Alternative pathway of fetal androgen synthesis (Homo sapiens)

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8, 313, 152, 6, 15, 2321212, 18, 225, 122, 27, 327, 9, 10, 171, 2, 2114, 16, 222, 3, 25, 2816, 22222, 1514, 16, 22194, 11, 1942, 35-alpha-reductasetype II deficiency17-beta-hydroxysteroiddehydrogenase deficiency13, 2620, 24TestosteroneAKR1C4AndrostanedioneAndrosteroneAKR1C2NADPHRODHAndrost-4-ene-3,17-dione5-alpha-reductase 1DHEAAndrostanediolAndrostenedione3-beta-HSDDihydrotestosterone (DHT)CholesterolAKR1C2/4NADP+17-hydroxyallopregnanoloneP450c1717-hydroxyprogesteronePORP450sccSTARProgesterone17-hydroxydihydroprogesterone17-HydroxypregnenoloneNAD+Cytb5Pregnenolone17-beta-HSD3 HSD3, 15R302302297, 10PORP450c173-beta-HSD17-beta-HSD314, 165-alpha-reductase 2P450c17RP450c17RP450c172, 3, 15R27P450c1727, 32R2P450c17OxPORP450c1721OxP450c17OxPOR21P450c17OxP450c17Ox2121PORPORNADHNADP+NADPH22NAD+22NADHAKR1C246,XY sex reversal 817-beta-hydroxysteroiddehydrogenase deficiency3-alpha-hydroxysteroiddehydrogenase deficiency17,20-lyase deficiencyP450 oxidoreductase deficiency


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 [1]), 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 [2]), and for more information on the disease linked to this pathway, please visit Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)).

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  1. Munro AW, Noble MA, Robledo L, Daff SN, Chapman SK; ''Determination of the redox properties of human NADPH-cytochrome P450 reductase.''; Biochemistry, 2001 PubMed Europe PMC Scholia
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  5. Shafqat N, Marschall HU, Filling C, Nordling E, Wu XQ, Björk L, Thyberg J, Mårtensson E, Salim S, Jörnvall H, Oppermann U; ''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.''; Biochem J, 2003 PubMed Europe PMC Scholia
  6. Yoshimoto FK, Gonzalez E, Auchus RJ, Guengerich FP; ''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.''; J Biol Chem, 2016 PubMed Europe PMC Scholia
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  9. Burstein S, Middleditch BS, Gut M; ''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.''; J Biol Chem, 1975 PubMed Europe PMC Scholia
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  12. Chetyrkin SV, Belyaeva OV, Gough WH, Kedishvili NY; ''Characterization of a novel type of human microsomal 3alpha -hydroxysteroid dehydrogenase: unique tissue distribution and catalytic properties.''; J Biol Chem, 2001 PubMed Europe PMC Scholia
  13. Engeli RT, Rhouma BB, Sager CP, Tsachaki M, Birk J, Fakhfakh F, Keskes L, Belguith N, Odermatt A; ''''; , PubMed Europe PMC Scholia
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  15. Simonov AN, Holien JK, Yeung JC, Nguyen AD, Corbin CJ, Zheng J, Kuznetsov VL, Auchus RJ, Conley AJ, Bond AM, Parker MW, Rodgers RJ, Martin LL; ''Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1).''; PLoS One, 2015 PubMed Europe PMC Scholia
  16. Weber S, Salabei JK, Möller G, Kremmer E, Bhatnagar A, Adamski J, Barski OA; ''Aldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates.''; J Biol Chem, 2015 PubMed Europe PMC Scholia
  17. 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
  18. Chetyrkin SV, Hu J, Gough WH, Dumaual N, Kedishvili NY; ''Further characterization of human microsomal 3alpha-hydroxysteroid dehydrogenase.''; Arch Biochem Biophys, 2001 PubMed Europe PMC Scholia
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  20. Moore RJ, Griffin JE, Wilson JD; ''Diminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2.''; J Biol Chem, 1975 PubMed Europe PMC Scholia
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  23. Bhatt MR, Khatri Y, Rodgers RJ, Martin LL; ''Role of cytochrome b5 in the modulation of the enzymatic activities of cytochrome P450 17α-hydroxylase/17,20-lyase (P450 17A1).''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
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  29. Hiort O; ''The differential role of androgens in early human sex development.''; BMC Med, 2013 PubMed Europe PMC Scholia
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  32. Kolar NW, Swart AC, Mason JI, Swart P; ''Functional expression and characterisation of human cytochrome P45017alpha in Pichia pastoris.''; J Biotechnol, 2007 PubMed Europe PMC Scholia


