Mechanisms of 2-oxoglutarate-dependent oxygenases: The hydroxylation paradigm and beyond

Joseph M. Bollinger, Jr., Wei Chen Chang, Megan L. Matthews, Ryan J. Martinie, Amie Kathleen Boal, Carsten Krebs

Research output: Chapter in Book/Report/Conference proceedingChapter

31 Citations (Scopus)

Abstract

In humans, Fe(ii)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenases are generally of the dioxygenase subclass and mediate hydroxylation of unactivated aliphatic carbon centres. Plants and microbes also employ Fe/2OG hydroxylases and, through investigations of the microbial enzymes, the mechanism of hydroxylation has been established to proceed via a potent high-spin (S = 2) Fe(iv)-oxo (ferryl) complex, which abstracts a hydrogen atom (H) from the substrate. Bacteria have further co-opted this central ferryl intermediate for a remarkable array of divergent reactivities, including olefin epoxidations, aliphatic halogenations, olefin-installing 1,2-dehydrogenations, oxacycle-installing 1,3- and 1,5-dehydrogenations, and a redox-neutral stereoinversion. An understanding of the mechanisms leading to this manifold of transformations, and the means by which the individual enzymes direct them, has potential to guide the design of new chemical catalysts and the development of novel bacterially- or chemo-enzymatically-derived drug compounds. In this chapter, we first summarize our understanding of hydroxylation reactions mediated by Fe/2OG hydroxylases and then review recent advances in the elucidation of two of the 'alternative' reactivities (halogenation and stereoinversion). Finally, we discuss the remaining, less well understood dehydrogenation reactions, highlighting possible problems with published mechanistic proposals, presenting alternatives to these published mechanisms, and briefly outlining experiments by which the operant mechanisms might be established.

Original languageEnglish (US)
Title of host publication2-Oxoglutarate-Dependent Oxygenases
EditorsRobert P. Hausinger, Christopher J. Schofield
PublisherRoyal Society of Chemistry
Pages95-122
Number of pages28
Edition3
DOIs
StatePublished - Jan 1 2015

Publication series

NameRSC Metallobiology
Number3
Volume2015-January
ISSN (Print)2045-547X

Fingerprint

Oxygenases
Hydroxylation
Dehydrogenation
Halogenation
Alkenes
Mixed Function Oxygenases
Dioxygenases
Epoxidation
Enzymes
Oxidation-Reduction
Hydrogen
Bacteria
Carbon
Atoms
Catalysts
Substrates
Pharmaceutical Preparations
alpha-ketoglutaric acid
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

Bollinger, Jr., J. M., Chang, W. C., Matthews, M. L., Martinie, R. J., Boal, A. K., & Krebs, C. (2015). Mechanisms of 2-oxoglutarate-dependent oxygenases: The hydroxylation paradigm and beyond. In R. P. Hausinger, & C. J. Schofield (Eds.), 2-Oxoglutarate-Dependent Oxygenases (3 ed., pp. 95-122). (RSC Metallobiology; Vol. 2015-January, No. 3). Royal Society of Chemistry. https://doi.org/10.1039/9781782621959-00095
Bollinger, Jr., Joseph M. ; Chang, Wei Chen ; Matthews, Megan L. ; Martinie, Ryan J. ; Boal, Amie Kathleen ; Krebs, Carsten. / Mechanisms of 2-oxoglutarate-dependent oxygenases : The hydroxylation paradigm and beyond. 2-Oxoglutarate-Dependent Oxygenases. editor / Robert P. Hausinger ; Christopher J. Schofield. 3. ed. Royal Society of Chemistry, 2015. pp. 95-122 (RSC Metallobiology; 3).
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Bollinger, Jr., JM, Chang, WC, Matthews, ML, Martinie, RJ, Boal, AK & Krebs, C 2015, Mechanisms of 2-oxoglutarate-dependent oxygenases: The hydroxylation paradigm and beyond. in RP Hausinger & CJ Schofield (eds), 2-Oxoglutarate-Dependent Oxygenases. 3 edn, RSC Metallobiology, no. 3, vol. 2015-January, Royal Society of Chemistry, pp. 95-122. https://doi.org/10.1039/9781782621959-00095

Mechanisms of 2-oxoglutarate-dependent oxygenases : The hydroxylation paradigm and beyond. / Bollinger, Jr., Joseph M.; Chang, Wei Chen; Matthews, Megan L.; Martinie, Ryan J.; Boal, Amie Kathleen; Krebs, Carsten.

2-Oxoglutarate-Dependent Oxygenases. ed. / Robert P. Hausinger; Christopher J. Schofield. 3. ed. Royal Society of Chemistry, 2015. p. 95-122 (RSC Metallobiology; Vol. 2015-January, No. 3).

Research output: Chapter in Book/Report/Conference proceedingChapter

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AU - Krebs, Carsten

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N2 - In humans, Fe(ii)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenases are generally of the dioxygenase subclass and mediate hydroxylation of unactivated aliphatic carbon centres. Plants and microbes also employ Fe/2OG hydroxylases and, through investigations of the microbial enzymes, the mechanism of hydroxylation has been established to proceed via a potent high-spin (S = 2) Fe(iv)-oxo (ferryl) complex, which abstracts a hydrogen atom (H) from the substrate. Bacteria have further co-opted this central ferryl intermediate for a remarkable array of divergent reactivities, including olefin epoxidations, aliphatic halogenations, olefin-installing 1,2-dehydrogenations, oxacycle-installing 1,3- and 1,5-dehydrogenations, and a redox-neutral stereoinversion. An understanding of the mechanisms leading to this manifold of transformations, and the means by which the individual enzymes direct them, has potential to guide the design of new chemical catalysts and the development of novel bacterially- or chemo-enzymatically-derived drug compounds. In this chapter, we first summarize our understanding of hydroxylation reactions mediated by Fe/2OG hydroxylases and then review recent advances in the elucidation of two of the 'alternative' reactivities (halogenation and stereoinversion). Finally, we discuss the remaining, less well understood dehydrogenation reactions, highlighting possible problems with published mechanistic proposals, presenting alternatives to these published mechanisms, and briefly outlining experiments by which the operant mechanisms might be established.

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Bollinger, Jr. JM, Chang WC, Matthews ML, Martinie RJ, Boal AK, Krebs C. Mechanisms of 2-oxoglutarate-dependent oxygenases: The hydroxylation paradigm and beyond. In Hausinger RP, Schofield CJ, editors, 2-Oxoglutarate-Dependent Oxygenases. 3 ed. Royal Society of Chemistry. 2015. p. 95-122. (RSC Metallobiology; 3). https://doi.org/10.1039/9781782621959-00095