Steroid 17-alpha-hydroxylase/17,20 lyase

Details

Name
Steroid 17-alpha-hydroxylase/17,20 lyase
Kind
protein
Synonyms
  • 1.14.14.19
  • 17-alpha-hydroxyprogesterone aldolase
  • CYP17
  • CYPXVII
  • Cytochrome P450 17A1
  • Cytochrome P450-C17
  • Cytochrome P450c17
  • S17AH
  • Steroid 17-alpha-monooxygenase
Gene Name
CYP17A1
UniProtKB Entry
P05093Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0018942|Steroid 17-alpha-hydroxylase/17,20 lyase
MWELVALLLLTLAYLFWPKRRCPGAKYPKSLLSLPLVGSLPFLPRHGHMHNNFFKLQKKY
GPIYSVRMGTKTTVIVGHHQLAKEVLIKKGKDFSGRPQMATLDIASNNRKGIAFADSGAH
WQLHRRLAMATFALFKDGDQKLEKIICQEISTLCDMLATHNGQSIDISFPVFVAVTNVIS
LICFNTSYKNGDPELNVIQNYNEGIIDNLSKDSLVDLVPWLKIFPNKTLEKLKSHVKIRN
DLLNKILENYKEKFRSDSITNMLDTLMQAKMNSDNGNAGPDQDSELLSDNHILTTIGDIF
GAGVETTTSVVKWTLAFLLHNPQVKKKLYEEIDQNVGFSRTPTISDRNRLLLLEATIREV
LRLRPVAPMLIPHKANVDSSIGEFAVDKGTEVIINLWALHHNEKEWHQPDQFMPERFLNP
AGTQLISPSVSYLPFGAGPRSCIGEILARQELFLIMAWLLQRFDLEVPDDGQLPSLEGIP
KVVFLIDSFKVKIKVRQAWREAQAEGST
Number of residues
508
Molecular Weight
57369.995
Theoretical pI
8.87
GO Classification
Functions
lyase activity
General Function
A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:9452426). Catalyzes 17-alpha hydroxylation of C21 steroids, which is common for both pathways. A second oxidative step, required only for androgen synthesis, involves an acyl-carbon cleavage. The 17-alpha hydroxy intermediates, as part of adrenal glucocorticoids biosynthesis pathway, are precursors of cortisol (Probable) (PubMed:25301938, PubMed:9452426). Hydroxylates steroid hormones, pregnenolone and progesterone to form 17-alpha hydroxy metabolites, followed by the cleavage of the C17-C20 bond to form C19 steroids, dehydroepiandrosterone (DHEA) and androstenedione (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:36640554, PubMed:9452426). Has 16-alpha hydroxylase activity. Catalyzes 16-alpha hydroxylation of 17-alpha hydroxy pregnenolone, followed by the cleavage of the C17-C20 bond to form 16-alpha-hydroxy DHEA (PubMed:36640554). Also 16-alpha hydroxylates androgens, relevant for estriol synthesis (PubMed:25301938, PubMed:27339894). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:22266943, PubMed:25301938, PubMed:27339894, PubMed:9452426)
Specific Function
heme binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
Not Available
Cellular Location
Endoplasmic reticulum membrane
Gene sequence
>lcl|BSEQ0018943|Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)
ATGTGGGAGCTCGTGGCTCTCTTGCTGCTTACCCTAGCTTATTTGTTTTGGCCCAAGAGA
AGGTGCCCTGGTGCCAAGTACCCCAAGAGCCTCCTGTCCCTGCCCCTGGTGGGCAGCCTG
CCATTCCTCCCCAGACACGGCCATATGCATAACAACTTCTTCAAGCTGCAGAAAAAATAT
GGCCCCATCTATTCGGTTCGTATGGGCACCAAGACTACAGTGATTGTCGGCCACCACCAG
CTGGCCAAGGAGGTGCTTATTAAGAAGGGCAAGGACTTCTCTGGGCGGCCTCAAATGGCA
ACTCTAGACATCGCGTCCAACAACCGTAAGGGTATCGCCTTCGCTGACTCTGGCGCACAC
TGGCAGCTGCATCGAAGGCTGGCGATGGCCACCTTTGCCCTGTTCAAGGATGGCGATCAG
AAGCTGGAGAAGATCATTTGTCAGGAAATCAGTACATTGTGTGATATGCTGGCCACCCAC
AACGGACAGTCCATAGACATCTCCTTTCCTGTCTTCGTGGCGGTAACCAATGTCATCTCC
TTGATCTGCTTCAATACCTCCTACAAGAATGGGGACCCTGAGTTGAATGTCATACAGAAT
