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

J. Martin Bollinger, Wei Chen Chang, Megan L. Matthews, Ryan J. Martinie, Amie K. Boal, Carsten Krebs

Research output: Chapter in Book/Report/Conference proceedingChapter

45 Scopus citations

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 - 2015

Publication series

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

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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