Replacement of Natural Cofactors by Selected Hydrogen Peroxide Donors or Organic Peroxides Results in Improved Activity for CYP3A4 and CYP2D6

Chefson, Amandine; Zhao, Jin; Auclair, Karine

doi:10.1002/cbic.200600006

Cited by 48 publications

(49 citation statements)

References 24 publications

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“…CHP was used to bypass the consumption of the expensive NADPH cofactor and CPR, as previously reported [66]. Product distribution and stereoselectivity for the P450 3A4-catalyzed hydroxylation of theobromine-substrates were confirmed to be indistinguishable for both the NADPH/O 2 /CPR and the CHP systems.…”

Section: Mammalian P450smentioning

confidence: 72%

“…In addition, nicotinate is inexpensive, has a chromophore and is easily functionalized, reversibly, at the carboxylic acid group. A series of nicotinate esters were thus generated and reacted with P450 2E1 in the presence of the natural NADPH cofactor and CPR, or CHP [66]. From the results obtained, the authors confirmed the preference of P450 2E1 to oxidize aliphatic CH 2 or alkenyl CH groups furthest from the auxiliary (ω-1).…”

Section: Mammalian P450smentioning

confidence: 78%

“…Most mammalian P450 enzymes show unequalled substrate promiscuity among P450s [2,20,66,67]. This is an attractive quality for a useful and versatile biocatalyst, and can eliminate the need for protein mutagenesis to expand the substrate scope.…”

Section: Mammalian P450smentioning

confidence: 99%

“…Product distribution and stereoselectivity for the P450 3A4-catalyzed hydroxylation of theobromine-substrates were confirmed to be indistinguishable for both the NADPH/O 2 /CPR and the CHP systems. CHP also has the advantage of improving the P450 3A4 initial catalytic rate by 30% [66]. The conversion yields of theobromine derivatives and product structures were determined using LC-MS and MS fragmentation patterns, by comparison with authentic synthetic standards (Fig.…”

Section: Mammalian P450smentioning

confidence: 99%

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Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Auclair

Polic

2015

Advances in Experimental Medicine and Biology

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Cytochrome P450 enzymes (P450s) have the ability to oxidize unactivated C-H bonds of substrates with remarkable regio-and stereoselectivity. Comparable selectivity for chemical oxidizing agents is typically difficult to achieve. Hence, there is an interest in exploiting P450s as potential biocatalysts. Despite their impressive attributes, the current use of P450s as biocatalysts is limited. While bacterial P450 enzymes typically show higher activity, they tend to be highly selective for one or a few substrates. On the other hand, mammalian P450s, especially the drugmetabolizing enzymes, display astonishing substrate promiscuity. However, product prediction continues to be challenging. This review discusses the use of small molecules for controlling P450 substrate specificity and product selectivity. The focus will be on two approaches in the area: (1) the use of decoy molecules, and (2) the application of substrate engineering to control oxidation by the enzyme.

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Section: Mammalian P450smentioning

confidence: 72%

Section: Mammalian P450smentioning

confidence: 78%

Section: Mammalian P450smentioning

confidence: 99%

Section: Mammalian P450smentioning

confidence: 99%

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Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Auclair

Polic

2015

Advances in Experimental Medicine and Biology

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“…2,[52][53][54] Human P450 3A4 for example accounts for the metabolism of approximately 50% of all xenobiotics. 55 Due to its large and flexible active site P450 3A4 is inherently highly promiscuous and unpredictable in terms of substrate specificity and product selectivity.…”

Section: Covalent Modifications To Extend the Substrate Promiscuity Amentioning

confidence: 99%

Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis

Polic

Auclair

2014

Bioorganic & Medicinal Chemistry

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P450 enzymes (P450s) are well known for their ability to oxidize unactivated C-H bonds with high regio-and stereoselectivity. Hence, there is emerging interest in exploiting P450s as potential biocatalysts. Although bacterial P450s typically show higher activity than their mammalian counterparts, they tend to be more substrate selective. Most drug-metabolizing P450s on the other hand, display remarkable substrate promiscuity, yet product prediction remains challenging. Protein engineering is one established strategy to overcome these issues. A less explored, yet promising alternative involves substrate engineering. This review discusses the use of small molecules for controlling the substrate specificity and product selectivity of P450s. The focus is on two approaches, one taking advantage of non-covalent decoy molecules, and the other involving covalent substrate modifications

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Oxidative Drug Metabolism by Mammalian CytochromeP450Enzymes Using Their Monooxygenase and Peroxygenase Functions

Hrycay

Bandiera

2017

Encyclopedia of Drug Metabolism and Interactions

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The cytochrome P450 (CYP) enzyme system represents the predominant biotransformation pathway in the human body for lipophilic exogenous and endogenous compounds. The monooxygenase reaction catalyzed by CYP enzymes involves the addition of one oxygen atom from molecular oxygen to a lipophilic substrate, while incorporating the other oxygen atom into a molecule of water, thereby leading to the production of more polar and easily excreted metabolites. Thus, CYP enzymes are major determinants of duration of action and clearance of drugs. In some cases, CYP enzymes are involved in the formation of chemically reactive and potentially toxic metabolites, as well as in clinically significant drug–drug interactions, which are a widely recognized cause of adverse drug reactions in humans. This chapter focuses on the oxidative biotransformation of therapeutic drugs catalyzed by human CYP enzymes. The topics covered include the identification of human hepatic and extrahepatic CYP enzymes involved in drug biotransformation, CYP bioactivation of prodrugs to pharmacologically active compounds, human CYP drug–drug interactions, CYP monooxygenase and peroxygenase reactions involving drug substrates, and mechanisms involved in CYP oxidative drug reactions.

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Replacement of Natural Cofactors by Selected Hydrogen Peroxide Donors or Organic Peroxides Results in Improved Activity for CYP3A4 and CYP2D6

Cited by 48 publications

References 24 publications

Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis

Oxidative Drug Metabolism by Mammalian CytochromeP450Enzymes Using Their Monooxygenase and Peroxygenase Functions

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