TACAATGAAGGCATCATAGACAACCTGAGCAAAGACAGCCTGGTGGACCTAGTCCCCTGG
TTGAAGATTTTCCCCAACAAAACCCTGGAAAAATTAAAGAGCCATGTTAAAATACGAAAT
GATCTGCTGAATAAAATACTTGAAAATTACAAGGAGAAATTCCGGAGTGACTCTATCACC
AACATGCTGGACACACTGATGCAAGCCAAGATGAACTCAGATAATGGCAATGCTGGCCCA
GATCAAGACTCAGAGCTGCTTTCAGATAACCACATTCTCACCACCATAGGGGACATCTTT
GGGGCTGGCGTGGAGACCACCACCTCTGTGGTTAAATGGACCCTGGCCTTCCTGCTGCAC
AATCCTCAGGTGAAGAAGAAGCTCTACGAGGAGATTGACCAGAATGTGGGTTTCAGCCGC
ACACCAACTATCAGTGACCGTAACCGTCTCCTCCTGCTGGAGGCCACCATCCGAGAGGTG
CTTCGCCTCAGGCCCGTGGCCCCTATGCTCATCCCCCACAAGGCCAACGTTGACTCCAGC
ATCGGTGAGTTTGCTGTGGACAAGGGCACAGAAGTTATCATCAATCTGTGGGCGCTGCAT
CACAATGAGAAGGAGTGGCACCAGCCGGATCAGTTCATGCCTGAGCGTTTCTTGAATCCA
GCGGGGACCCAGCTCATCTCACCGTCAGTAAGCTATTTGCCCTTCGGAGCAGGACCTCGC
TCCTGTATAGGTGAGATCCTGGCCCGCCAGGAGCTCTTCCTCATCATGGCCTGGCTGCTG
CAGAGGTTCGACCTGGAGGTGCCAGATGATGGGCAGCTGCCCTCCCTGGAAGGCATCCCC
AAGGTGGTCTTTCTGATCGACTCTTTCAAAGTGAAGATCAAGGTGCGCCAGGCCTGGAGG
GAAGCCCAGGCTGAGGGTAGCACCTAA
Chromosome Location
10
Locus
10q24.32
External Identifiers
ResourceLink
UniProtKB IDP05093
UniProtKB Entry NameCP17A_HUMAN
GenBank Protein ID181342
GenBank Gene IDM14564
GeneCard IDCYP17A1
GenAtlas IDCYP17A1
HGNC IDHGNC:2593
PDB ID(s)3RUK, 3SWZ, 4NKV, 4NKW, 4NKX, 4NKY, 4NKZ, 5IRQ, 5IRV, 5UYS, 6CHI, 6CIR, 6CIZ, 6WR0, 6WR1, 6WW0, 8FDA
KEGG IDhsa:1586
IUPHAR/Guide To Pharmacology ID1361
NCBI Gene ID1586
General References
  1. Chung BC, Picado-Leonard J, Haniu M, Bienkowski M, Hall PF, Shively JE, Miller WL: Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad Sci U S A. 1987 Jan;84(2):407-11. [Article]
  2. Picado-Leonard J, Miller WL: Cloning and sequence of the human gene for P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): similarity with the gene for P450c21. DNA. 1987 Oct;6(5):439-48. [Article]
  3. Bradshaw KD, Waterman MR, Couch RT, Simpson ER, Zuber MX: Characterization of complementary deoxyribonucleic acid for human adrenocortical 17 alpha-hydroxylase: a probe for analysis of 17 alpha-hydroxylase deficiency. Mol Endocrinol. 1987 May;1(5):348-54. [Article]
  4. Brentano ST, Picado-Leonard J, Mellon SH, Moore CC, Miller WL: Tissue-specific, cyclic adenosine 3',5'-monophosphate-induced, and phorbol ester-repressed transcription from the human P450c17 promoter in mouse cells. Mol Endocrinol. 1990 Dec;4(12):1972-9. [Article]
  5. Kagimoto M, Winter JS, Kagimoto K, Simpson ER, Waterman MR: Structural characterization of normal and mutant human steroid 17 alpha-hydroxylase genes: molecular basis of one example of combined 17 alpha-hydroxylase/17,20 lyase deficiency. Mol Endocrinol. 1988 Jun;2(6):564-70. [Article]
  6. Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR, Rogers J: The DNA sequence and comparative analysis of human chromosome 10. Nature. 2004 May 27;429(6990):375-81. [Article]
  7. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  8. Auchus RJ, Miller WL: Molecular modeling of human P450c17 (17alpha-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations. Mol Endocrinol. 1999 Jul;13(7):1169-82. [Article]
