Classical pathway of steroidogenesis with glucocorticoid and mineralocorticoid metabolism (Homo sapiens)

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19, 20, 2620, 2620, 2643132521542213159Lipoid adrenal hyperplasia16P450c21CorticosteroneP450c1717-hydroxyprogesteroneTestosterone18-hydroxycorticosteronePORH6PDPOR(11)-Deoxycorticosterone11-Deoxycortisol11beta-HSD2Cytochrome b55-alpha-Reductase2P450Aro11beta-HSD13-beta-HSD17-beta-HSD3DihydrotestosteroneAndrostenedioneAldosterone17-hydroxypregnenoloneP450sccCortisoneCholesterolCorticosterone Methyl OxidaseProgesteroneCortisolPORSTAROestradiolPregnenoloneDHEA2520, 2620, 263-beta-HSDP450c11P450c17P450c173-beta-HSDCholesterol side-chain cleavage deficiency817-Alpha-hydroxylase / 17-lyase deficiency233-beta-HSD type II deficiency121-Hydroxylase deficiency11-beta-hydroxylase type I deficiency1110Corticosterone methyl oxidase deficiencyCortisone reductase deficiency214Apparent mineralocorticoid excess17-beta-HSD deficiency75-alpha-reductase type II deficiency24Aromatase deficiency1812P450 oxidoreductase deficiency273-beta-HSD type II deficiencyPOR1Progesterone resistance17Oestrogen resistance6NADP+NADPHCholesterol BiosynthesisCYP11A120, 26HSD3B13B-OH-delta-Steroid DhHSD3B1HSD3B2Androgen Synthesis and MetabolismCYP11B220, 26Corticosterone 18-Monooxy11b, 21-Dihydroxy-3,20-5b-Pregnan-18-al20, 263a,11b,21-Trihydroxy-20-Oxo-5b-Pregnan-18-al3-Oxo-5b-Steroid Dh3a-Hydroxy-steroid Dh3a-OH-5b-Pregnane-20-one5b-Pregnane-3,20-dioneProgesterone Degradation20b-Hydroxy-steroid DhPregnanediolGlucuronides17a,21-Dihydroxy-5b-17a,21-Dihydroxy-5b-Pregnane-3,11,20-trioneUrocortisoneCortoloneCortisone beta-reductase3a-Hydroxy-steroid Dh(R)20-hydroxy-steroid DhUrocortisol11b,17a 21-Trihydroxy-5bPregnane 3,20-dioneCortisolGlucocorticoidsSteroid Hormone Signaling


Description

The biosynthesis of steroid hormones is a difficult process in which 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 is meant to produce an important steroid called Androgen, which is a synthetic steroid hormone that regulates sexual development and the maintenance of the male sex organs via binding to androgen receptors. Next to the classical pathway of androgen synthesis, alternative pathways are known, such as [1].

For more information and details about Androgens and the diseases linked with this molecular pathway, please visit Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)) .

We have recently expanded this pathway with information from the Glucocorticoid and Mineralocorticoid Metabolism (previously captured in WP273; overlapping content is indicated with double borders for individual datanodes; 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 modulcation of AP-1- and NF-kappa-B-induced transcription through G-receptors. Specifically for the first case, aldosterone resistance in an autosomal form (aka pseudohypoaldosteronism) is linked to loss-of-function in epithelical Na-channel subunits [2].

