Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia
Open accessAbstract
Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants ( K s ) for four variants were 37–13,000-fold higher than for WT P450 21A2. Cytochrome b 5 , which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21- d 3 -progesterone, indicating that C–H bond breaking is a rate-limiting step over a 10 4 -fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.
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- Authors
- Wang, C., Pallan, P. S., Zhang, W., Lei, L., Yoshimoto, F. K., Waterman, M. R., Egli, M., & Guengerich, F. P.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Egli, Martin
- Guengerich, F. Peter
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 292
- Issue
- 26
- Pages
- 10767-10778
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5491764
- OpenAlex
- W2618360191
- Cited by
- 43
- References
- 36
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 2
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institutes of Health (R01 GM103937)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- CYP21A2, congenital adrenal hyperplasia, 21-hydroxylase, 17-hydroxyprogesterone, progesterone, enzyme variants, salt-wasting CAH, heme incorporation, cytochrome b5, deuterium isotope effect, thermal stability, protein structure
- MeSH terms
- Protein Domains, Adrenal Hyperplasia, Congenital, Circular Dichroism, Enzyme Stability, Hot Temperature, Humans, Mutation, Spectrophotometry, Ultraviolet, Steroid 21-Hydroxylase, Cytochromes b5, Deuterium Exchange Measurement
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