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Androstenedione and testosterone biosynthesis and metabolism p.1
Androstenedione and testosterone biosynthesis and metabolism p.1

Object List (links open in MetaCore):

1.14.14.1, 16 alpha-hydroxy- dehydro- epiandrosterone, 1.14.14.1, HSD17B2, 1.14.14.1, 17-alpha-hydroxy-pregnenolone, HSD3B2, SULT2A1, 3.1.6.2, 7alpha-hydroxy-androstenedione, 1.14.99.9, 1.14.14.1, 16 alpha-hydroxy- androstenedione, CYP3A5, None, HSD17B1, CYP3A4, CYP3A7, 1.14.14.1, 1.1.1.145 /5.3.3.1, 3.1.6.2, HSD17B3, 7alpha-hydroxy testosterone, Androstenediol, androstenedione, Dehydroepiandrosterone, 2.8.2.4, CYP17, 3.1.6.2, 1.14.14.1, CYP1A2, CYP2C19, dehydroepiandro sterone sulfate, CYP2A13, STS, testosterone, 16 alpha-hydroxy- dehydro- epiandrosterone 3-sulfate, 1.1.1.62, CYP2C9, 2.8.2.2, SULT1E1, 17-alpha-hydroxyprogesterone, 1.1.1.62, Androstenediol sulfate, 1.1.1.62, 1.1.1.145 /5.3.3.1, 1.14.99.9, HSD3B1, 1.1.1.145 /5.3.3.1, HSD17B8, 1.1.1.62, HSD17B7, CYP1A1

Description

Androstenedione and testosterone biosynthesis and metabolism part 1

Androstenedione is a 19-carbon steroid hormone produced as an intermediate step in the biochemical pathway that produces the androgen Testosterone and the estrogens Estrone and Estradiol.

Androstenedione originates either from the conversion of Dehydroepiandrosterone or from 17-alpha-Hydroxyprogesterone. These two metabolites have the common precursor - 17-alpha-Hydroxypregnenolone and they are produced as results of different transformations. The first one - formation of Dehydroepiandrosterone catalyzed by Cytochrome P450, family 17, subfamily A, polypeptide 1 ( CYP17 ) [1], [2], [3]. And the second reaction is mediated by Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 ( HSD3B1 ) [4], [5], and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 ( HSD3B2 ) [6], [7], [8], [9] with 17-alpha-Hydroxyprogesterone as a product. 17-alpha-Hydroxypregnenolone is a product of oxidative metabolism of Cholesterol.

Dehydroepiandrosterone comes into subsequent oxidative transformation with production of 16Alpha-hydroxydehydroepiandrosterone. This oxidation is catalyzed by Cytochrome P450, family 3, subfamily A, polypeptide 7 ( CYP3A7) [10], [11], [12] and Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4) [13], [10], [11]. Oxidative metabolite of this reaction as well as Dehydroepiandrosterone can be further sulfated by steroid sulfatase (microsomal), isozyme S ( STS ) [14], [15], [16], [15], [14]. Dehydroepiandrosterone and Dehydroepiandrosterone sulfate can be transformed into other compounds with hormonal activity, Androstendiol and Androstendiol sulfate, respectively. These two reactions are catalyzed by Hydroxysteroid (17-beta) dehydrogenase 1 ( HSD17B1) [17], [18], [17], [18], Hydroxysteroid (17-beta) dehydrogenase 2 ( HSD17B2) [19], [20], [20], [21], and Hydroxysteroid (17-beta) dehydrogenase 7 ( HSD17B7 ) [22], [23], [23], [24].

Androstendiol and Androstenedione are further converted to Testosterone. Formation of Testosterone from Androstendiol is catalyzed by HSD3B1 [25], [26] and HSD3B2 [27], [28], [26], whereas Hydroxysteroid (17-beta) dehydrogenase 3 ( HSD17B3 ), HSD17B7, HSD17B2 and HSD17B1 catalyze formation of testosterone from Androstenedione [29], [30], [31], [32], [22], [33], [23], [34], [30], [21], [20].

