Molecular evolution of adrenarche: structural and functional analysis of p450c17 from four primate species
Abstract
Adrenarche is the prepubertal onset of increased adrenal secretion of 19-carbon steroids, especially dehydroepiandrosterone (DHEA). However, while human beings and chimpanzees exhibit adrenarche, other primates such as the baboon and rhesus monkey do not, and the adrenals of most other mammals produce little or no DHEA. Thus, the acquisition of adrenarche is a very recent evolutionary event. DHEA is produced from pregnenolone by the successive 17alpha-hydroxylase and 17,20 lyase activities of a single enzyme, P450c17. To ascertain whether sequence differences in P450c17 contribute to adrenarche, we cloned the rhesus monkey cDNA from adrenal tissue and cloned the chimpanzee and baboon cDNAs from genomic DNA using an exon-trapping strategy. Using microsomes from yeast transformed with rhesus, baboon, chimp, or human P450c17, we measured the Michaelis constant and maximum velocity for the 17alpha-hydroxylase and 17,20 lyase activities. The human and chimp enzymes differ at only two amino acids and baboon and rhesus P450c17 only at a single residue; the human/chimp enzyme differed from the baboon/rhesus enzyme by 25-27 residues (95% identity). Surprisingly, the greatest difference in enzymatic activities was a marked increase in 17alpha-hydroxylase activity of P450c17 in the baboon, which differs from rhesus only at residue 255 [arginine (Arg) in baboon, histine (His) in rhesus]. Residue 255 is also Arg in human and chimp. Wild-type human P450c17 and its Arg255His mutant had similar 17alpha-hydroxylase activities, but the Arg255Ala mutant had decreased 17alpha-hydroxylase activity. These data establish that Arg255 is important for 17alpha-hydroxylase activity and show that the evolution of adrenarche in higher primates is not determined by variations in the sequence of P450c17.
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Adrenal cortex is responsible for biosynthesis of mineralocorticoids and glucocorticoids, as well as production of adrenal androgen precursors and androgens, a function unique to higher primates.
“The cortex of the adrenal gland is responsible for the biosynthesis of mineralocorticoids and glucocorticoids, as well as the production of adrenal androgen precursors and androgens, a function unique to higher primates [19,20].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [20]
Adrenal C19 steroid production is initiated during adrenarche, a pre-pubertal event approximately age 8 in girls and 9 in boys, unique to humans and higher primates.
“It should be noted that adrenal C19 steroid production is initiated during adrenarche, a pre-pubertal event (approximately age 8 in girls and 9 in boys (Idkowiak et al., 2011)) unique to humans and higher primates (Abbott and Bird, 2009, Arlt et al., 2002, Auchus and Rainey, 2004, Miller, 2008).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Arlt et al., 2002
Cites
Improved method for high efficiency transformation of intact yeast cells.
Gietz, D., Jean, A. S., Woods, R. A., & Schiestl, R. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.6.1425 · Cited by 3,379 · see citing works
Molecular biology of steroid hormone synthesis
MILLER, W. L. (1988) · Endocrine Reviews · doi:10.1210/edrv-9-3-295 · Cited by 1,397 · see citing works
Self-citationORENTREICH, N., BRIND, J. L., RIZER, R. L., & VOGELMAN, J. H. (1984) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-59-3-551 · Cited by 1,349 · see citing works
[6] Yeast expression of animal and plant P450s in optimized redox environments
Pompon, D., Louërat-Oriou, B., Bronine, A., & Urban, P. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)72008-6 · Cited by 654 · see citing works
Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer
Auchus, R. J., Lee, T. C., & Miller, W. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.6.3158 · Cited by 541 · see citing works
Self-citationZhang, L. H., Rodriguez, H., Ohno, S., & Miller, W. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.23.10619 · Cited by 455 · see citing works
Self-citationChung, B. C., Picado-Leonard, J., Haniu, M., Bienkowski, M., Hall, P. F., Shively, J. E., & Miller, W. L. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.2.407 · Cited by 444 · see citing works
Self-citationPICADO-LEONARD, J., & MILLER, W. L. (1987) · DNA · doi:10.1089/dna.1987.6.439 · Cited by 415 · see citing works
Self-citationRhéaume, E., Lachance, Y., Zhao, H.-F., Breton, N., Dumont, M., Launoit, Y. D., Trudel, C., Luu-The, V., Simard, J., & Labrie, F. (1991) · Molecular Endocrinology · doi:10.1210/mend-5-8-1147 · Cited by 362 · see citing works
Analysis of enzyme kinetic data
(1995) · Biochemical Education · doi:10.1016/0307-4412(95)90181-7 · Cited by 324 · see citing works
Adrenarche: a survey of rodents, domestic animals and primates
