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• W2013133441 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 × 107 m−1 s−1) is only ∼2-fold greater than the catalytic efficiency (kcat/Km = 1.3 × 107 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.Background: P450 21A2 catalyzes 21-hydroxylation of both progesterone and 17α-hydroxyprogesterone, an important step in adrenal steroidogenesis.Results: A crystal structure of human P450 21A2 with progesterone can explain many functional variants.Conclusion: High kinetic deuterium isotope effects show the importance of a closely spaced site for C21 hydrogen abstraction.Significance: The structure provides insight into enzyme deficiencies in congenital adrenal hyperplasia. 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 × 107 m−1 s−1) is only ∼2-fold greater than the catalytic efficiency (kcat/Km = 1.3 × 107 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. Background: P450 21A2 catalyzes 21-hydroxylation of both progesterone and 17α-hydroxyprogesterone, an important step in adrenal steroidogenesis. Results: A crystal structure of human P450 21A2 with progesterone can explain many functional variants. Conclusion: High kinetic deuterium isotope effects show the importance of a closely spaced site for C21 hydrogen abstraction. Significance: The structure provides insight into enzyme deficiencies in congenital adrenal hyperplasia." @default.
• W2013133441 created "2016-06-24" @default.
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• W2013133441 date "2015-05-01" @default.
• W2013133441 modified "2023-10-14" @default.
• W2013133441 title "Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase" @default.
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• W2013133441 cites W1951469402 @default.
• W2013133441 cites W1963680434 @default.
• W2013133441 cites W1967240005 @default.
• W2013133441 cites W1969303894 @default.
• W2013133441 cites W1970095537 @default.
• W2013133441 cites W1979223030 @default.
• W2013133441 cites W1980640153 @default.
• W2013133441 cites W1984700793 @default.
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• W2013133441 cites W1991812090 @default.
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• W2013133441 cites W2010445932 @default.
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• W2013133441 cites W2056097417 @default.
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• W2013133441 doi "https://doi.org/10.1074/jbc.m115.646307" @default.
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