References:

  1. Lin CJ, Martens JW, Miller WL
    NF-1C, Sp1, and Sp3 are essential for transcription of the human gene for P450c17 (steroid 17alpha-hydroxylase/17,20 lyase) in human adrenal NCI-H295A cells. Molecular endocrinology (Baltimore, Md.) 2001 Aug;15(8):1277-93
  2. 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. The Journal of clinical endocrinology and metabolism 2002 Dec;87(12):5714-21
  3. Fluck CE, Miller WL, Auchus RJ
    The 17, 20-lyase activity of cytochrome p450c17 from human fetal testis favors the delta5 steroidogenic pathway. The Journal of clinical endocrinology and metabolism 2003 Aug;88(8):3762-6
  4. Shimozawa K, Saisho S, Yata J, Kambegawa A
    [Age-related changes of serum 17 alpha-hydroxypregnenolone and 17 alpha-hydroxypregnenolone sulfate concentrations in infancy and childhood] Nippon Naibunpi Gakkai zasshi 1985 Aug 20;61(8):785-93
  5. Byrne GC, Perry YS, Winter JS
    Kinetic analysis of adrenal 3 beta-hydroxysteroid dehydrogenase activity during human development. The Journal of clinical endocrinology and metabolism 1985 May;60(5):934-9
  6. Degryse E, Cauet G, Spagnoli R, Achstetter T
    Pregnenolone metabolized to 17alpha-hydroxyprogesterone in yeast: biochemical analysis of a metabolic pathway. The Journal of steroid biochemistry and molecular biology 1999 Dec 31;71(5-6):239-46
  7. Zhang L, Mason JI, Naiki Y, Copeland KC, Castro-Magana M, Gordon-Walker TT, Chang YT, Pang S
    Characterization of two novel homozygous missense mutations involving codon 6 and 259 of type II 3beta-hydroxysteroid dehydrogenase (3betaHSD) gene causing, respectively, nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder. The Journal of clinical endocrinology and metabolism 2000 Apr;85(4):1678-85
  8. Codner E, Okuma C, Iniguez G, Boric MA, Avila A, Johnson MC, Cassorla FG
    Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in patients with hypospadias. The Journal of clinical endocrinology and metabolism 2004 Feb;89(2):957-64
  9. Mermejo LM, Elias LL, Marui S, Moreira AC, Mendonca BB, de Castro M
    Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. The Journal of clinical endocrinology and metabolism 2005 Mar;90(3):1287-93
  10. Miller KK, Cai J, Ripp SL, Pierce WM Jr, Rushmore TH, Prough RA
    Stereo- and regioselectivity account for the diversity of dehydroepiandrosterone (DHEA) metabolites produced by liver microsomal cytochromes P450. Drug metabolism and disposition: the biological fate of chemicals 2004 Mar;32(3):305-13
  11. Nakamura H, Torimoto N, Ishii I, Ariyoshi N, Nakasa H, Ohmori S, Kitada M
    CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. Drug metabolism and disposition: the biological fate of chemicals 2003 Apr;31(4):432-8
  12. Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, Zaya MJ
    Developmental expression of the major human hepatic CYP3A enzymes. The Journal of pharmacology and experimental therapeutics 2003 Nov;307(2):573-82
  13. Leeder JS, Gaedigk R, Marcucci KA, Gaedigk A, Vyhlidal CA, Schindel BP, Pearce RE
    Variability of CYP3A7 expression in human fetal liver. The Journal of pharmacology and experimental therapeutics 2005 Aug;314(2):626-35
  14. Suzuki T, Hirato K, Yanaihara T, Kadofuku T, Sato T, Hoshino M, Yanaihara N
    Purification and properties of steroid sulfatase from human placenta. Endocrinologia japonica. 1992 Feb;39(1):93-101
  15. Kawano J, Kotani T, Ohtaki S, Minamino N, Matsuo H, Oinuma T, Aikawa E
    Characterization of rat and human steroid sulfatases. Biochimica et biophysica acta 1989 Aug 31;997(3):199-205
  16. Gniot-Szulzycka J, Januszewska B
    Purification of steroid sulphohydrolase from human placenta microsomes. Acta biochimica Polonica 1986;33(3):203-15
  17. Zhu SJ, Li Y, Li H, Wang YL, Xiao ZJ, Vihko P, Piao YS
    Retinoic acids promote the action of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 on the biosynthesis of 17beta-estradiol in placental cells. The Journal of endocrinology 2002 Jan;172(1):31-43