CUTLER, G. B., GLENN, M., BUSH, M., HODGEN, G. D., GRAHAM, C. E., & LORIAUX, D. L. (1978) · Endocrinology · doi:10.1210/endo-103-6-2112 · Cited by 321 · see citing works
The genetic and functional basis of isolated 17,20 lyase deficiency
Geller, D. H., Auchus, R. J., Mendonça, B. B., & Miller, W. L. (1997) · Nature Genetics · doi:10.1038/ng1097-201 · Cited by 318 · see citing works
Self-citationVOUTILAINEN, R., TAPANAINEN, J., CHUNG, B.-C., MATTESON, K. J., & MILLER, W. L. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-1-202 · Cited by 253 · see citing works
Self-citationSKLAR, C. A., KAPLAN, S. L., & GRUMBACH, M. M. (1980) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-51-3-548 · Cited by 245 · see citing works
Endoh, A., Kristiansen, S. B., Casson, P. R., Buster, J. E., & Hornsby, P. J. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.10.8855801 · Cited by 219 · see citing works
Suzuki, T., Sasano, H., Takeyama, J., Kaneko, C., Freije, W. A., Carr, B. R., & Rainey, W. E. (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.01144.x · Cited by 199 · see citing works
Auchus, R. J., & Miller, W. L. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.7.0326 · Cited by 185 · see citing works
Self-citationGeller, D. H., Auchus, R. J., & Miller, W. L. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.1.0219 · Cited by 183 · see citing works
Self-citationLin, D., Black, S. M., Nagahama, Y., & Miller, W. L. (1993) · Endocrinology · doi:10.1210/endo.132.6.8504753 · Cited by 174 · see citing works
Self-citationGell, J. S., Carr, B. R., Sasano, H., Atkins, B., Margraf, L. R., Mason, J. I., & Rainey, W. E. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.10.5070 · Cited by 136 · see citing works
Missense mutation serine106—-proline causes 17 alpha-hydroxylase deficiency
Lin, D., Harikrishna, J. A., Moore, C. C., Jones, K. L., & Miller, W. L. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98506-6 · Cited by 135 · see citing works
Self-citationSwart, P., Swart, A. C., Waterman, M. R., Estabrook, R. W., & Mason, J. I. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.77.1.8325965 · Cited by 106 · see citing works
Copeland, K. C., Eichberg, J. W., Parker, C. R., & BARTKE, A. (1985) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-60-6-1154 · Cited by 103 · see citing works
ADRENOCORTICAL FUNCTION IN PUBERTY Serum ACTH, Cortisol and Dehydroepiandrosterone in Girls and Boys
APTER, D., PAKARINEN, A., HAMMOND, G. L., & VIHKO, R. (1979) · Acta Paediatrica · doi:10.1111/j.1651-2227.1979.tb05062.x · Cited by 95 · see citing works
Mapes, S., Corbin, C. J., Tarantal, A., & Conley, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.6105 · Cited by 86 · see citing works
Further studies on adrenarche in nonhuman primates
SMAIL, P. J., FAIMAN, C., HOBSON, W. C., FULLER, G. B., & WINTER, J. S. D. (1982) · Endocrinology · doi:10.1210/endo-111-3-844 · Cited by 84 · see citing works
Mutation of histidine 373 to leucine in cytochrome P450c17 causes 17 alpha-hydroxylase deficiency.
Monno, S., Ogawa, H., Date, T., Fujioka, M., Miller, W. L., & Kobayashi, M. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74462-7 · Cited by 74 · see citing works
Self-citationAn efficient chloramphenicol-resistance marker for Saccharomyces cerevisiae and Escherichia coli
Hadfield, C., Cashmore, A. M., & Meacock, P. A. (1986) · Gene · doi:10.1016/0378-1119(86)90249-0 · Cited by 73 · see citing works
Kemnitz, J. W., Roecker, E. B., Haffa, A. L., Pinheiro, J. C., Kurzman, I. D., Ramsey, J. J., & MacEwen, E. G. (2000) · Journal of Medical Primatology · doi:10.1034/j.1600-0684.2000.290504.x · Cited by 61 · see citing works
The molecular basis of premature adrenarche: an hypothesis
Miller, W. L. (1999) · Acta Paediatrica · doi:10.1111/j.1651-2227.1999.tb14405.x · Cited by 60 · see citing works
Self-citationYANASE, T., SASANO, H., YUBISUI, T., SAKAI, Y., TAKAYANAGI, R., & NAWATA, H. (1998) · Endocrine Journal · doi:10.1507/endocrj.45.89 · Cited by 54 · see citing works
Pubertal endocrinology of the baboon: adrenarche
Castracane, V. D., Cutler, G. B., & Loriaux, D. L. (1981) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1981.241.4.e305 · Cited by 45 · see citing works
Dardis, A., Saraco, N., Rivarola, M. A., & Belgorosky, A. (1999) · Pediatric Research · doi:10.1203/00006450-199903000-00016 · Cited by 45 · see citing works
Sapolsky, R., Vogelman∥, J. H., Orentreich∥, N., & Jeanne Altmann, A. (1993) · Journal of Gerontology · doi:10.1093/geronj/48.5.b196 · Cited by 44 · see citing works
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Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
“The cortex of the adrenal gland is responsible for the biosynthesis of mineralocorticoids and glucocorticoids, as well as the production of adrenal androgen precursors and androgens, a function unique to higher primates [19,20].”