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Bibliography

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  1. Yong AB, Montalto J, Pitt J, Oakes S, Preston T, Buchanan C; ''Corticosterone methyl oxidase type II (CMO II) deficiency: biochemical approach to diagnosis.''; Clin Biochem, 1994 PubMed Europe PMC Scholia
  2. Makridakis NM, di Salle E, Reichardt JK; ''Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.''; Pharmacogenetics, 2000 PubMed Europe PMC Scholia
  3. Parsa AA, New MI; ''Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  4. Kim SM, Rhee JH; ''A case of 17 alpha-hydroxylase deficiency.''; Clin Exp Reprod Med, 2015 PubMed Europe PMC Scholia
  5. Blau, Nenad, Duran, Marinus, Gibson, K, Michael, Dionisi-Vici, Carlo; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Disease'''; ISBN 978-3-64240337-8, 2014
  6. Baquedano MS, Ciaccio M, Marino R, Perez Garrido N, Ramirez P, Maceiras M, Turjanski A, Defelipe LA, Rivarola MA, Belgorosky A; ''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.''; J Clin Endocrinol Metab, 2015 PubMed Europe PMC Scholia
  7. Unal E, TaÅŸ FF, Demir V, Onay H, Haspolat YK; ''Aromatase Deficiency due to a Novel Mutation inCYP19A1Gene''; J Clin Res Pediatr Endocrinol, 2018 PubMed Europe PMC Scholia
  8. Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ; ''11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.''; Proc Natl Acad Sci U S A, 1997 PubMed Europe PMC Scholia
  9. Katsumata N; ''Cholesterol Side-Chain Cleavage Enzyme (SCC) Deficiency.''; Clin Pediatr Endocrinol, 2007 PubMed Europe PMC Scholia
  10. Funder JW; ''Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.''; Annu Rev Med, 1997 PubMed Europe PMC Scholia
  11. Burkhard FZ, Parween S, Udhane SS, Flück CE, Pandey AV; ''P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  12. HAYANO M, DORFMAN RI; ''On the mechanism of the C11 beta-hydroxylation of steroids.''; J Biol Chem, 1954 PubMed Europe PMC Scholia
  13. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN; ''Progesterone resistance in endometriosis: origins, consequences and interventions.''; Acta Obstet Gynecol Scand, 2017 PubMed Europe PMC Scholia
  14. Kostyrko A, Antkowiak J, Warenik-Szymankiewicz A, Trzeciak WH; ''[The importance of DNA analysis in the diagnosis of steroid 5-alpha-reductase deficiency].''; Ginekol Pol, 1994 PubMed Europe PMC Scholia
  15. Kaur J, Casas L, Bose HS; ''Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient.''; Endocrinol Diabetes Metab Case Rep, 2016 PubMed Europe PMC Scholia
  16. Funder JW; ''Apparent mineralocorticoid excess.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  17. Carvajal CA, Gonzalez AA, Romero DG, González A, Mosso LM, Lagos ET, Hevia Mdel P, Rosati MP, Perez-Acle TO, Gomez-Sanchez CE, Montero JA, Fardella CE; ''Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.''; J Clin Endocrinol Metab, 2003 PubMed Europe PMC Scholia
  18. Palmisano BT, Zhu L, Stafford JM; ''Role of Estrogens in the Regulation of Liver Lipid Metabolism.''; Adv Exp Med Biol, 2017 PubMed Europe PMC Scholia
  19. Mendonca BB, Gomes NL, Costa EM, Inacio M, Martin RM, Nishi MY, Carvalho FM, Tibor FD, Domenice S; ''46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  20. Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC; ''Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.''; Proc Natl Acad Sci U S A, 1992 PubMed Europe PMC Scholia
  21. Mindnich R, Haller F, Halbach F, Moeller G, Hrabé de Angelis M, Adamski J; ''Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme.''; J Mol Endocrinol, 2005 PubMed Europe PMC Scholia
  22. Fardella CE, Miller WL; ''Molecular biology of mineralocorticoid metabolism.''; Annu Rev Nutr, 1996 PubMed Europe PMC Scholia
  23. Kuribayashi I, Nomoto S, Massa G, Oostdijk W, Wit JM, Wolffenbuttel BH, Shizuta Y, Honke K; ''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.''; Horm Res, 2005 PubMed Europe PMC Scholia
  24. Ghosh D, Griswold J, Erman M, Pangborn W; ''Structural basis for androgen specificity and oestrogen synthesis in human aromatase.''; Nature, 2009 PubMed Europe PMC Scholia
  25. Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW; ''Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.''; Proc Natl Acad Sci U S A, 2011 PubMed Europe PMC Scholia
  26. Pang S, Wang W, Rich B, David R, Chang YT, Carbunaru G, Myers SE, Howie AF, Smillie KJ, Mason JI; ''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.''; J Clin Endocrinol Metab, 2002 PubMed Europe PMC Scholia
  27. Lawson AJ, Walker EA, Lavery GG, Bujalska IJ, Hughes B, Arlt W, Stewart PM, Ride JP; ''Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1.''; Proc Natl Acad Sci U S A, 2011 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134327view12:40, 20 July 2024EweitzModified description
134326view12:39, 20 July 2024EweitzModified description
134325view12:37, 20 July 2024EweitzModified description
134294view05:57, 20 July 2024EgonwRemoved template comments
128197view01:37, 29 January 2024EweitzRefine padding, spelling; standardize color, shape
128196view01:35, 29 January 2024EweitzSoften color, use rounded rectangle for disease nodes
128040view22:14, 21 January 2024EweitzStandardize case
125468view12:45, 16 February 2023DeSlOntology Term : 'classic metabolic pathway' added !
121849view16:18, 7 March 2022DeSlAdded arrow from metabolic conversion to two disorders (linked to complex protein)
120403view09:13, 30 November 2021Fehrhartboxed pathway nodes
120015view18:10, 13 October 2021EgonwPubChem CID of the same compound but with stereochemistry
119309view13:12, 23 June 2021FinterlyAdded ISBN for book citation
116370view12:46, 4 May 2021EweitzModified title
113593view09:42, 4 November 2020DeSlUpdated second cortisol ID to avoid duplicate mappings
113574view16:12, 2 November 2020DeSlAdded missing protein IDs (Ec numbers only).
113573view16:10, 2 November 2020DeSlAdded more IDs for metabolites
113572view16:03, 2 November 2020DeSlStarted annotating metabolites missing an ID.
113048view15:20, 31 October 2020EgonwModified title
113034view09:45, 30 October 2020DeSlAnother small layout change, converted complex with 3B-OH-delta steroid DH to proteins iso GeneProducts
113033view09:38, 30 October 2020DeSlSmall layout change in bottom left corner
113032view09:36, 30 October 2020DeSlAdded 3 EC ID from comments as DataNode IDs
113031view08:56, 30 October 2020DeSlOntology Term : 'C21-steroid hormone biosynthetic pathway' added !
113030view08:55, 30 October 2020DeSlOntology Term : 'glucocorticoid biosynthetic pathway' added !
113029view08:54, 30 October 2020DeSlAdded progesterone link to steroid hormone signalling.
113025view08:49, 30 October 2020DeSlAdded missing refrence on cortisone -> cortisol conversion through 11beta-HSD1
113024view08:37, 30 October 2020DeSlAdded details on merging PWs.
113023view08:35, 30 October 2020DeSlUpdated description to include new PW info
113022view08:25, 30 October 2020DeSlUpdated title
113010view16:12, 29 October 2020DeSlSmall layout change
113009view16:08, 29 October 2020DeSlAdded "Glucocorticoids" path from WP237
113007view15:59, 29 October 2020DeSlUpdated until cortolone metabolite
113004view15:51, 29 October 2020DeSlAdded progesteron degradation track
113003view15:39, 29 October 2020DeSlAdded up to androgen synthesis and metabolism PW-node from WP237
113002view15:32, 29 October 2020DeSlStarted integrating WP237 info (in dark grey)
112970view09:13, 24 October 2020DeSlUpdating ID for cortisol to avoid duplicate mappings
108086view11:53, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
104251view12:05, 12 May 2019EgonwRemoved the RHEA: prefix from the identifier.
104033view17:45, 25 April 2019IreneHemelModified description
103565view09:57, 15 March 2019ElineSandersChanged geneproducts into proteins
103497view14:17, 6 March 2019DeSlModified description
103496view14:14, 6 March 2019DeSlRemoved weird signs in lit. ref (second try).
103402view09:45, 27 February 2019DeSlRemoved weird signs in lit. ref; changed long OMIM links to short ones.
103345view12:55, 22 February 2019DeSlConnected unconnected line to P450c17
103344view12:54, 22 February 2019DeSlUpdated OMIM for Aromatase deficiency (was linked to gene iso disease before).
103343view12:51, 22 February 2019DeSlOntology Term : 'pseudohermaphroditism' added !
103342view12:47, 22 February 2019DeSlOntology Term : 'congenital adrenal hyperplasia' added !
103341view12:45, 22 February 2019DeSlOntology Term : 'congenital adrenal hyperplasia pathway' added !
103340view12:44, 22 February 2019DeSlOntology Term : 'apparent mineralocorticoid excess syndrome pathway' added !
103339view12:43, 22 February 2019DeSlOntology Term : 'lipoid congenital adrenal hyperplasia pathway' added !
103338view12:43, 22 February 2019DeSlOntology Term : 'congenital adrenal insufficiency' added !