  18. Zhou Z, Speiser PW
    Regulation of HSD17B1 and SRD5A1 in lymphocytes. Molecular genetics and metabolism 1999 Nov;68(3):410-7
  19. Durocher F, Morissette J, Labrie Y, Labrie F, Simard J
    Mapping of the HSD17B2 gene encoding type II 17 beta-hydroxysteroid dehydrogenase close to D16S422 on chromosome 16q24.1-q24.2. Genomics 1995 Feb 10;25(3):724-6
  20. Day JM, Tutill HJ, Newman SP, Purohit A, Lawrence HR, Vicker N, Potter BV, Reed MJ
    17Beta-hydroxysteroid dehydrogenase Type 1 and Type 2: association between mRNA expression and activity in cell lines. Molecular and cellular endocrinology 2006 Mar 27;248(1-2):246-9
  21. Provost PR, Blomquist CH, Drolet R, Flamand N, Tremblay Y
    Androgen inactivation in human lung fibroblasts: variations in levels of 17 beta-hydroxysteroid dehydrogenase type 2 and 5 alpha-reductase activity compatible with androgen inactivation. The Journal of clinical endocrinology and metabolism 2002 Aug;87(8):3883-92
  22. Krazeisen A, Breitling R, Imai K, Fritz S, Moller G, Adamski J
    Determination of cDNA, gene structure and chromosomal localization of the novel human 17beta-hydroxysteroid dehydrogenase type 7(1). FEBS letters 1999 Oct 29;460(2):373-9
  23. Marijanovic Z, Laubner D, Moller G, Gege C, Husen B, Adamski J, Breitling R
    Closing the gap: identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis. Molecular endocrinology (Baltimore, Md.) 2003 Sep;17(9):1715-25
  24. Ohnesorg T, Adamski J
    Analysis of the 5' flanking regions of human and murine HSD17B7: identification of a cholesterol dependent enhancer region. Molecular and cellular endocrinology 2006 Mar 27;248(1-2):164-7
  25. Gingras S, Moriggl R, Groner B, Simard J
    Induction of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. Molecular endocrinology (Baltimore, Md.) 1999 Jan;13(1):66-81
  26. Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA, Melner MH
    Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Endocrine reviews 2005 Jun;26(4):525-82
  27. Pang S, Carbunaru G, Haider A, Copeland KC, Chang YT, Lutfallah C, Mason JI
    Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test. Clinical endocrinology 2003 Mar;58(3):323-31
  28. Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S
    The human kidney is a progesterone-metabolizing and androgen-producing organ. The Journal of clinical endocrinology and metabolism 2003 Jun;88(6):2803-9
  29. Tremblay Y, Ringler GE, Morel Y, Mohandas TK, Labrie F, Strauss JF 3rd, Miller WL
    Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen----q25. The Journal of biological chemistry 1989 Dec 5;264(34):20458-62
  30. Zhang Y, Word RA, Fesmire S, Carr BR, Rainey WE
    Human ovarian expression of 17 beta-hydroxysteroid dehydrogenase types 1, 2, and 3. The Journal of clinical endocrinology and metabolism 1996 Oct;81(10):3594-8
  31. Moghrabi N, Hughes IA, Dunaif A, Andersson S
    Deleterious missense mutations and silent polymorphism in the human 17beta-hydroxysteroid dehydrogenase 3 gene (HSD17B3). The Journal of clinical endocrinology and metabolism 1998 Aug;83(8):2855-60
  32. Torn S, Nokelainen P, Kurkela R, Pulkka A, Menjivar M, Ghosh S, Coca-Prados M, Peltoketo H, Isomaa V, Vihko P
    Production, purification, and functional analysis of recombinant human and mouse 17beta-hydroxysteroid dehydrogenase type 7. Biochemical and biophysical research communications 2003 May 23;305(1):37-45
  33. Ohnesorg T, Keller B, Hrabe de Angelis M, Adamski J
    Transcriptional regulation of human and murine 17beta-hydroxysteroid dehydrogenase type-7 confers its participation in cholesterol biosynthesis. Journal of molecular endocrinology 2006 Aug;37(1):185-97
  34. Wu L, Einstein M, Geissler WM, Chan HK, Elliston KO, Andersson S
    Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity. The Journal of biological chemistry 1993 Jun 15;268(17):12964-9