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128554view04:47, 12 February 2024EweitzSoften disease color, standardize case
119308view13:11, 23 June 2021FinterlyAdded ISBN for book citation
117184view10:19, 18 May 2021EweitzModified title
108087view11:53, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
106166view12:06, 16 August 2019MaintBotHMDB identifier normalization
104252view12:18, 12 May 2019EgonwRemoved the RHEA: prefix from the identifier.
104034view17:46, 25 April 2019IreneHemelModified description
103502view14:41, 6 March 2019DeSlAnother lit. ref. update
103501view14:40, 6 March 2019DeSlRemoved weird signs in lit. ref
103500view14:36, 6 March 2019DeSlAdded more lit. refs.
103498view14:25, 6 March 2019DeSlAdded more diseases to PW.
103452view21:40, 1 March 2019DeSlAdded several diseases to PW.
103369view13:37, 24 February 2019EgonwReplaced a secondary ChEBI ID with primary ID.
103281view13:15, 21 February 2019DeSlChanged conversion to modification fot POR catalysed reaction between protein nodes
103280view21:00, 20 February 2019DeSlOntology Term : 'steroid inherited metabolic disorder' added !
103279view20:58, 20 February 2019DeSlAnnotated missing protein Nodes.
103278view20:51, 20 February 2019DeSlAdded more Rheas for bottom left part.
103277view20:25, 20 February 2019DeSlAdded more Rhea Ids to the right bottom part
103274view17:28, 20 February 2019DeSlAnnotated some more reaction with Rhea (top part), added lit. refs, added first disease node.
103202view16:31, 15 February 2019DeSlModified description
103201view16:29, 15 February 2019DeSlAdded info for POR enzyme
103200view15:58, 15 February 2019DeSlChanged weird symbols to written alpha/beta for enzymes.
103197view15:43, 15 February 2019DeSlAnnotated left top side, added Rhea's, added lit. refs.
103195view15:27, 15 February 2019DeSlModified description
103194view15:27, 15 February 2019DeSlAdded first 2 lit refs
103193view15:23, 15 February 2019DeSlOntology Term : 'steroid hormone biosynthetic pathway' added !
103192view15:22, 15 February 2019DeSlOntology Term : 'altered isoprenoid biosynthetic pathway' added !
103191view15:21, 15 February 2019DeSlOntology Term : 'altered steroid biosynthetic pathway' added !
103190view15:20, 15 February 2019DeSlOntology Term : 'PW:0000752' removed !
103189view15:19, 15 February 2019DeSlOntology Term : 'altered cholesterol biosynthetic pathway' added !
103188view15:19, 15 February 2019DeSlOntology Term : 'steroid metabolic pathway' added !
103187view15:16, 15 February 2019DeSlOntology Term : 'cholesterol metabolic pathway' added !
103186view15:14, 15 February 2019DeSlOntology Term : 'steroid hormone metabolic pathway' added !
103184view15:12, 15 February 2019DeSlOntology Term : 'testosterone biosynthetic pathway' added !
103182view15:07, 15 February 2019DeSlModified description
103154view13:07, 15 February 2019ElineSandersNew pathway

