Adrenal steroidogenesis — cholesterol to corticosteroids and adrenal androgens; STAR/CYP11A1/HSD3B2/CYP17A1/CYP21A2/CYP11B1/CYP11B2

Adrenal steroidogenesis converts cholesterol into the three classes of steroid hormone — glucocorticoids (cortisol), mineralocorticoids (aldosterone) and adrenal androgens (DHEA, androstenedione) — through a branched network of mitochondrial and endoplasmic-reticulum enzymes. The acute, rate-limiting step is the delivery of cholesterol from the outer to the inner mitochondrial membrane by the steroidogenic acute regulatory protein STAR; there the side-chain-cleavage cytochrome P450 CYP11A1 (P450scc) makes pregnenolone, the common precursor of all steroid hormones. Pregnenolone is then routed by two ER enzymes whose order and combination select the branch: the 3beta-hydroxysteroid dehydrogenase/isomerase HSD3B2 (Delta5 -> Delta4, giving progesterone, 17-hydroxyprogesterone or androstenedione) and the bifunctional 17alpha-hydroxylase/17,20-lyase CYP17A1 (17-hydroxylation commits to cortisol; the 17,20-lyase reaction commits to androgens). 21-hydroxylase CYP21A2 then hydroxylates progesterone -> 11-deoxycorticosterone (mineralocorticoid branch) and 17-hydroxyprogesterone -> 11-deoxycortisol (glucocorticoid branch). The final oxidations return to the mitochondrion: CYP11B1 (11beta-hydroxylase) makes cortisol, while its close paralog CYP11B2 (aldosterone synthase), uniquely possessing 18-hydroxylase/18-oxidase activity, converts deoxycorticosterone through corticosterone and 18-hydroxycorticosterone to aldosterone in the zona glomerulosa. Inherited defects define the congenital adrenal hyperplasias and related disorders: STAR (congenital lipoid adrenal hyperplasia), CYP11A1 (adrenal insufficiency), HSD3B2 (3beta-HSD-deficiency CAH), CYP17A1 (combined 17alpha- hydroxylase/17,20-lyase deficiency), CYP21A2 (21-hydroxylase deficiency, >90% of CAH), CYP11B1 (11beta-hydroxylase-deficiency CAH) and CYP11B2 (aldosterone synthase / CMO deficiency; a CYP11B1/B2 chimera causes glucocorticoid-remediable aldosteronism).

MODULE:adrenal_steroidogenesisDRAFTMetabolic Pathwaymodules/adrenal_steroidogenesis.yaml
steroid hormone biosynthetic processGO:0120178 C21-steroid hormone biosynthetic processGO:0006700
GO:0120178
steroid hormone biosynthetic process
The module is grounded in steroid hormone biosynthetic process (GO:0120178); it covers adrenal conversion of cholesterol to glucocorticoids, mineralocorticoids and androgens.
GO:0006700
C21-steroid hormone biosynthetic process
The corticosteroid backbone (pregnenolone -> progesterone/17OHP -> DOC/11-deoxycortisol -> aldosterone/cortisol) is C21-steroid hormone biosynthesis (GO:0006700).
Reactome:R-HSA-196108
Pregnenolone biosynthesis
The cholesterol-to-pregnenolone entry (STAR translocation + CYP11A1 side-chain cleavage) follows the human Reactome "Pregnenolone biosynthesis" reactions R-HSA-196126/193101.
Reactome:R-HSA-194002
Glucocorticoid biosynthesis
The glucocorticoid branch (CYP17A1 17-hydroxylation -> CYP21A2 21-hydroxylation -> CYP11B1 11beta-hydroxylation to cortisol) follows human Reactome "Glucocorticoid biosynthesis".
Reactome:R-HSA-193993
Mineralocorticoid biosynthesis
The mineralocorticoid branch (CYP21A2 -> DOC; CYP11B2 through corticosterone and 18-hydroxycorticosterone to aldosterone) follows human Reactome "Mineralocorticoid biosynthesis".
Reactome:R-HSA-193048
Androgen biosynthesis
The androgen branch (CYP17A1 17,20-lyase -> DHEA; HSD3B2 -> androstenedione) follows human Reactome "Androgen biosynthesis".
file:human/STAR/STAR-ai-review.yaml
STAR gene review (human)
The rate-limiting cholesterol-transfer step (UniProtKB:P49675, GO:0120020/GO:0015485, mitochondrial outer membrane) matches the completed human STAR review.
file:human/CYP11A1/CYP11A1-ai-review.yaml
CYP11A1 gene review (human)
The cholesterol side-chain-cleavage step to pregnenolone (UniProtKB:P05108, GO:0008386) matches the completed human CYP11A1 review.
file:human/HSD3B2/HSD3B2-ai-review.yaml
HSD3B2 gene review (human)
The 3beta-HSD/Delta5-Delta4-isomerase step (UniProtKB:P26439, GO:0003854/GO:0004769) matches the completed human HSD3B2 review.
file:human/CYP17A1/CYP17A1-ai-review.yaml
CYP17A1 gene review (human)
The 17alpha-hydroxylase/17,20-lyase branch-point step (UniProtKB:P05093, GO:0004508) matches the completed human CYP17A1 review.
file:human/CYP21A2/CYP21A2-ai-review.yaml
CYP21A2 gene review (human)
The 21-hydroxylase step feeding both corticosteroid branches (UniProtKB:P08686, GO:0004509) matches the completed human CYP21A2 review.
file:human/CYP11B1/CYP11B1-ai-review.yaml
CYP11B1 gene review (human)
The mitochondrial 11beta-hydroxylase step to cortisol (UniProtKB:P15538, GO:0004507) matches the completed human CYP11B1 review.
file:human/CYP11B2/CYP11B2-ai-review.yaml
CYP11B2 gene review (human)
The aldosterone-synthase step (11beta-/18-hydroxylase/18-oxidase; UniProtKB:P19099, GO:0047783/GO:0004507) matches the completed human CYP11B2 review.
8Nodes
7Parts
0Variant Sets
0Variants
7Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:adrenal_steroidogenesis 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 (7/7 grounded genes reviewed)

