Cholesterol Hydroperoxides as Substrates for Cholesterol‐Metabolizing Cytochrome P450 Enzymes and Alternative Sources of 25‐Hydroxycholesterol and other Oxysterols

Lier, Johan E. van; Mast, Natalia; Pikuleva, Irina A.

doi:10.1002/ange.201505002

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…Over time, the hydroperoxide substrate had converted to ( 20S )-20,21-dihydroxycholesterol, which can be explained by 21-hydrogen atom abstraction by the Compound I generated in situ . The conversion of hydroperoxycholesterol derivatives to dihydroxycholesterol products was confirmed using the purified recombinant bovine CYP11A1 enzyme in a later report [35]. …”

Section: Stopped-flow Technique (Steps 1 2 9 – Substrate Bindingmentioning

confidence: 91%

Rapid kinetic methods to dissect steroidogenic cytochrome P450 reaction mechanisms

Yoshimoto

Auchus

2016

The Journal of Steroid Biochemistry and Molecular Biology

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All cytochrome P450 enzyme reactions involve a catalytic cycle with several discreet physical or chemical steps. This cycle ends with the formation of the reactive heme iron-oxygen complex, which oxygenates substrate. While the steps might be very similar for each P450 enzyme, the rates of each step varies tremendously for each enzyme and sometimes even for different reactions catalyzed by the same enzyme. For example, the rate-limiting step for most bacterial P450 enzymes, with turnover numbers over 1,000 sec−1, is the second electron transfer. In contrast, steroidogenic P450s from eukaryotes catalyze much slower reactions, with turnover numbers of ~5–250 min−1; therefore, assumptions about kinetic properties for the mammalian P450 enzymes based on the bacterial enzymes are tenuous. In order to dissect the rates for individual steps, special techniques that isolate individual steps and/or single turnovers are required. This article will review the theoretical principles and practical considerations for several of these techniques, with illustrative published examples. The reader should gain an appreciation for the appropriate methods used to interrogate particular steps in the P450 reaction cycle.

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Section: Stopped-flow Technique (Steps 1 2 9 – Substrate Bindingmentioning

confidence: 91%

Rapid kinetic methods to dissect steroidogenic cytochrome P450 reaction mechanisms

Yoshimoto

Auchus

2016

The Journal of Steroid Biochemistry and Molecular Biology

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“…Peroxygenase reactions are thought to react in a chemically similar way to the monooxygenase activity. Various hydroperoxide substrates have been explored in the oxidation of P450 substrates [101–104]. This provides further evidence that P450s may utilize endogenous hydroperoxides as co-substrates in vivo.…”

Section: Introductionmentioning

confidence: 99%

The relationships between cytochromes P450 and H 2 O 2 : Production, reaction, and inhibition

Albertolle

Guengerich

2018

Journal of Inorganic Biochemistry

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In this review we address the relationship between cytochromes P450 (P450) and HO. This association can affect biology in three distinct ways. First, P450s produce HO as a byproduct either during catalysis or when no substrate is present. This reaction, known as uncoupling, releases reactive oxygen species that may have implications in disease. Second, HO is used as an oxygen-donating co-substrate in peroxygenase and peroxidase reactions catalyzed by P450s. This activity has proven to be important mainly in reactions involving prokaryotic P450s, and investigators have harnessed this reaction with the aim of adaptation for industrial use. Third, HO-dependent inhibition of human P450s has been studied in our laboratory, demonstrating heme destruction and also the inactivating oxidation of the heme-thiolate ligand to a sulfenic acid (-SOH). This reversible oxidative modification of P450s may have implications in the prevention of uncoupling and may give new insights into the oxidative regulation of these enzymes. Research has elucidated many of the chemical mechanisms involved in the relationship between P450 and HO, but the application to biology is difficult to evaluate. Further studies are needed reveal both the harmful and protective natures of reactive oxygen species in an organismal context.

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Cholesterol Hydroperoxides as Substrates for Cholesterol‐Metabolizing Cytochrome P450 Enzymes and Alternative Sources of 25‐Hydroxycholesterol and other Oxysterols

Cited by 2 publications

References 41 publications

Rapid kinetic methods to dissect steroidogenic cytochrome P450 reaction mechanisms

Rapid kinetic methods to dissect steroidogenic cytochrome P450 reaction mechanisms

The relationships between cytochromes P450 and H 2 O 2 : Production, reaction, and inhibition

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