  9. DeVore NM, Scott EE: Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature. 2012 Jan 22;482(7383):116-9. doi: 10.1038/nature10743. [Article]
  10. Yanase T, Kagimoto M, Suzuki S, Hashiba K, Simpson ER, Waterman MR: Deletion of a phenylalanine in the N-terminal region of human cytochrome P-450(17 alpha) results in partial combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem. 1989 Oct 25;264(30):18076-82. [Article]
  11. Lin D, Harikrishna JA, Moore CC, Jones KL, Miller WL: Missense mutation serine106----proline causes 17 alpha-hydroxylase deficiency. J Biol Chem. 1991 Aug 25;266(24):15992-8. [Article]
  12. Yanase T, Waterman MR, Zachmann M, Winter JS, Simpson ER, Kagimoto M: Molecular basis of apparent isolated 17,20-lyase deficiency: compound heterozygous mutations in the C-terminal region (Arg(496)----Cys, Gln(461)----Stop) actually cause combined 17 alpha-hydroxylase/17,20-lyase deficiency. Biochim Biophys Acta. 1992 Aug 25;1139(4):275-9. [Article]
  13. Ahlgren R, Yanase T, Simpson ER, Winter JS, Waterman MR: Compound heterozygous mutations (Arg 239----stop, Pro 342----Thr) in the CYP17 (P45017 alpha) gene lead to ambiguous external genitalia in a male patient with partial combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Clin Endocrinol Metab. 1992 Mar;74(3):667-72. [Article]
  14. Imai T, Globerman H, Gertner JM, Kagawa N, Waterman MR: Expression and purification of functional human 17 alpha-hydroxylase/17,20-lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem. 1993 Sep 15;268(26):19681-9. [Article]
  15. Monno S, Ogawa H, Date T, Fujioka M, Miller WL, Kobayashi M: Mutation of histidine 373 to leucine in cytochrome P450c17 causes 17 alpha-hydroxylase deficiency. J Biol Chem. 1993 Dec 5;268(34):25811-7. [Article]
  16. Fardella CE, Zhang LH, Mahachoklertwattana P, Lin D, Miller WL: Deletion of amino acids Asp487-Ser488-Phe489 in human cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency. J Clin Endocrinol Metab. 1993 Aug;77(2):489-93. [Article]
  17. Fardella CE, Hum DW, Homoki J, Miller WL: Point mutation of Arg440 to His in cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency. J Clin Endocrinol Metab. 1994 Jul;79(1):160-4. [Article]
  18. Laflamme N, Leblanc JF, Mailloux J, Faure N, Labrie F, Simard J: Mutation R96W in cytochrome P450c17 gene causes combined 17 alpha-hydroxylase/17-20-lyase deficiency in two French Canadian patients. J Clin Endocrinol Metab. 1996 Jan;81(1):264-8. [Article]
  19. Biason-Lauber A, Kempken B, Werder E, Forest MG, Einaudi S, Ranke MB, Matsuo N, Brunelli V, Schonle EJ, Zachmann M: 17alpha-hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation. J Clin Endocrinol Metab. 2000 Mar;85(3):1226-31. [Article]
  20. Gupta MK, Geller DH, Auchus RJ: Pitfalls in characterizing P450c17 mutations associated with isolated 17,20-lyase deficiency. J Clin Endocrinol Metab. 2001 Sep;86(9):4416-23. [Article]
