Bile acid synthesis I — ring modification (cholesterol -> 5-beta-cholestane intermediates); CYP7A1/CYP7B1/HSD3B7/AKR1D1

The first phase of bile-acid biosynthesis modifies the cholesterol steroid nucleus, producing the 7-alpha-hydroxylated, 3-oxo, 5-beta-reduced cholestane intermediates that are later shortened in the side chain to the C24 bile acids. Two entry routes converge: the CLASSIC (neutral) pathway begins with cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting, feedback-regulated enzyme that hydroxylates cholesterol at C7-alpha; the ACIDIC (alternative) pathway begins when oxysterols (25- and 27-hydroxycholesterol, from CH25H/CYP27A1) are 7-alpha-hydroxylated by oxysterol 7-alpha-hydroxylase (CYP7B1). The 7-alpha-hydroxy sterols are then oxidised and isomerised by the 3-beta-hydroxy-Delta5-C27- steroid dehydrogenase HSD3B7 to the 3-oxo-Delta4 intermediate (7-alpha-hydroxy-4-cholesten- 3-one), and the Delta4 double bond is reduced to the 5-beta configuration by steroid 5-beta-reductase (AKR1D1), giving the cis-fused (5-beta) A/B ring junction characteristic of bile acids. (CYP8B1 branches here to specify cholic vs chenodeoxycholic acid.) Inherited defects: CYP7A1 deficiency (hypercholesterolemia/gallstones); CYP7B1 deficiency (hereditary spastic paraplegia type 5A and severe neonatal liver failure); HSD3B7 deficiency (congenital bile acid synthesis defect type 1); and AKR1D1 deficiency (bile acid synthesis defect type 2) — the HSD3B7/AKR1D1 defects present as neonatal cholestasis with fat-soluble-vitamin malabsorption.

MODULE:bile_acid_synthesis_ring_modificationDRAFTMetabolic Pathwaymodules/bile_acid_synthesis_ring_modification.yaml
bile acid biosynthetic processGO:0006699
GO:0006699
bile acid biosynthetic process
The module is grounded in bile acid biosynthetic process (GO:0006699); it covers the ring-modification phase (cholesterol/oxysterol -> 5-beta-cholestane intermediates).
Reactome:R-HSA-192105
Synthesis of bile acids and bile salts
Reactions follow the human Reactome bile-acid-synthesis reactions R-HSA-192051 (CYP7A1), R-HSA-192065 (CYP7B1), R-HSA-192097 (HSD3B7) and R-HSA-192033 (AKR1D1).
file:human/CYP7A1/CYP7A1-ai-review.yaml
CYP7A1 gene review (human)
The classic-pathway cholesterol 7-alpha-hydroxylation step (UniProtKB:P22680, GO:0008123) matches the completed human CYP7A1 review.
file:human/CYP7B1/CYP7B1-ai-review.yaml
CYP7B1 gene review (human)
The acidic-pathway oxysterol 7-alpha-hydroxylation step (UniProtKB:O75881, GO:0008396) matches the completed human CYP7B1 review.
file:human/HSD3B7/HSD3B7-ai-review.yaml
HSD3B7 gene review (human)
The 3-beta-HSD/isomerase step (UniProtKB:Q9H2F3, GO:0003854) matches the completed human HSD3B7 review.
file:human/AKR1D1/AKR1D1-ai-review.yaml
AKR1D1 gene review (human)
The steroid 5-beta-reductase step (UniProtKB:P51857, GO:0047787) matches the completed human AKR1D1 review.
5Nodes
4Parts
0Variant Sets
0Variants
4Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:bile_acid_synthesis_ring_modification 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 (4/4 grounded genes reviewed)

4 complete review(s) · 0 with deep research · 0 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
AKR1D1 P51857 ✓ ✓ ✗
CYP7A1 P22680 ✓ ✓ ✗
CYP7B1 O75881 ✓ ✓ ✗
HSD3B7 Q9H2F3 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
Bile acid synthesis (ring modification)Metabolic Pathwaybile_acid_synthesis_ring_modification
bile acid biosynthetic processGO:0006699
Context
endoplasmic reticulum membraneGO:0005789

The ring-modification phase of bile-acid biosynthesis grounded to the human enzymes CYP7A1 (UniProtKB:P22680, GO:0008123, EC 1.14.14.23), CYP7B1 (O75881, GO:0008396, EC 1.14.14.29), HSD3B7 (Q9H2F3, GO:0003854, EC 1.1.1.181) and AKR1D1 (P51857, GO:0047787, EC 1.3.1.3). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. CYP7A1 and CYP7B1 share the P450 family PTHR24304 (each represented by its own gene); HSD3B7 and AKR1D1 use their own family selectors. Two entry routes converge: the classic/neutral pathway (CYP7A1, the rate-limiting committed step) and the acidic/alternative pathway (CYP7B1, on oxysterols from CYP27A1/CH25H); both feed HSD3B7 then AKR1D1. CYP8B1 (12-alpha-hydroxylase, not in this batch) branches at the HSD3B7/AKR1D1 intermediates to specify cholic vs chenodeoxycholic acid. Downstream, the 5-beta-cholestane intermediates undergo side-chain oxidation (CYP27A1) and peroxisomal beta-oxidation (AMACR, ACOX2, then conjugation by SLC27A5/BAAT) to the mature C24 bile acids (a separate module, to follow). Disorders: CYP7A1 (hypercholesterolemia/gallstones); CYP7B1 (SPG5A / neonatal liver failure); HSD3B7 (bile acid synthesis defect type 1); AKR1D1 (bile acid synthesis defect type 2).