7 complete review(s) · 0 with deep research · 0 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
CYP11A1 P05108 ✓ ✓ ✗
CYP11B1 P15538 ✓ ✓ ✗
CYP11B2 P19099 ✓ ✓ ✗
CYP17A1 P05093 ✓ ✓ ✗
CYP21A2 P08686 ✓ ✓ ✗
HSD3B2 P26439 ✓ ✓ ✗
STAR P49675 ✓ ✓ ✗

Details

Context
mitochondrial inner membraneGO:0005743 endoplasmic reticulum membraneGO:0005789
Adrenal steroidogenesis (cholesterol to corticosteroids/androgens)Metabolic Pathwayadrenal_steroidogenesis
steroid hormone biosynthetic processGO:0120178 C21-steroid hormone biosynthetic processGO:0006700
Context
mitochondrial inner membraneGO:0005743 endoplasmic reticulum membraneGO:0005789

Adrenal steroidogenesis grounded to the human enzymes STAR (UniProtKB:P49675, GO:0120020, cholesterol transfer), CYP11A1 (P05108, GO:0008386, EC 1.14.15.6), HSD3B2 (P26439, GO:0003854/GO:0004769, EC 1.1.1.145), CYP17A1 (P05093, GO:0004508, EC 1.14.14.19), CYP21A2 (P08686, GO:0004509, EC 1.14.14.16), CYP11B1 (P15538, GO:0004507, EC 1.14.15.4) and CYP11B2 (P19099, GO:0047783/GO:0004507, EC 1.14.15.4). 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. Each step uses a PANTHER family selector with the human enzyme as representative so the module generalises across orthologs/paralogs: CYP11A1/CYP11B1/CYP11B2 share the mitochondrial P450 family PTHR24279, and CYP17A1/CYP21A2 share the microsomal P450 clade PTHR24289. The pathway is branched, not linear: the Delta4 (via HSD3B2 first) and Delta5 (via CYP17A1 first) routes interconvert, CYP17A1 selects cortisol (17-hydroxylase) vs androgen (17,20-lyase) fate, and CYP21A2 feeds both the mineralocorticoid (DOC->CYP11B2->aldosterone) and glucocorticoid (11-deoxycortisol->CYP11B1-> cortisol) endpoints. Gonadal/peripheral sex-steroid steps (CYP19A1 aromatase, SRD5A2 5alpha-reductase) and the cortisol/cortisone shuttle (HSD11B1/HSD11B2) are a separate module. Disorders span the pathway: lipoid CAH (STAR), adrenal insufficiency (CYP11A1), 3beta-HSD CAH (HSD3B2), 17OHD (CYP17A1), 21-hydroxylase-deficiency CAH (CYP21A2, >90%), 11beta-OHD CAH (CYP11B1), and aldosterone-synthase/CMO deficiency and glucocorticoid-remediable aldosteronism (CYP11B2).