  21. Di Cerbo A, Biason-Lauber A, Savino M, Piemontese MR, Di Giorgio A, Perona M, Savoia A: Combined 17alpha-Hydroxylase/17,20-lyase deficiency caused by Phe93Cys mutation in the CYP17 gene. J Clin Endocrinol Metab. 2002 Feb;87(2):898-905. [Article]
  22. Van Den Akker EL, Koper JW, Boehmer AL, Themmen AP, Verhoef-Post M, Timmerman MA, Otten BJ, Drop SL, De Jong FH: Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab. 2002 Dec;87(12):5714-21. [Article]
  23. Martin RM, Lin CJ, Costa EM, de Oliveira ML, Carrilho A, Villar H, Longui CA, Mendonca BB: P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. J Clin Endocrinol Metab. 2003 Dec;88(12):5739-46. [Article]
  24. Katsumata N, Ogawa E, Fujiwara I, Fujikura K: Novel CYP17A1 mutation in a Japanese patient with combined 17alpha-hydroxylase/17,20-lyase deficiency. Metabolism. 2010 Feb;59(2):275-8. doi: 10.1016/j.metabol.2009.07.024. Epub 2009 Sep 29. [Article]
  25. Mula-Abed WA, Pambinezhuth FB, Al-Kindi MK, Al-Busaidi NB, Al-Muslahi HN, Al-Lamki MA: Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman. Oman Med J. 2014 Jan;29(1):55-9. doi: 10.5001/omj.2014.12. [Article]
  26. Kim YM, Kang M, Choi JH, Lee BH, Kim GH, Ohn JH, Kim SY, Park MS, Yoo HW: A review of the literature on common CYP17A1 mutations in adults with 17-hydroxylase/17,20-lyase deficiency, a case series of such mutations among Koreans and functional characteristics of a novel mutation. Metabolism. 2014 Jan;63(1):42-9. doi: 10.1016/j.metabol.2013.08.015. Epub 2013 Oct 18. [Article]
  27. Rubtsov P, Nizhnik A, Dedov I, Kalinchenko N, Petrov V, Orekhova A, Spirin P, Prassolov V, Tiulpakov A: Partial deficiency of 17alpha-hydroxylase/17,20-lyase caused by a novel missense mutation in the canonical cytochrome heme-interacting motif. Eur J Endocrinol. 2015 May;172(5):K19-25. doi: 10.1530/EJE-14-0834. Epub 2015 Feb 3. [Article]

Associated Data

Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
NADHapproved, nutraceuticalunknowntargetDetails
Progesteroneapproved, vet_approvedunknowntargetsubstrateinhibitorDetails
AbirateroneapprovedyestargetinhibitorDetails
Aldosteroneexperimental, investigationalunknownenzymeinducerDetails
Aminophenazoneapproved, withdrawnunknownenzymesubstrateDetails
Stanoloneillicit, investigationalunknownenzymesubstrateDetails
Dexamethasoneapproved, investigational, vet_approvedunknownenzymeinhibitorDetails
Progesteroneapproved, vet_approvedunknownenzymeinhibitorDetails
Ketoconazoleapproved, investigationalyestargetinhibitorDetails
Clomifeneapproved, investigationalunknownenzymeinhibitorDetails
Cannabidiolapproved, investigationalunknowntargetinhibitorDetails
NabiximolsinvestigationalunknowntargetinhibitorDetails
Medical Cannabisexperimental, investigationalunknowntargetinhibitorDetails
Prasteroneapproved, investigational, nutraceuticalunknownenzymeproduct ofDetails
Dexamethasone acetateapproved, investigational, vet_approvedunknownenzymeinhibitorDetails
Levoketoconazoleapproved, investigationalyestargetinhibitorDetails
IsoconazoleapprovedyestargetinhibitorDetails
CFG-920investigationalyestargetinhibitorDetails
SeviteronelinvestigationalyestargetinhibitorDetails