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(11)-DeoxycorticosteroneMetaboliteCHEBI:16973 (ChEBI)
(R)20-hydroxy- steroid DhProtein1.1.1.53 (Enzyme Nomenclature) 1.1.1.53, similiar SP:2BHD STREX
11-DeoxycortisolMetaboliteCHEBI:28324 (ChEBI)
11b, 21-Dihydroxy-3,20- 5b-Pregnan-18-alMetabolite
11b,17a 21-Trihydroxy-5b Pregnane 3,20-dioneMetabolite
11beta-HSD1ProteinENSG00000117594 (Ensembl) Reference study in mice [PMID:9405715]
11beta-HSD2ProteinENSG00000176387 (Ensembl)
17-beta-HSD3ProteinENSG00000130948 (Ensembl)
17-hydroxypregnenoloneMetaboliteCHEBI:28750 (ChEBI)
17-hydroxyprogesteroneMetaboliteCHEBI:17252 (ChEBI)
17a,21-Dihydroxy-5b-17a,21-Dihydroxy-5b- Pregnane-3,11,20-trioneMetabolite
18-hydroxycorticosteroneMetaboliteCHEBI:16485 (ChEBI)
20b-Hydroxy- steroid DhProtein1.1.1.53, similiar SP:2BHD STREX
3-Oxo-5b- Steroid DhGeneProduct3O5B (Uniprot-TrEMBL)
3-beta- HSDProteinENSG00000203859 (Ensembl)
3-beta-HSDProteinENSG00000203859 (Ensembl)
3B-OH-delta- Steroid DhGeneProduct
3a,11b,21-Trihydroxy-20-Oxo- 5b-Pregnan-18-alMetabolite
3a-Hydroxy- steroid DhGeneProductSPs:DIDH RAT
3a-OH-5b-Pregnane-20-oneMetabolite
5-alpha-Reductase2ProteinENSG00000277893 (Ensembl)
5b-Pregnane-3,20-dioneMetabolite
AldosteroneMetaboliteCHEBI:27584 (ChEBI)
Androgen Synthesis and MetabolismPathwayWP496 (WikiPathways)
AndrostenedioneMetaboliteCHEBI:16422 (ChEBI)
CYP11A1GeneProduct1583 (Entrez Gene)
CYP11B2GeneProduct1585 (Entrez Gene)
Cholesterol BiosynthesisPathwayWP197 (WikiPathways)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
Corticosterone 18-MonooxyGeneProductEC number: 1.14.15.5
Corticosterone Methyl OxidaseProteinENSG00000179142 (Ensembl)
CorticosteroneMetaboliteCHEBI:16827 (ChEBI)
CortisolMetabolite50-23-7 (CAS)
CortisolMetaboliteQ190875 (Wikidata)
Cortisone beta-reductaseProtein1.3.1.3
CortisoneMetaboliteCHEBI:16962 (ChEBI)
CortoloneMetabolite516-42-7 (CAS)
Cytochrome b5ProteinJ3KNC7 (Uniprot-TrEMBL)
DHEAMetaboliteCHEBI:28689 (ChEBI)
DihydrotestosteroneMetaboliteCHEBI:16330 (ChEBI)
GlucuronidesMetabolite
H6PDProteinENSG00000049239 (Ensembl)
  • This enzyme produces NADPH which is neccessary for 11beta-HSD1 to convert cortisone into cortisol.
  • Type your comment here
HSD3B1GeneProduct3283 (Entrez Gene)
HSD3B2GeneProduct3284 (Entrez Gene)
NADP+MetaboliteCHEBI:58349 (ChEBI)
NADPHMetaboliteCHEBI:57783 (ChEBI)
OestradiolMetaboliteCHEBI:16469 (ChEBI)
P450AroProteinENSG00000137869 (Ensembl)
P450c11ProteinENSG00000160882 (Ensembl)
P450c17ProteinENSG00000148795 (Ensembl)
P450c21ProteinENSG00000231852 (Ensembl)
P450sccProteinENSG00000140459 (Ensembl)
  • also known as CYP11A1
  • Type your comment here
PORProteinP16435 (Uniprot-TrEMBL)
PregnanediolMetabolite80-92-2 (CAS)
PregnenoloneMetaboliteCHEBI:16581 (ChEBI)
ProgesteroneMetaboliteCHEBI:17026 (ChEBI)
STARProteinENSG00000147465 (Ensembl)
Steroid Hormone SignalingPathwayWP170 (WikiPathways)
TestosteroneMetaboliteCHEBI:17347 (ChEBI)
UrocortisolMetabolite
UrocortisoneMetabolite

