Alternative pathway of fetal androgen synthesis (WP4524)

Homo sapiens

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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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

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

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