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Schiffer, L., Arlt, W., & Storbeck, K.-H. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.08.016 · Cited by 217 · see citing works
“It should be noted that adrenal C19 steroid production is initiated during adrenarche, a pre-pubertal event (approximately age 8 in girls and 9 in boys (Idkowiak et al., 2011)) unique to humans and higher primates (Abbott and Bird, 2009; Arlt et al., 2002; Auchus and Rainey, 2004; Miller, 2008).”
Self-citationUrinary markers of adrenarche: reference values in healthy subjects, aged 3–18 years
Remer, T., Boye, K. R., Hartmann, M. F., & Wudy, S. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1571 · Cited by 193 · see citing works
Flück, C. E., Miller, W. L., & Auchus, R. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030143 · Cited by 173 · see citing works
Self-citationRegulation of 17,20 lyase activity by cytochrome b5 and by serine phosphorylation of P450c17
Pandey, A. V., & Miller, W. L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414673200 · Cited by 165 · see citing works
Self-citationPremature adrenarche: novel lessons from early onset androgen excess
Idkowiak, J., Lavery, G. G., Dhir, V., Barrett, T. G., Stewart, P. M., Krone, N., & Arlt, W. (2011) · European Journal of Endocrinology · doi:10.1530/eje-11-0223 · Cited by 158 · see citing works
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Pandey, A. V., Mellon, S. H., & Miller, W. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209527200 · Cited by 137 · see citing works
Self-citationSherbet, D. P., Tiosano, D., Kwist, K. M., Hochberg, Z., & Auchus, R. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307586200 · Cited by 131 · see citing works
Self-citationBhargava, A., Arnold, A. P., Bangasser, D. A., Denton, K. M., Gupta, A., Hilliard Krause, L. M., Mayer, E. A., McCarthy, M., Miller, W. L., Raznahan, A., et al. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa034 · Cited by 130 · see citing works
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Miller, W. L. (2009) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-008-9102-4 · Cited by 127 · see citing works
Self-citationStructures of human steroidogenic cytochrome P450 17A1 with substrates
Petrunak, E. M., DeVore, N. M., Porubsky, P. R., & Scott, E. E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.610998 · Cited by 119 · see citing works
Tee, M. K., Dong, Q., & Miller, W. L. (2008) · Endocrinology · doi:10.1210/en.2007-1527 · Cited by 55 · see citing works
Self-citationJohnston, Z. C., Bellingham, M., Filis, P., Soffientini, U., Hough, D., Bhattacharya, S., Simard, M., Hammond, G. L., King, P., O’Shaughnessy, P. J., et al. (2018) · BMC Medicine · doi:10.1186/s12916-018-1009-7 · Cited by 44 · see citing works
Nguyen, A. D., Mapes, S. M., Corbin, C. J., & Conley, A. J. (2008) · Journal of Endocrinology · doi:10.1677/joe-08-0337 · Cited by 38 · see citing works
- Authors
- Arlt, W., Martens, J. W. M., Song, M., Wang, J. T., Auchus, R. J., & Miller, W. L.
- Affiliations
- University of California, San Francisco (US)
- The University of Texas Southwestern Medical Center (US)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2002-12-01
- Volume
- 143
- Issue
- 12
- Pages
- 4665-4672
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2142886860
- Cited by
- 101
- References
- 34
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 3 · 2021: 4 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Institutes of Health (1r43dk041958-01, 5k08dk002387-06)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, K08 DK 02387, R01DK037922)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54-HD34449, U54HD034449, HD/DK 41958)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- adrenarche, CYP17, P450c17, 17α-hydroxylase, 17,20-lyase, dehydroepiandrosterone, pregnenolone, primate evolution, chimpanzees, baboons, rhesus monkeys, enzyme kinetics, steroidogenesis, adrenal gland
- MeSH terms
- Adrenal Glands, Amino Acid Sequence, Animals, Arginine, Pan troglodytes, Cloning, Molecular, Computer Simulation, Humans, Kinetics, Macaca mulatta, Microsomes, Models, Molecular, Molecular Sequence Data, Papio, Steroid 17-alpha-Hydroxylase, Structure-Activity Relationship, Mutagenesis, Site-Directed, Sequence Alignment, DNA, Complementary, Evolution, Molecular
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