proposed for DAOCS and CAS.…”

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

“…Subsequent desaturation across the C2-C3 linkage via Hatom abstraction from C2 by the Fe(III)-OH species would be directly analogous to the mechanisms proposed for DAOCS and CAS. 17 …”

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

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Non‐Heme Fe(IV)—Oxo Intermediates

et al. 2007

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High-valent non-heme iron-oxo intermediates have been proposed for decades as the key intermediates in numerous biological oxidation reactions. In the last three years, the first direct characterization of such intermediates has been provided by studies of several αKG-dependent oxygenases that catalyze either hydroxylation or halogenation of their substrates. In each case, the Fe(IV)-oxo intermediate is implicated in cleavage of the aliphatic C-H bond to initiate hydroxylation or halogenation. The observation of non-heme Fe(IV)-oxo intermediates and Fe(II)-containing product(s) complexes with almost identical spectroscopic parameters in the reactions of two distantly related αKG-dependent hydroxylases suggests that members of this sub-family follow a conserved mechanism for substrate hydroxylation. In contrast, for the αKG-dependent non-heme-iron halogenase, CytC3, two distinct Fe(IV) complexes form and decay together, suggesting that they are in rapid equilibrium. The existence of two distinct conformers of the Fe site may be the key factor accounting for the divergence of the halogenase reaction from the more usual hydroxylation pathway after C-H cleavage. Distinct transformations catalyzed by other mononuclear non-heme enzymes are likely also to involve initial C-H-cleavage by Fe(IV)-oxo complexes, followed by diverging reactivities of the resulting Fe(III)-hydroxo/substrate radical intermediates.

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Section: The First Non-heme Fe(iv)-oxo Intermediatementioning

confidence: 99%

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

“…Subsequent desaturation across the C2-C3 linkage via Hatom abstraction from C2 by the Fe(III)-OH species would be directly analogous to the mechanisms proposed for DAOCS and CAS. 17 …”

Section: Mechanistic Diversity Of Presumptive Fe(iv)-oxo Intermediatementioning

confidence: 99%

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Non‐Heme Fe(IV)—Oxo Intermediates

et al. 2007

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Blends of thermotropic liquid crystalline polymer and O‐cresol formaldehyde epoxy resin. II. Curing kinetics

Tan

Huang

Liu

et al. 2005

J of Applied Polymer Sci

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Curing kinetics of O-cresol formaldehyde epoxy resin and its blends with a liquid crystalline block copolymer (PDBH) cured with linear phenol-formaldehyde resin were studied by the nonisothermal differential scanning calorimetry (DSC) and isothermal DSC methods. The parameters of nonisothemal curing kinetics were obtained according to the Kissinger method, and those of isothermal curing kinetics were deduced on the basis of the n-order mechanism proposed by Kamal. The curing reaction is considered 1-order reaction as shown by the nonisothermal and isothermal results. The model gave a good description of curing kinetics up to the onset of vitrification. A diffusion factor has been introduced in the latter stage of reaction to describe the degree of conversion over the whole range. The obtained n-order model modified by diffusion-controlled factor is consistent with the experimental data almost over the whole range of conversion.

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Freeze-quench 57Fe-Mössbauer spectroscopy: trapping reactive intermediates

Krebs

Bollinger

2009

Photosynth Res

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(57)Fe-Mössbauer spectroscopy is a method that probes transitions between the nuclear ground state (I=1/2) and the first nuclear excited state (I=3/2). This technique provides detailed information about the chemical environment and electronic structure of iron. Therefore, it has played an important role in studies of the numerous iron-containing proteins and enzymes. In conjunction with the freeze-quench method, (57)Fe-Mössbauer spectroscopy allows for monitoring changes of the iron site(s) during a biochemical reaction. This approach is particularly powerful for detection and characterization of reactive intermediates. Comparison of experimentally determined Mössbauer parameters to those predicted by density functional theory for hypothetical model structures can then provide detailed insight into the structures of reactive intermediates. We have recently used this methodology to study the reactions of various mononuclear non-heme-iron enzymes by trapping and characterizing several Fe(IV)-oxo reaction intermediates. In this article, we summarize these findings and demonstrate the potential of the method.

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The Enzymology of Clavam and Carbapenem Biosynthesis

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 13 publications

References 1 publication

Non‐Heme Fe(IV)—Oxo Intermediates

Non‐Heme Fe(IV)—Oxo Intermediates

Blends of thermotropic liquid crystalline polymer and O‐cresol formaldehyde epoxy resin. II. Curing kinetics

Freeze-quench 57Fe-Mössbauer spectroscopy: trapping reactive intermediates

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