Unusual Metabolic Reactions and Pathways

Guengerich, F. Peter; Isin, Emre M.

doi:10.1002/9781118541203.xen0006

Cited by 11 publications

(10 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For more extensive lists of rearrangements and more unusual oxidation reactions catalyzed by P450s, see references 6, 8, 19, 49, 50. Most of these can be rationalized by mechanisms involving Compound I, with Compound 0 (Scheme 1) possibly involved in others.…”

Section: Current Understandingmentioning

confidence: 99%

Mechanisms of Cytochrome P450-Catalyzed Oxidations

2018

Self Cite

View full text Add to dashboard Cite

Enzymes are complex biological catalysts and are critical to life. Most oxidations of chemicals are catalyzed by cytochrome P450 (P450, CYP) enzymes, which generally utilize mixed-function oxidase stoichiometry, utilizing pyridine nucleotides as electron donors: NAD(P)H + O2 + R → NAD(P)+ + RO + H2O (where R is a carbon substrate and RO is an oxidized product). The catalysis of oxidations is largely understood in the context of the heme iron-oxygen complex generally referred to as Compound I, formally FeO3+, whose basis was in peroxidase chemistry. Many X-ray crystal structures of P450s are now available (≥ 822 structures from ≥146 different P450s) and have helped in understanding catalytic specificity. In addition to hydroxylations, P450s catalyze more complex oxidations, including C-C bond formation and cleavage. Enzymes derived from P450s by directed evolution can even catalyze more unusual reactions, e.g. cyclopropanation. Current P450 questions under investigation include the potential role of the intermediate Compound 0 (formally FeIII-O2−) in catalysis of some reactions, the roles of high- and low-spin forms of Compound I, the mechanism of desaturation, the roles of open and closed structures of P450s in catalysis, the extent of processivity in multi-step oxidations, and the role of the accessory protein cytochrome b5. More global questions include exactly how structure drives function, prediction of catalysis, and roles of multiple protein conformations.

show abstract

Section: Current Understandingmentioning

confidence: 99%

Mechanisms of Cytochrome P450-Catalyzed Oxidations

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…C -Dealkylation (Figure ) has been reported, and two reactions have been attributed to P450 2A6 and to P450 3A4. , No mechanism has been proposed …”

Section: C–c Bond Breaking Reactionsmentioning

confidence: 99%

“…The C-demethylation of a tert -butyl group was reported for a drug candidate (LC15–0133) by an unidentified P450 in rat liver microsomes (Figure ). , …”

Section: C–c Bond Breaking Reactionsmentioning

confidence: 99%

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

2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…87 Since Cytochrome P450 reductase does not have a metal center only a 1 electron reduction of a molecule can be done. 89,90 Quinone activation by a 2-electron reduction The enzyme, NAD(P)H: quinone oxidoreductase 1 (NQO1, DT-diaphorase), reduces a quinone by 2 electrons to afford a hydroquinone (Figure 7). They accept various substrates that can be part of biosynthesis, degradation as well as activation of both xenobiotics and endogenous compounds.…”

Section: Quinone Activation By a 1-electron Reductionmentioning

confidence: 99%

Understanding cancer and the anticancer activities of naphthoquinones – a review

2015

View full text Add to dashboard Cite

The non-communicable disease, cancer, is one of the major causes of death across the world and is forecast to increase by 75% to reach close to 25 million cases over the next two decades. Radiotherapy and surgical approaches have been unsuccessful in controlling the incidence of most cancers. The development of chemotherapeutic strategies involving novel small molecule antitumour agents has therefore been the focus area of cancer chemotherapy for several decades as another strategy to combat and control the incidence of cancer. Many natural products as well as several synthetic drugs have a naphthoquinone chromophore. The anticancer activities of naphthoquinones have been the focus of much research to discover novel anticancer agents. The naturally occurring 1,2-naphthoquinone-based compound, ß-Lapachone (ARQ 761), is currently being assessed for its anti-tumour activity against advanced solid tumours. This review describes the most recent applications of naphthoquinones and their derivatives in cancer drug discovery. The biology relevant to the design of novel naphthoquinone anticancer agents is also discussed. Furthermore, the discussion of the biology will contribute to understanding cancer as well as the applications of naphthoquinones as anticancer agents.

show abstract

Unusual Metabolic Reactions and Pathways

Cited by 11 publications

References 116 publications

Mechanisms of Cytochrome P450-Catalyzed Oxidations

Mechanisms of Cytochrome P450-Catalyzed Oxidations

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

Understanding cancer and the anticancer activities of naphthoquinones – a review

Contact Info

Product

Resources

About