Classical pathway of steroidogenesis with glucocorticoid and mineralocorticoid metabolism (WP4523)

Homo sapiens

In the biosynthesis of steroid hormones, cholesterol is transformed into mineralocorticoids, glucocorticoids and sex hormones via a series of hydroxylation, oxidation and reduction steps. To better understand the molecular level of sexual organ maturation in humans, the classical pathway and the alternative pathway of this process are produced. The pathways produce the main steroid hormones in humans, namely progestogen, corticosteroids, androgens and estrogens. The classical pathway produces androgen, a synthetic steroid hormone that regulates sexual development and maintenance of male sex organs by binding to androgen receptors. Next to the classical pathway of androgen synthesis, alternative pathways are known, such as [https://www.wikipathways.org/index.php/Pathway:WP4524]. For more information and details about androgens and the diseases linked with this molecular pathway, see Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)). This pathway also includes information on glucocorticoid and mineralocorticoid metabolism (previously captured in WP273; overlapping content is indicated with double borders for individual nodes; information previously missing is added with dashed borders). Mineralocorticoid (M) and glucocorticoid (G) receptors regulate transcription; either through 11-beta-hydroxysteroid dehydrogenase influencing aldosterone specificity on epithelial M-receptors or by modulation of AP-1- and NF-kappa-B-induced transcription through G-receptors. Specifically for the first case, aldosterone resistance in an autosomal form (a.k.a. pseudohypoaldosteronism) is linked to loss-of-function in epithelial Na-channel subunits [http://www.annualreviews.org/doi/abs/10.1146/annurev.med.48.1.231].

Authors

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

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology

cortisone reductase deficiency congenital adrenal hyperplasia obsolete apparent mineralocorticoid excess pseudohermaphroditism congenital adrenal insufficiency apparent mineralocorticoid excess syndrome

Pathway Ontology

lipoid congenital adrenal hyperplasia pathway steroid biosynthetic pathway disease pathway classic metabolic pathway C19-steroid hormone biosynthetic pathway congenital adrenal hyperplasia pathway C21-steroid hormone biosynthetic pathway apparent mineralocorticoid excess syndrome pathway glucocorticoid biosynthetic pathway

Participants

Label Type Compact URI Comment
Dihydrotestosterone Metabolite chebi:16330
Testosterone Metabolite chebi:17347
Oestradiol Metabolite chebi:16469
Cholesterol Metabolite chebi:16113
17-hydroxyprogesterone Metabolite chebi:17252
Cortisone Metabolite chebi:16962
Progesterone Metabolite chebi:17026
Corticosterone Metabolite chebi:16827
11-Deoxycortisol Metabolite chebi:28324
DHEA Metabolite chebi:28689
Cortisol Metabolite wikidata:Q190875
Androstenedione Metabolite chebi:16422
(11)-Deoxycorticosterone Metabolite chebi:16973
18-hydroxycorticosterone Metabolite chebi:16485
Aldosterone Metabolite chebi:27584
17-hydroxypregnenolone Metabolite chebi:28750
Pregnenolone Metabolite chebi:16581
NADP+ Metabolite chebi:58349
NADPH Metabolite chebi:57783
11b, 21-Dihydroxy-3,20-5b-Pregnan-18-al Metabolite pubchem.compound:44263338
3a,11b,21-Trihydroxy-20-Oxo-5b-Pregnan-18-al Metabolite pubchem.compound:44263346
3a-OH-5b-Pregnane-20-one Metabolite pubchem.compound:24779614
5b-Pregnane-3,20-dione Metabolite pubchem.compound:92745
Pregnanediol Metabolite cas:80-92-2
Glucuronides Metabolite chebi:26763
17a,21-Dihydroxy-5b-17a,21-Dihydroxy-5b-Pregnane-3,11,20-trione Metabolite pubchem.compound:65554 aka 4,5beta-Dihydrocortisone
Urocortisone Metabolite pubchem.compound:5754
Cortolone Metabolite cas:516-42-7
Urocortisol Metabolite pubchem.compound:5864 AKA Tetrahydrocortisol
11b,17a 21-Trihydroxy-5bPregnane 3,20-dione Metabolite cas:1482-50-4 AKA 11-BETA,17-ALPHA,21-TRIHYDROXY-5-BETA-PREGNANE-3,20-DIONE
CYP11A1 GeneProduct ncbigene:1583
HSD3B1 GeneProduct ncbigene:3283
HSD3B2 GeneProduct ncbigene:3284
CYP11B2 GeneProduct ncbigene:1585
Corticosterone methyl oxidase Protein ensembl:ENSG00000179142
P450scc Protein ensembl:ENSG00000140459 also known as CYP11A1
P450c21 Protein ensembl:ENSG00000231852
11beta-HSD1 Protein ensembl:ENSG00000117594 Reference study in mice [PMID:9405715]
3-beta-HSD Protein ensembl:ENSG00000203859
STAR Protein ensembl:ENSG00000147465
11beta-HSD2 Protein ensembl:ENSG00000176387
POR Protein uniprot:P16435
17-beta-HSD3 Protein ensembl:ENSG00000130948
H6PD Protein ensembl:ENSG00000049239 This enzyme produces NADPH which is neccessary for 11beta-HSD1 to convert cortisone into cortisol.
Cytochrome b5 Protein uniprot:J3KNC7
P450c17 Protein ensembl:ENSG00000148795
steroid 5 alpha-reductase 2 Protein ensembl:ENSG00000277893
P450Aro Protein ensembl:ENSG00000137869
P450c11 Protein ensembl:ENSG00000160882
HSD3B1 Protein ncbigene:3283
3B-OH-delta-Steroid Dh Protein eccode:1.1.1.145
Corticosterone 18-Monooxy Protein eccode:1.14.15.5 EC number: 1.14.15.5
3-Oxo-5b-Steroid Dh Protein uniprot:3O5B
3a-Hydroxy-steroid Dh Protein eccode:1.1.1.50 SPs:DIDH RAT
20b-Hydroxy-steroid Dh Protein eccode:1.1.1.53 1.1.1.53, similiar SP:2BHD STREX
Cortisone beta-reductase Protein eccode:1.3.1.3 1.3.1.3
(R)20-hydroxy-steroid Dh Protein eccode:1.1.1.53 1.1.1.53, similiar SP:2BHD STREX

