Sex-steroid biosynthesis and androgen activation — HSD17B3/CYP19A1/SRD5A2

The C19 androgen precursors made in the gonads and adrenal (androstenedione, from the CYP17A1 17,20-lyase reaction) are converted into the active sex steroids by three endoplasmic-reticulum-membrane enzymes. The testis-specific 17beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) reduces the 17-keto group of androstenedione to give testosterone, the principal circulating androgen. Testosterone then has two activation fates in target tissues: the microsomal cytochrome P450 aromatase (CYP19A1) aromatizes the A-ring of C19 androgens to the C18 estrogens (androstenedione -> estrone, testosterone -> 17beta-estradiol), the committed and rate-limiting step of estrogen synthesis; and steroid 5alpha-reductase type 2 (SRD5A2) irreversibly reduces the C4-C5 double bond of testosterone to 5alpha-dihydrotestosterone (DHT), the most potent androgen, in prostate and genital skin. Inherited defects define disorders of sex development and hormone imbalance: HSD17B3 (46,XY DSD, 17beta-HSD3 deficiency), CYP19A1 (aromatase deficiency / aromatase excess syndrome; CYP19A1 is also the aromatase-inhibitor breast-cancer drug target) and SRD5A2 (5alpha-reductase-2 deficiency 46,XY DSD; the finasteride/dutasteride target for benign prostatic hyperplasia and androgenetic alopecia).

MODULE:sex_steroid_biosynthesisDRAFTMetabolic Pathwaymodules/sex_steroid_biosynthesis.yaml
steroid hormone biosynthetic processGO:0120178 androgen biosynthetic processGO:0006702 estrogen biosynthetic processGO:0006703
GO:0120178
steroid hormone biosynthetic process
The module is grounded in steroid hormone biosynthetic process (GO:0120178); it covers the conversion of C19 androgen precursors into active androgens (testosterone, DHT) and estrogens.
GO:0006702
androgen biosynthetic process
HSD17B3 (-> testosterone) and SRD5A2 (-> DHT) carry out androgen biosynthesis.
GO:0006703
estrogen biosynthetic process
CYP19A1 (aromatase) carries out estrogen biosynthesis from C19 androgens.
Reactome:R-HSA-193048
Androgen biosynthesis
The androgen steps (HSD17B3 androstenedione->testosterone; SRD5A2 testosterone->DHT) follow the human Reactome "Androgen biosynthesis" sub-pathway.
Reactome:R-HSA-193144
Estrogen biosynthesis
The aromatase reactions (CYP19A1 androstenedione->estrone, testosterone->estradiol) follow the human Reactome "Estrogen biosynthesis" sub-pathway.
file:human/HSD17B3/HSD17B3-ai-review.yaml
HSD17B3 gene review (human)
The androstenedione->testosterone step (UniProtKB:P37058, GO:0047045) matches the completed human HSD17B3 review.
file:human/CYP19A1/CYP19A1-ai-review.yaml
CYP19A1 gene review (human)
The aromatase step (UniProtKB:P11511, GO:0070330) matches the completed human CYP19A1 review.
file:human/SRD5A2/SRD5A2-ai-review.yaml
SRD5A2 gene review (human)
The testosterone->DHT 5alpha-reduction step (UniProtKB:P31213, GO:0003865) matches the completed human SRD5A2 review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:sex_steroid_biosynthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (3/3 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
CYP19A1 P11511 ✓ ✓ ✗
HSD17B3 P37058 ✓ ✓ ✗
SRD5A2 P31213 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
Sex-steroid biosynthesis and androgen activationMetabolic Pathwaysex_steroid_biosynthesis
steroid hormone biosynthetic processGO:0120178 androgen biosynthetic processGO:0006702 estrogen biosynthetic processGO:0006703
Context
endoplasmic reticulum membraneGO:0005789

