Futile cycling by human microsomal cytochrome P450 enzymes within intact fission yeast cells

Weldemichael, Dawit M.; Zhou, Kun; Su, Shijia; Zhao, Lin; Marchisio, Mario Andrea; Bureik, Matthias

doi:10.1016/j.abb.2021.108791

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…This process is known as futile cycling. In a systematic screening of all 50 microsomal human CYPs, we have recently shown that both CYP2A6 and CYP2A7 have significant futile cycling activity [7]. Moreover, they were much more similar in this regard as compared to CYP2A13, the third human member of the CYP2A subfamily.…”

Section: Introductionmentioning

confidence: 99%

Identification of New Substrates and Inhibitors of Human CYP2A7

Ashraf,

Liu,

Wolf

et al. 2024

Molecules

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CYP2A7 is one of the most understudied human cytochrome P450 enzymes and its contributions to either drug metabolism or endogenous biosynthesis pathways are not understood, as its only known enzymatic activities are the conversions of two proluciferin probe substrates. In addition, the CYP2A7 gene contains four single-nucleotide polymorphisms (SNPs) that cause missense mutations and have minor allele frequencies (MAFs) above 0.5. This means that the resulting amino acid changes occur in the majority of humans. In a previous study, we employed the reference standard sequence (called CYP2A7*1 in P450 nomenclature). For the present study, we created another CYP2A7 sequence that contains all four amino acid changes (Cys311, Glu169, Gly479, and Arg274) and labeled it CYP2A7-WT. Thus, it was the aim of this study to identify new substrates and inhibitors of CYP2A7 and to compare the properties of CYP2A7-WT with CYP2A7*1. We found several new proluciferin probe substrates for both enzyme variants (we also performed in silico studies to understand the activity difference between CYP2A7-WT and CYP2A7*1 on specific substrates), and we show that while they do not act on the standard CYP2A6 substrates nicotine, coumarin, or 7-ethoxycoumarin, both can hydroxylate diclofenac (as can CYP2A6). Moreover, we found ketoconazole, 1-benzylimidazole, and letrozole to be CYP2A7 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Identification of New Substrates and Inhibitors of Human CYP2A7

Ashraf,

Liu,

Wolf

et al. 2024

Molecules

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View full text Add to dashboard Cite

show abstract

“…Thus, P450s are important for maintaining homeostasis and metabolising drugs [ 12 ]. Human cytochrome P450s have been expressed in S. pombe for long time [ [13] , [14] , [15] , [16] , [17] , [18] ]. In particular, the permeabilized fission yeast system known as enzyme bags is a very efficient platform to scrutinize all human P450s against any potential candidate drug in a quick time [ 13 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Design and engineering of logic genetic-enzymatic gates based on the activity of the human CYP2C9 enzyme in permeabilized Saccharomyces cerevisiae cells

Ashraf,

Bureik,

Marchisio

2024

Synthetic and Systems Biotechnology

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Futile cycling by human microsomal cytochrome P450 enzymes within intact fission yeast cells

Cited by 2 publications

References 41 publications

Identification of New Substrates and Inhibitors of Human CYP2A7

Identification of New Substrates and Inhibitors of Human CYP2A7

Design and engineering of logic genetic-enzymatic gates based on the activity of the human CYP2C9 enzyme in permeabilized Saccharomyces cerevisiae cells

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