ArticleThe Journal of biological chemistry2015
Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: STRUCTURE OF THE ENZYME·PROGESTERONE SUBSTRATE COMPLEX AND RATE-LIMITING C-H BOND CLEAVAGE.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 90 citations in OpenAlex.
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- Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review.Biomedicines · 2024Review
- Non-classical animal models for studying adrenal diseases: advantages, limitations, and implications for research.Laboratory animal research · 2024Review
- Autoimmune diseases: targets, biology, and drug discovery.Acta pharmacologica Sinica · 2024Review
- Ninety-eight semesters of cytochrome P450 enzymes and related topics-What have I taught and learned?The Journal of biological chemistry · 2024Article
- Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes.Frontiers in pharmacology · 2023Article
- Non-Ionic Inulin-Based Polymer Nanodiscs Enable Functional Reconstitution of a Redox Complex Composed of Oppositely Charged CYP450 and CPR in a Lipid Bilayer Membrane.Analytical chemistry · 2022Article
- The adrenal steroid profile in adolescent depression: a valuable bio-readout?Translational psychiatry · 2022Article
- Diverse reactions catalyzed by cytochrome P450 and biosynthesis of steroid hormone.Biophysics and physicobiology · 2022Article
- Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations.International journal of molecular sciences · 2021Article
- Effects of fluorine substitution on substrate conversion by cytochromes P450 17A1 and 21A2.Organic & biomolecular chemistry · 2021Article
- The cytochrome P450 (CYP) superfamily in cnidarians.Scientific reports · 2021Article
- CYP154C5 Regioselectivity in Steroid Hydroxylation Explored by Substrate Modifications and Protein Engineering*.Chembiochem : a European journal of chemical biology · 2021Article
- Corticosteroid Biosynthesis Revisited: No Direct Hydroxylation of Pregnenolone by Steroid 21-Hydroxylase.Frontiers in endocrinology · 2021Article
- In Silico Structural and Biochemical Functional Analysis of a NovelInternational journal of molecular sciences · 2020Article
- Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death.Journal of medicinal chemistry · 2020Article
- Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia.Endocrine · 2020Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Cytochrome P450 (P450) 21A2 is the major steroid 21-hydroxylase, and deficiency of this enzyme is involved in ∼95% of cases of human congenital adrenal hyperplasia, a disorder of adrenal steroidogenesis. A structure of the bovine enzyme that we published previously (Zhao, B., Lei, L., Kagawa, N., Sundaramoorthy, M., Banerjee, S., Nagy, L. D., Guengerich, F. P., and Waterman, M. R. (2012) Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J. Biol. Chem. 287, 10613-10622), containing two molecules of the substrate 17α-hydroxyprogesterone, has been used as a template for understanding genetic deficiencies. We have now obtained a crystal structure of human P450 21A2 in complex with progesterone, a substrate in adrenal 21-hydroxylation. Substrate binding and release were fast for human P450 21A2 with both substrates, and pre-steady-state kinetics showed a partial burst but only with progesterone as substrate and not 17α-hydroxyprogesterone. High intermolecular non-competitive kinetic deuterium isotope effects on both kcat and kcat/Km, from 5 to 11, were observed with both substrates, indicative of rate-limiting C-H bond cleavage and suggesting that the juxtaposition of the C21 carbon in the active site is critical for efficient oxidation. The estimated rate of binding of the substrate progesterone (kon 2.4 × 10(7) M(-1) s(-1)) is only ∼2-fold greater than the catalytic efficiency (kcat/Km = 1.3 × 10(7) M(-1) s(-1)) with this substrate, suggesting that the rate of substrate binding may also be partially rate-limiting. The structure of the human P450 21A2-substrate complex provides direct insight into mechanistic effects of genetic variants.
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