Sex-steroid biosynthesis/activation grounded to the human enzymes HSD17B3 (UniProtKB:P37058, GO:0047045, EC 1.1.1.62), CYP19A1 (P11511, GO:0070330, EC 1.14.14.14) and SRD5A2 (P31213, GO:0003865, EC 1.3.1.22). GO molecular-function and location terms were taken from the completed human gene reviews and verified against the local go.db; Reactome reaction ids/titles were verified against the local reactome cache (including the "reducde" display-name typo in R-HSA-193064, left verbatim). Each step uses a PANTHER family selector with the human enzyme as representative so the module generalises across orthologs/paralogs. Upstream, the C19 androgen precursor androstenedione comes from the adrenal/gonadal steroidogenesis module (CYP17A1 17,20-lyase). The three enzymes are all ER-membrane proteins but define divergent fates: HSD17B3 makes testosterone, CYP19A1 diverts C19 androgens to estrogens, and SRD5A2 amplifies androgen signalling by making DHT. The pre-receptor cortisol/cortisone glucocorticoid shuttle (HSD11B1/HSD11B2) is a separate module. Disorders: 46,XY DSD (HSD17B3, SRD5A2), aromatase deficiency/excess (CYP19A1); CYP19A1 and SRD5A2 are major drug targets (aromatase inhibitors; finasteride/dutasteride).

Connections

hsd17b3_step -> cyp19a1_step Provides Input For
Testosterone from HSD17B3 is a substrate for aromatization to 17beta-estradiol by CYP19A1.
hsd17b3_step -> srd5a2_step Provides Input For
Testosterone from HSD17B3 is 5alpha-reduced by SRD5A2 to DHT.
Part 1: testosterone synthesis (17-ketoreduction)
androstenedione to testosteroneReactionhsd17b3_step

Annotons

HSD17B3: 17beta-hydroxysteroid dehydrogenase type 3
hsd17b3_activity
Participant: Family: 17beta-hydroxysteroid dehydrogenase type 3 family (SDR)
Family:
17beta-hydroxysteroid dehydrogenase type 3 family (SDR)PANTHER:PTHR43899
Representative Members: HSD17B3 (human)UniProtKB:P37058

Function

testosterone dehydrogenase (NADP+) activityGO:0047045
Substrates: androstenedione NADPH
Products: testosterone NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Testis-specific final step of testosterone biosynthesis. Deficiency = 46,XY DSD (17beta-HSD3 deficiency), with elevated androstenedione/testosterone ratio.

Part 2: estrogen synthesis (aromatization)
C19 androgens to C18 estrogensReactioncyp19a1_step

Annotons

CYP19A1: aromatase
cyp19a1_activity
Participant: Family: Aromatase cytochrome P450 family (CYP19)
Family:
Aromatase cytochrome P450 family (CYP19)PANTHER:PTHR24291
Representative Members: CYP19A1 (human)UniProtKB:P11511

Function

aromatase activityGO:0070330
Substrates: testosterone (or androstenedione) O2 NADPH (via POR)
Products: 17beta-estradiol (or estrone) formate

Locations

endoplasmic reticulum membraneGO:0005789

Committed, rate-limiting estrogen-synthesis step; expressed in gonad, placenta, adipose, brain, bone. Aromatase-inhibitor breast-cancer drug target; loss = aromatase deficiency, gain = aromatase excess.

Part 3: potent-androgen activation (5alpha-reduction)
testosterone to 5alpha-dihydrotestosterone (DHT)Reactionsrd5a2_step

Annotons

SRD5A2: steroid 5alpha-reductase type 2
srd5a2_activity
Participant: Family: Steroid 5-alpha reductase family (SRD5A)
Family:
Steroid 5-alpha reductase family (SRD5A)PANTHER:PTHR10556
Representative Members: SRD5A2 (human)UniProtKB:P31213

Function

3-oxo-5-alpha-steroid 4-dehydrogenase activityGO:0003865
Substrates: testosterone NADPH
Products: 5alpha-dihydrotestosterone (DHT) NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Local activation of testosterone to DHT in prostate/genital skin. Deficiency = 5alpha-reductase-2 deficiency (46,XY DSD); finasteride/dutasteride target.