Connections

star_step -> cyp11a1_step Provides Input For
STAR delivers cholesterol to the inner membrane for CYP11A1 side-chain cleavage.
cyp11a1_step -> hsd3b2_step Provides Input For
Pregnenolone from CYP11A1 is dehydrogenated/isomerized by HSD3B2 to progesterone (Delta4 pathway).
cyp11a1_step -> cyp17a1_step Provides Input For
Pregnenolone can also be 17-hydroxylated first by CYP17A1 (Delta5 pathway).
hsd3b2_step -> cyp17a1_step Provides Input For
Progesterone from HSD3B2 is 17-hydroxylated by CYP17A1 toward the cortisol branch.
hsd3b2_step -> cyp21a2_step Provides Input For
Progesterone from HSD3B2 is 21-hydroxylated by CYP21A2 to DOC (mineralocorticoid branch).
cyp17a1_step -> cyp21a2_step Provides Input For
17-hydroxyprogesterone from CYP17A1 is 21-hydroxylated by CYP21A2 to 11-deoxycortisol.
cyp21a2_step -> cyp11b1_step Provides Input For
11-deoxycortisol from CYP21A2 is 11beta-hydroxylated by CYP11B1 to cortisol.
cyp21a2_step -> cyp11b2_step Provides Input For
DOC from CYP21A2 is converted by CYP11B2 through corticosterone/18OH-corticosterone to aldosterone.
Part 1: cholesterol delivery (acute rate-limiting step)
cholesterol translocation to the inner mitochondrial membraneReactionstar_step

Annotons

STAR: steroidogenic acute regulatory protein
star_activity
Participant: Family: StAR/START-domain family (STARD1)
Family:
StAR/START-domain family (STARD1)PANTHER:PTHR46489
Representative Members: STAR (human)UniProtKB:P49675

Function

cholesterol transfer activityGO:0120020
Substrates: cholesterol (outer mitochondrial membrane)
Products: cholesterol (inner mitochondrial membrane)

Locations

mitochondrial outer membraneGO:0005741

Delivers cholesterol to the inner membrane for CYP11A1; the acute (minutes-scale) rate-limiting control point of steroid output. Deficiency = congenital lipoid CAH.

Part 2: side-chain cleavage (first, committed enzymatic step)
cholesterol to pregnenoloneReactioncyp11a1_step

Annotons

CYP11A1: cholesterol side-chain cleavage (P450scc)
cyp11a1_activity
Participant: Family: Mitochondrial steroidogenic cytochrome P450 (CYP11 family)
Family:
Mitochondrial steroidogenic cytochrome P450 (CYP11 family)PANTHER:PTHR24279
Representative Members: CYP11A1 (human)UniProtKB:P05108

Function

cholesterol monooxygenase (side-chain-cleaving) activityGO:0008386
Substrates: cholesterol O2 reduced adrenodoxin
Products: pregnenolone 4-methylpentanal

Locations

mitochondrial inner membraneGO:0005743

First and rate-limiting enzymatic step; produces the pregnenolone common precursor of all steroid hormones. Deficiency = adrenal insufficiency.

Part 3: 3beta-dehydrogenation/isomerization (Delta5 -> Delta4)
pregnenolone to progesterone (and 17OH-pregnenolone to 17OH-progesterone; DHEA to androstenedione)Reactionhsd3b2_step

Annotons

HSD3B2: 3beta-HSD / Delta5-Delta4 isomerase (type 2)
hsd3b2_activity
Participant: Family: 3-beta-hydroxysteroid dehydrogenase/isomerase family (HSD3B)
Family:
3-beta-hydroxysteroid dehydrogenase/isomerase family (HSD3B)PANTHER:PTHR43245
Representative Members: HSD3B2 (human)UniProtKB:P26439

Function

3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activityGO:0003854
Substrates: pregnenolone NAD+
Products: progesterone NADH

Locations

endoplasmic reticulum membraneGO:0005789

Obligatory Delta5->Delta4 conversion common to all three hormone branches; also acts on 17OH-pregnenolone and DHEA. Deficiency = 3beta-HSD-deficiency CAH.