External references


View all...
NameTypeDatabase referenceComment
17-HydroxypregnenoloneMetaboliteQ2064889 (Wikidata)
17-beta-HSD3GeneProductENSG00000130948 (Ensembl)
17-beta-HSDGeneProductENSG00000130948 (Ensembl)
17-hydroxyallopregnanoloneMetaboliteCHEBI:11909 (ChEBI)
17-hydroxydihydroprogesteroneMetaboliteCHEBI:36723 (ChEBI)
17-hydroxyprogesteroneMetaboliteHMDB0000374 (HMDB)
3 HSDProteinP26439 (Uniprot-TrEMBL) Aka HSD3B2; 3 beta-hydroxysteroid dehydrogenase type II
3-beta-HSDGeneProductENSG00000203859 (Ensembl)
5-alpha-reductase 1GeneProductENSG00000277893 (Ensembl)
5-alpha-reductase 2ProteinP31213 (Uniprot-TrEMBL)
AKR1C2/4GeneProductENSG00000151632 (Ensembl)
AKR1C2ProteinP52895 (Uniprot-TrEMBL) Responsible protein found through Rhea (not part of Blau book)
AKR1C4GeneProductENSG00000198610 (Ensembl)
Androst-4-ene- 3,17-dioneMetaboliteCHEBI:16422 (ChEBI)
AndrostanediolMetaboliteCHEBI:27727 (ChEBI)
AndrostanedioneMetaboliteCHEBI:15994 (ChEBI)
AndrostenedioneMetaboliteCHEBI:16422 (ChEBI)
AndrosteroneMetaboliteCHEBI:16032 (ChEBI)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
Cytb5ProteinP00167 (Uniprot-TrEMBL)
DHEAMetaboliteCHEBI:28689 (ChEBI)
Dihydrotestosterone (DHT)MetaboliteCHEBI:16330 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NADP+MetaboliteCHEBI:58349 (ChEBI)
NADPHMetaboliteCHEBI:57783 (ChEBI)
P450c17ProteinENSG00000148795 (Ensembl)
P450c17ProteinP05093 (Uniprot-TrEMBL) 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" []
P450sccGeneProductENSG00000140459 (Ensembl)
PORProteinP16435 (Uniprot-TrEMBL) Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" []
PregnenoloneMetaboliteCHEBI:16581 (ChEBI)
ProgesteroneMetaboliteCHEBI:17026 (ChEBI)
RODHProteinO14756 (Uniprot-TrEMBL)
STARGeneProductENSG00000147465 (Ensembl)
TestosteroneMetaboliteCHEBI:17347 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
17-Hydroxypregnenolone17-hydroxyprogesteronemim-conversion24077 (Rhea) Specific Rhea for this reaction is not available at the moment; added Rhea for compounds classes reaction
17-HydroxypregnenoloneDHEAmim-conversion50245 (Rhea)
17-hydroxyprogesteroneAndrostenedionemim-conversion14754 (Rhea)
AndrostanedioneDihydrotestosterone (DHT)mim-conversion41993 (Rhea)
AndrostanedioneDihydrotestosterone (DHT)mim-conversion42121 (Rhea)
AndrostenedioneTestosteronemim-conversion14983 (Rhea)
Androstenedionemim-conversion50817 (Rhea)
AndrosteroneAndrostanedionemim-conversion20378 (Rhea)
AndrosteroneAndrostanedionemim-conversion20382 (Rhea)
CholesterolPregnenolonemim-conversion35740 (Rhea)
NAD+mim-conversion20382 (Rhea)
NAD+mim-conversion41993 (Rhea)
NADHmim-conversion20382 (Rhea)
NADHmim-conversion41993 (Rhea)
NADP+mim-conversion20378 (Rhea)
NADP+mim-conversion42121 (Rhea)
NADPHmim-conversion20378 (Rhea)
NADPHmim-conversion42121 (Rhea)
P450c17P450c17mim-modification24041 (Rhea)
Pregnenolone17-Hydroxypregnenolonemim-conversion50237 (Rhea)
PregnenoloneProgesteronemim-conversion24077 (Rhea)
Progesterone17-hydroxyprogesteronemim-conversion46309 (Rhea)
ProgesteroneAndrost-4-ene- 3,17-dionemim-conversion14754 (Rhea)
TestosteroneDihydrotestosterone (DHT)mim-conversion50822 (Rhea)
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