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. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4996–5000. PubMed Europe PMC Scholia
  3. Corticosterone methyl oxidase type II (CMO II) deficiency: biochemical approach to diagnosis. Yong AB, Montalto J, Pitt J, Oakes S, Preston T, Buchanan C. Clin Biochem. 1994 Dec;27(6):491–4. PubMed Europe PMC Scholia
  4. The importance of DNA analysis in the diagnosis of steroid 5-alpha-reductase deficiency. Kostyrko A, Antkowiak J, Warenik-Szymankiewicz A, Trzeciak WH. Ginekol Pol. 1994 Jul;65(7):400–6. PubMed Europe PMC Scholia
  5. Molecular biology of mineralocorticoid metabolism. Fardella CE, Miller WL. Annu Rev Nutr. 1996;16:443–70. PubMed Europe PMC Scholia
  6. Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Funder JW. Annu Rev Med. 1997;48:231–40. PubMed Europe PMC Scholia
  7. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, et al. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924–9. PubMed Europe PMC Scholia
  8. 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
  9. A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia. Pang S, Wang W, Rich B, David R, Chang YT, Carbunaru G, et al. J Clin Endocrinol Metab. 2002 Jun;87(6):2556–63. PubMed Europe PMC Scholia
  10. Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. Carvajal CA, Gonzalez AA, Romero DG, González A, Mosso LM, Lagos ET, et al. J Clin Endocrinol Metab. 2003 Jun;88(6):2501–7. PubMed Europe PMC Scholia
  11. On the mechanism of the C11 beta-hydroxylation of steroids. HAYANO M, DORFMAN RI. J Biol Chem. 1954 Nov;211(1):227–35. PubMed Europe PMC Scholia
  12. Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele. Kuribayashi I, Nomoto S, Massa G, Oostdijk W, Wit JM, Wolffenbuttel BHR, et al. Horm Res. 2005;63(6):284–93. PubMed Europe PMC Scholia
  13. 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
  14. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Ghosh D, Griswold J, Erman M, Pangborn W. Nature. 2009 Jan 8;457(7226):219–23. PubMed Europe PMC Scholia
  15. Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1. Lawson AJ, Walker EA, Lavery GG, Bujalska IJ, Hughes B, Arlt W, et al. Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4111–6. PubMed Europe PMC Scholia
  16. 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
  17. Cholesterol Side-Chain Cleavage Enzyme (SCC) Deficiency. Katsumata N. Clin Pediatr Endocrinol. 2007;16(3):63–8. PubMed Europe PMC Scholia
  18. A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. new insight into the structure-function relationships of 3β-hydroxysteroid dehidrogenase type II. Baquedano MS, Ciaccio M, Marino R, Perez Garrido N, Ramirez P, Maceiras M, et al. J Clin Endocrinol Metab. 2015 Jan;100(1):E191-6. PubMed Europe PMC Scholia
  19. A case of 17 alpha-hydroxylase deficiency. Kim SM, Rhee JH. Clin Exp Reprod Med. 2015 Jun;42(2):72–6. PubMed Europe PMC Scholia
  20. Apparent mineralocorticoid excess. Funder JW. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):151–3. PubMed Europe PMC Scholia
  21. Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient. Kaur J, Casas L, Bose HS. Endocrinol Diabetes Metab Case Rep. 2016;2016:150119. PubMed Europe PMC Scholia
  22. P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms. Burkhard FZ, Parween S, Udhane SS, Flück CE, Pandey AV. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):38–50. PubMed Europe PMC Scholia
  23. 46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency. Mendonca BB, Gomes NL, Costa EMF, Inacio M, Martin RM, Nishi MY, et al. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):79–85. PubMed Europe PMC Scholia
  24. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. Parsa AA, New MI. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):2–11. PubMed Europe PMC Scholia
  25. Progesterone resistance in endometriosis: origins, consequences and interventions. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Acta Obstet Gynecol Scand. 2017 Jun;96(6):623–32. PubMed Europe PMC Scholia
  26. Role of Estrogens in the Regulation of Liver Lipid Metabolism. Palmisano BT, Zhu L, Stafford JM. Adv Exp Med Biol. 2017;1043:227–56. PubMed Europe PMC Scholia
  27. Aromatase Deficiency due to a Novel Mutation in CYP19A1 Gene. Unal E, Yıldırım R, Taş FF, Demir V, Onay H, Haspolat YK. J Clin Res Pediatr Endocrinol. 2018 Nov 29;10(4):377–81. PubMed Europe PMC Scholia