Part 4: 17alpha-hydroxylation / 17,20-lyase (cortisol vs androgen branch point)
17alpha-hydroxylation and 17,20-lyase (to 17OH-steroids and DHEA/androstenedione)Reactioncyp17a1_step

Annotons

CYP17A1: 17alpha-hydroxylase/17,20-lyase (P450c17)
cyp17a1_activity
Participant: Family: Microsomal steroidogenic cytochrome P450 (CYP17/CYP21 clade)
Family:
Microsomal steroidogenic cytochrome P450 (CYP17/CYP21 clade)PANTHER:PTHR24289
Representative Members: CYP17A1 (human)UniProtKB:P05093

Function

steroid 17-alpha-monooxygenase activityGO:0004508
Substrates: progesterone (or pregnenolone) O2 NADPH (via POR; 17,20-lyase also needs cytochrome b5)
Products: 17-hydroxyprogesterone (or 17-hydroxypregnenolone) (17,20-lyase) DHEA / androstenedione

Locations

endoplasmic reticulum membraneGO:0005789

Branch point: 17-hydroxylation routes toward cortisol; 17,20-lyase routes toward androgens/estrogens. Deficiency = combined 17alpha-hydroxylase/17,20-lyase deficiency.

Part 5: 21-hydroxylation (both corticosteroid branches)
21-hydroxylation (progesterone to DOC; 17OH-progesterone to 11-deoxycortisol)Reactioncyp21a2_step

Annotons

CYP21A2: steroid 21-hydroxylase (P450c21)
cyp21a2_activity
Participant: Family: Microsomal steroidogenic cytochrome P450 (CYP17/CYP21 clade)
Family:
Microsomal steroidogenic cytochrome P450 (CYP17/CYP21 clade)PANTHER:PTHR24289
Representative Members: CYP21A2 (human)UniProtKB:P08686

Function

steroid 21-monooxygenase activityGO:0004509
Substrates: progesterone / 17-hydroxyprogesterone O2 NADPH (via POR)
Products: 11-deoxycorticosterone (DOC) / 11-deoxycortisol

Locations

endoplasmic reticulum membraneGO:0005789

Supplies both the mineralocorticoid (DOC) and glucocorticoid (11-deoxycortisol) branches. Deficiency is the commonest cause of CAH (>90%).

Part 6: 11beta-hydroxylation to cortisol (glucocorticoid endpoint)
11-deoxycortisol to cortisolReactioncyp11b1_step

Annotons

CYP11B1: 11beta-hydroxylase (P450c11beta)
cyp11b1_activity
Participant: Family: Mitochondrial steroidogenic cytochrome P450 (CYP11 family)
Family:
Mitochondrial steroidogenic cytochrome P450 (CYP11 family)PANTHER:PTHR24279
Representative Members: CYP11B1 (human)UniProtKB:P15538

Function

steroid 11-beta-monooxygenase activityGO:0004507
Substrates: 11-deoxycortisol O2 reduced adrenodoxin
Products: cortisol

Locations

mitochondrial inner membraneGO:0005743

Glucocorticoid endpoint; 11beta-hydroxylates 11-deoxycortisol to cortisol. Deficiency = 11beta-hydroxylase-deficiency CAH (second commonest CAH).

Part 7: aldosterone synthesis (mineralocorticoid endpoint)
11-deoxycorticosterone to aldosterone (11beta-/18-hydroxylase/18-oxidase)Reactioncyp11b2_step

Annotons

CYP11B2: aldosterone synthase (P450c11AS)
cyp11b2_activity
Participant: Family: Mitochondrial steroidogenic cytochrome P450 (CYP11 family)
Family:
Mitochondrial steroidogenic cytochrome P450 (CYP11 family)PANTHER:PTHR24279
Representative Members: CYP11B2 (human)UniProtKB:P19099

Function

corticosterone 18-monooxygenase activityGO:0047783
Substrates: 11-deoxycorticosterone (DOC) O2 reduced adrenodoxin
Products: corticosterone -> 18-hydroxycorticosterone -> aldosterone

Locations

mitochondrial inner membraneGO:0005743

Mineralocorticoid endpoint in the zona glomerulosa; uniquely completes the 18-oxidation to aldosterone. Deficiency = aldosterone synthase (CMO) deficiency.