Connections

cyp7a1_step -> hsd3b7_step Provides Input For
7-alpha-hydroxycholesterol (classic pathway) is oxidised/isomerised by HSD3B7.
cyp7b1_step -> hsd3b7_step Provides Input For
7-alpha-hydroxy-oxysterols (acidic pathway) are also processed by HSD3B7.
hsd3b7_step -> akr1d1_step Provides Input For
The 3-oxo-Delta4 intermediate from HSD3B7 is 5-beta-reduced by AKR1D1.
Part 1: classic-pathway entry (rate-limiting 7-alpha-hydroxylation of cholesterol)
cholesterol to 7-alpha-hydroxycholesterolReactioncyp7a1_step

Annotons

CYP7A1: cholesterol 7-alpha-hydroxylase
cyp7a1_activity
Participant: Family: Cytochrome P450 family (CYP7A1/CYP7B1)
Family:
Cytochrome P450 family (CYP7A1/CYP7B1)PANTHER:PTHR24304
Representative Members: CYP7A1 (human)UniProtKB:P22680

Function

cholesterol 7-alpha-monooxygenase activityGO:0008123
Substrates: cholesterol O2 / NADPH (via P450 reductase)
Products: 7-alpha-hydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

Rate-limiting, feedback-regulated (FXR/bile-acid) committed entry to the classic (neutral) bile-acid pathway. Deficiency -> hypercholesterolemia/gallstones.

Part 2: acidic-pathway entry (oxysterol 7-alpha-hydroxylation)
25-/27-hydroxycholesterol to 7-alpha,X-dihydroxycholesterolReactioncyp7b1_step

Annotons

CYP7B1: oxysterol 7-alpha-hydroxylase
cyp7b1_activity
Participant: Family: Cytochrome P450 family (CYP7A1/CYP7B1)
Family:
Cytochrome P450 family (CYP7A1/CYP7B1)PANTHER:PTHR24304
Representative Members: CYP7B1 (human)UniProtKB:O75881

Function

oxysterol 7-alpha-hydroxylase activityGO:0008396
Substrates: 25-/27-hydroxycholesterol O2 / NADPH
Products: 7-alpha-hydroxy-oxysterol

Locations

endoplasmic reticulum membraneGO:0005789

Committed 7-alpha-hydroxylation of oxysterols in the acidic (alternative) bile-acid pathway. Deficiency -> hereditary spastic paraplegia type 5A / neonatal liver failure.

Part 3: 3-oxidation / Delta5-Delta4 isomerisation (shared)
7-alpha-hydroxycholesterol to 7-alpha-hydroxy-4-cholesten-3-oneReactionhsd3b7_step

Annotons

HSD3B7: 3-beta-hydroxy-Delta5-C27-steroid dehydrogenase
hsd3b7_activity
Participant: Family: 3-beta-hydroxysteroid dehydrogenase family (HSD3B7)
Family:
3-beta-hydroxysteroid dehydrogenase family (HSD3B7)PANTHER:PTHR10366
Representative Members: HSD3B7 (human)UniProtKB:Q9H2F3

Function

3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activityGO:0003854
Substrates: 7-alpha-hydroxycholesterol (C27, 3-beta-OH-Delta5) NAD+
Products: 7-alpha-hydroxy-4-cholesten-3-one (3-oxo-Delta4)

Locations

endoplasmic reticulum membraneGO:0005789

Oxidises the 3-beta-hydroxyl and isomerises the Delta5 double bond of the 7-alpha-hydroxy sterols to the 3-oxo-Delta4 intermediate (shared by both entry routes). Deficiency = bile acid synthesis defect type 1.

Part 4: 5-beta-reduction (cis A/B ring junction; shared)
7-alpha-hydroxy-4-cholesten-3-one to 5-beta-cholestan-7-alpha-ol-3-oneReactionakr1d1_step

Annotons

AKR1D1: steroid 5-beta-reductase
akr1d1_activity
Participant: Family: Aldo-keto reductase / steroid 5-beta-reductase family (AKR1D1)
Family:
Aldo-keto reductase / steroid 5-beta-reductase family (AKR1D1)PANTHER:PTHR11732
Representative Members: AKR1D1 (human)UniProtKB:P51857

Function

Delta4-3-oxosteroid 5beta-reductase activityGO:0047787
Substrates: 7-alpha-hydroxy-4-cholesten-3-one (3-oxo-Delta4) NADPH
Products: 5-beta-cholestan-7-alpha-ol-3-one

Locations

cytosolGO:0005829

Reduces the Delta4 double bond to the 5-beta configuration, giving the cis-fused A/B ring junction characteristic of bile acids (also 5-beta-reduces steroid hormones). Deficiency = bile acid synthesis defect type 2.