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(11)-DeoxycorticosteroneCorticosteronemim-conversion15630 (Rhea)
11-DeoxycortisolCortisolmim-conversion15630 (Rhea)
17-hydroxypregnenolone17-hydroxyprogesteronemim-conversion24077 (Rhea)
17-hydroxypregnenoloneDHEAmim-conversion50245 (Rhea)
17-hydroxyprogesteroneAndrostenedionemim-conversion14754 (Rhea)
18-hydroxycorticosteroneAldosteronemim-conversion11874 (Rhea)
AndrostenedioneTestosteronemim-conversion14983 (Rhea)
CholesterolPregnenolonemim-conversion35740 (Rhea)
Corticosterone18-hydroxycorticosteronemim-conversion11873 (Rhea)
CortisolCortisonemim-conversion53117 (Rhea)
CortisoneCortisolmim-conversion11390 (Rhea) Reference study in mice [PMID:9405715]
Pregnenolone17-hydroxypregnenolonemim-conversion50237 (Rhea)
PregnenoloneProgesteronemim-conversion24077 (Rhea)
Progesterone17-hydroxyprogesteronemim-conversion46309 (Rhea)
TestosteroneDihydrotestosteronemim-conversion54385 (Rhea)
TestosteroneOestradiolmim-conversion38192 (Rhea)
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