Alternative pathway of fetal androgen synthesis (WP4524)

Homo sapiens

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The development of sexual organs in humans is still not completely understood at the molecular level, controlled through the chromosomal difference between men and women. Steroids related to sexual development can have a temporary or permanent effects. Androgens are the leading compounds differentiating between (among other sexual organs) the internal and external genitalia of men. Next to the classical pathway of androgen synthesis (see [https://www.wikipathways.org/index.php/Pathway:WP4523]), alternative pathways are known, which make use of either selective expression patterns of isoenzymes or alternate enzymes. As an alternative, a socalled 'backdoor pathway', which can create dihydrotestosterone (DHT), skipping testosterone. Several enzymes between the classical and backdoor pathway are shared, however the later one utilises one unique enzyme, 3-alpha hydroxysteroid dehydrogenase 3 (gene: AKR1C2). Even though the relevance of this backdoor pathway for humans is not completely clear yet, mutations in the human AKR1C2 gene can lead to disordered sexual differentiation. This finding would indicate that both the classical and the alternative pathway are needed for normal development of male genitalia in humans. For more information on androgens, see Hiort (2013 [https://www.ncbi.nlm.nih.gov/pubmed/23800242]), and for more information on the disease linked to this pathway, please visit Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)).

Authors

Eline Sanders , Denise Slenter , Egon Willighagen , Irene Hemel , Friederike Ehrhart , Eric Weitz , and Finterly Hu

Activity

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Cited In

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Pathway Ontology

altered isoprenoid biosynthetic pathway disease pathway steroid hormone metabolic pathway testosterone biosynthetic pathway steroid metabolic pathway altered steroid biosynthetic pathway steroid hormone biosynthetic pathway cholesterol metabolic pathway

Disease Ontology

steroid inherited metabolic disorder

Participants
Query Drugst.One

Label Type Compact URI Comment
Dihydrotestosterone (DHT) Metabolite chebi:16330
Pregnenolone Metabolite chebi:16581
Androsterone Metabolite chebi:16032
17-hydroxyallopregnanolone Metabolite chebi:11909
DHEA Metabolite chebi:28689
17-Hydroxypregnenolone Metabolite wikidata:Q2064889
17-hydroxyprogesterone Metabolite hmdb:HMDB0000374
NADP+ Metabolite chebi:58349
17-hydroxydihydroprogesterone Metabolite chebi:36723
NADPH Metabolite chebi:57783
Androstanedione Metabolite chebi:15994
Androstenedione Metabolite chebi:16422
Androst-4-ene-3,17-dione Metabolite chebi:16422
Progesterone Metabolite chebi:17026
Cholesterol Metabolite chebi:16113
NAD+ Metabolite chebi:57540
Testosterone Metabolite chebi:17347
Androstanediol Metabolite chebi:27727
NADH Metabolite chebi:57945
P450scc GeneProduct ensembl:ENSG00000140459
STAR GeneProduct ensembl:ENSG00000147465
5-alpha-reductase 1 GeneProduct ensembl:ENSG00000277893
17-beta-HSD GeneProduct ensembl:ENSG00000130948
3-beta-HSD GeneProduct ensembl:ENSG00000203859
AKR1C2/4 GeneProduct ensembl:ENSG00000151632
AKR1C4 GeneProduct ensembl:ENSG00000198610
P450c17 GeneProduct ensembl:ENSG00000148795
17-beta-HSD3 GeneProduct ensembl:ENSG00000130948
Cytb5 Protein uniprot:P00167
3 HSD Protein uniprot:P26439 Aka HSD3B2; 3 beta-hydroxysteroid dehydrogenase type II
AKR1C2 Protein uniprot:P52895 Responsible protein found through Rhea (not part of Blau book)
P450c17 Protein ensembl:ENSG00000148795
RODH Protein uniprot:O14756
POR Protein uniprot:P16435 Function:'This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes' [https://www.uniprot.org/uniprot/P16435]
POR Protein uniprot:P16435
5-alpha-reductase 2 Protein uniprot:P31213
P450c17 Protein uniprot:P05093 Function:'Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty' [https://www.uniprot.org/uniprot/P05093]

