Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions

Abstract

Many oxidation-reduction (redox) enzymes, particularly oxygenases, have roles in reactions that make and break C-C bonds. The list includes cytochrome P450 and other heme-based monooxygenases, heme-based dioxygenases, nonheme iron mono- and dioxygenases, flavoproteins, radical S-adenosylmethionine enzymes, copper enzymes, and peroxidases. Reactions involve steroids, intermediary metabolism, secondary natural products, drugs, and industrial and agricultural chemicals. Many C-C bonds are formed via either (i) coupling of diradicals or (ii) generation of unstable products that rearrange. C-C cleavage reactions involve several themes: (i) rearrangement of unstable oxidized products produced by the enzymes, (ii) oxidation and collapse of radicals or cations via rearrangement, (iii) oxygenation to yield products that are readily hydrolyzed by other enzymes, and (iv) activation of O in systems in which the binding of a substrate facilitates O activation. Many of the enzymes involve metals, but of these, iron is clearly predominant.

Selective C H bond functionalization with engineered heme proteins: new tools to generate complexity

“…Cytochromes P450 are nature's most prevalent catalysts for C-H functionalization [9]. Enzymes of this vast family directly activate inert C-H bonds for a broad spectrum of oxidative transformations such as hydroxylation, desaturation, decarboxylation, and carbonskeleton rearrangement [10,11]. The exceptional activities of P450s have driven interest in utilizing them for diverse synthetic purposes [12].…”

“…Natural heme proteins have their own strategies to mediate C-H to C-C bond conversions [10]. Many of these transformations are catalyzed by cytochromes P450 and result from radical coupling (e.g.…”

A Continuing Career in Biocatalysis: Frances H. Arnold

“…21,22 Cytochrome P450 monooxygenases make up a large class of heme-dependent enzymes 23 which have evolved across all kingdoms of life to carry out a myriad of oxidation reactions, while sharing a common three-dimensional fold. [24][25][26][27] This enzyme superfamily provides an impressive example of how nature can generate a broad range of oxidation catalysts from a common protein scaffold.…”

Bacterial CYP154C8 catalyzes carbon‐carbon bond cleavage in steroids

“…OleT (CY152L1), BS b (cyp152A1), CYP51, and P450 BioI (CYP107H1) are the only known CYPs isolated from a bacterial source that catalyze C-C bond cleavage reactions with fatty acids [10][11][12][13]. These reactions generate unstable intermediates, which render the investigation of the mechanism involved and their characterization a difficult task [3,15]. Enzymatic cleavage of C-C bonds has been found to be a sequential oxidation reaction at the adjacent, which is Abbreviations C-C, carbon-carbon; CYP, Cytochrome P450; Fdr, ferredoxin reductase; Fdx, ferredoxin.…”

“…usually catalyzed by a single CYP. These reactions generate unstable intermediates, which render the investigation of the mechanism involved and their characterization a difficult task [3,15]. The hydroxylation reaction catalyzed by CYP uses Fe 4+ Àoxo intermediate, which is also known as compound I, although the participation of ferric peroxide (FeO À 2 ) versus perferryl (FeO 3+ , compound I) in the C-C cleavage reactions catalyzed with CYPs including 17A1, 19A1, and 51A1 has long been of interest and under debate [3, [16][17][18][19][20].…”