References

  1. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
  2. Genetic and hormonal control of male sexual differentiation. Goldstein JL, Wilson JD. J Cell Physiol. 1975 Apr;85(2 Pt 2 Suppl 1):365–77. PubMed Europe PMC Scholia
  3. Diminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2. Moore RJ, Griffin JE, Wilson JD. J Biol Chem. 1975 Sep 25;250(18):7168–72. PubMed Europe PMC Scholia
  4. Dihydrotestosterone formation in cultured human fibroblasts. Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, Type 2. Wilson JD. J Biol Chem. 1975 May 10;250(9):3498–504. PubMed Europe PMC Scholia
  5. Mass spectrometric study of the enzymatic conversion of cholesterol to (22R)-22-hydroxycholesterol, (20R,22R)-20,22-dihydroxycholesterol, and pregnenolone, and of (22R)-22-hydroxycholesterol to the lgycol and pregnenolone in bovine adrenocortical preparations. Mode of oxygen incorporation. Burstein S, Middleditch BS, Gut M. J Biol Chem. 1975 Dec 10;250(23):9028–37. PubMed Europe PMC Scholia
  6. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Andersson S, Russell DW. Proc Natl Acad Sci U S A. 1990 May;87(10):3640–4. PubMed Europe PMC Scholia
  7. Adrenal mitochondrial cytochrome P-450scc. Cholesterol and adrenodoxin interactions at equilibrium and during turnover. Hanukoglu I, Spitsberg V, Bumpus JA, Dus KM, Jefcoate CR. J Biol Chem. 1981 May 10;256(9):4321–8. PubMed Europe PMC Scholia
  8. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, Mendonca BB, et al. Nat Genet. 1994 May;7(1):34–9. PubMed Europe PMC Scholia
  9. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. Auchus RJ, Lee TC, Miller WL. J Biol Chem. 1998 Feb 6;273(6):3158–65. PubMed Europe PMC Scholia
  10. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Makridakis NM, di Salle E, Reichardt JK. Pharmacogenetics. 2000 Jul;10(5):407–13. PubMed Europe PMC Scholia
  11. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, et al. Biochem J. 2000 Oct 1;351(Pt 1):67–77. PubMed Europe PMC Scholia
  12. Characterization of a novel type of human microsomal 3alpha -hydroxysteroid dehydrogenase: unique tissue distribution and catalytic properties. Chetyrkin SV, Belyaeva OV, Gough WH, Kedishvili NY. J Biol Chem. 2001 Jun 22;276(25):22278–86. PubMed Europe PMC Scholia
  13. Determination of the redox properties of human NADPH-cytochrome P450 reductase. Munro AW, Noble MA, Robledo L, Daff SN, Chapman SK. Biochemistry. 2001 Feb 20;40(7):1956–63. PubMed Europe PMC Scholia
  14. Further characterization of human microsomal 3alpha-hydroxysteroid dehydrogenase. Chetyrkin SV, Hu J, Gough WH, Dumaual N, Kedishvili NY. Arch Biochem Biophys. 2001 Feb 1;386(1):1–10. PubMed Europe PMC Scholia
  15. Expanded substrate screenings of human and Drosophila type 10 17beta-hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile acid and steroid hormone metabolism: characterization of multifunctional 3alpha/7alpha/7beta/17beta/20beta/21-HSD. Shafqat N, Marschall HU, Filling C, Nordling E, Wu XQ, Björk L, et al. Biochem J. 2003 Nov 15;376(Pt 1):49–60. PubMed Europe PMC Scholia
  16. Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Mast N, Norcross R, Andersson U, Shou M, Nakayama K, Bjorkhem I, et al. Biochemistry. 2003 Dec 9;42(48):14284–92. PubMed Europe PMC Scholia
  17. Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme. Mindnich R, Haller F, Halbach F, Moeller G, Hrabé de Angelis M, Adamski J. J Mol Endocrinol. 2005 Oct;35(2):305–16. PubMed Europe PMC Scholia
  18. Functional expression and characterisation of human cytochrome P45017alpha in Pichia pastoris. Kolar NW, Swart AC, Mason JI, Swart P. J Biotechnol. 2007 May 10;129(4):635–44. PubMed Europe PMC Scholia
  19. Engineering, expression, and purification of “soluble” human cytochrome P45017alpha and its functional characterization. Pechurskaya TA, Lukashevich OP, Gilep AA, Usanov SA. Biochemistry (Mosc). 2008 Jul;73(7):806–11. PubMed Europe PMC Scholia
  20. Measurement of cytochrome P450 and NADPH-cytochrome P450 reductase. Guengerich FP, Martin MV, Sohl CD, Cheng Q. Nat Protoc. 2009;4(9):1245–51. PubMed Europe PMC Scholia
  21. Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1. Mast N, Annalora AJ, Lodowski DT, Palczewski K, Stout CD, Pikuleva IA. J Biol Chem. 2011 Feb 18;286(7):5607–13. PubMed Europe PMC Scholia
  22. High-yield expression of a catalytically active membrane-bound protein: human P450 oxidoreductase. Sandee D, Miller WL. Endocrinology. 2011 Jul;152(7):2904–8. PubMed Europe PMC Scholia
  23. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10139–43. PubMed Europe PMC Scholia
  24. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Flück CE, Meyer-Böni M, Pandey AV, Kempná P, Miller WL, Schoenle EJ, et al. Am J Hum Genet. 2011 Aug 12;89(2):201–18. PubMed Europe PMC Scholia
  25. The differential role of androgens in early human sex development. Hiort O. BMC Med. 2013 Jun 24;11:152. PubMed Europe PMC Scholia
  26. Aldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates. Weber S, Salabei JK, Möller G, Kremmer E, Bhatnagar A, Adamski J, et al. J Biol Chem. 2015 Mar 6;290(10):6531–45. PubMed Europe PMC Scholia
  27. Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY Disorders of Sex Development. Engeli RT, Rhouma BB, Sager CP, Tsachaki M, Birk J, Fakhfakh F, et al. J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):147–54. PubMed Europe PMC Scholia
  28. Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1). Simonov AN, Holien JK, Yeung JCI, Nguyen AD, Corbin CJ, Zheng J, et al. PLoS One. 2015 Nov 20;10(11):e0141252. PubMed Europe PMC Scholia
  29. Unveiling the crucial intermediates in androgen production. Mak PJ, Gregory MC, Denisov IG, Sligar SG, Kincaid JR. Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15856–61. PubMed Europe PMC Scholia
  30. Characterization of 5α-reductase activity and isoenzymes in human abdominal adipose tissues. Fouad Mansour M, Pelletier M, Tchernof A. J Steroid Biochem Mol Biol. 2016 Jul;161:45–53. PubMed Europe PMC Scholia
  31. Role of cytochrome b5 in the modulation of the enzymatic activities of cytochrome P450 17α-hydroxylase/17,20-lyase (P450 17A1). Bhatt MR, Khatri Y, Rodgers RJ, Martin LL. J Steroid Biochem Mol Biol. 2017 Jun;170:2–18. PubMed Europe PMC Scholia
  32. Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN. Yoshimoto FK, Gonzalez E, Auchus RJ, Guengerich FP. J Biol Chem. 2016 Aug 12;291(33):17143–64. PubMed Europe PMC Scholia