Bile-acid biosynthesis (classic + alternative pathways from cholesterol to conjugated bile acids)

Bile acids are the amphipathic end-products of hepatic cholesterol catabolism; their synthesis is the major route of cholesterol elimination and produces the detergents that emulsify dietary lipids. Two pathways convert cholesterol to the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA). In the CLASSIC (neutral) pathway, the rate-limiting ER cytochrome P450 CYP7A1 7-alpha-hydroxylates cholesterol; HSD3B7 then oxidises/isomerises the 3-beta-hydroxy-Delta5 sterol to a 3-oxo-Delta4 intermediate; the branch-point enzyme CYP8B1 (sterol 12-alpha-hydroxylase) 12-alpha-hydroxylates that intermediate to commit flux toward CA (its absence yields CDCA), setting the CA:CDCA ratio; AKR1D1 (Delta4-3-oxosteroid 5-beta-reductase) and AKR1C4 (3-alpha-hydroxysteroid dehydrogenase) then reduce the A/B-ring to the 5-beta-3-alpha-hydroxy configuration. In the ALTERNATIVE (acidic) pathway, the sterol side chain is oxidised first: the mitochondrial CYP27A1 (sterol 27-hydroxylase), the ER di-iron enzyme CH25H (25-hydroxylase) and the neuron-specific CYP46A1 (24-hydroxylase, the main route of brain cholesterol elimination) generate oxysterols, which the oxysterol 7-alpha-hydroxylases CYP7B1 (25-/27-OHC) and CYP39A1 (24S-OHC) route into bile-acid synthesis. Both pathways converge on side-chain shortening: CYP27A1 oxidises the C27 side chain to a C27 acid, AMACR racemises the (25R)- to the (25S)-acyl-CoA, and peroxisomal beta-oxidation (ACOX2 -> the D-bifunctional protein -> the SCPx thiolase, curated in the peroxisomal module) removes a propionyl unit to give the C24 bile-acyl-CoA. Finally the bile acid is activated by the CoA ligase SLC27A5 (BACS) and conjugated to glycine or taurine by BAAT. Inherited defects across the pathway cause bile-acid synthesis disorders: CYP7B1 (oxysterol 7-alpha-hydroxylase deficiency / SPG5), HSD3B7, AKR1D1, ACOX2, BAAT and SLC27A5 deficiencies, and CYP27A1 causes cerebrotendinous xanthomatosis.

MODULE:bile_acid_biosynthesisDRAFTMetabolic Pathwaymodules/bile_acid_biosynthesis.yaml
bile acid biosynthetic processGO:0006699 cholesterol metabolic processGO:0008203
GO:0006699
bile acid biosynthetic process
CYP7A1/CYP8B1/HSD3B7/AKR1D1/AKR1C4/CYP27A1/CYP7B1/CYP39A1 and the conjugation enzymes carry out bile acid biosynthesis (GO:0006699).
GO:0008203
cholesterol metabolic process
The pathway is the principal catabolic route eliminating cholesterol (GO:0008203).
file:human/CYP7A1/CYP7A1-ai-review.yaml
CYP7A1 gene review (human)
The rate-limiting cholesterol 7-alpha-hydroxylation step (UniProtKB:P22680, GO:0008123) matches the completed human CYP7A1 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/CYP8B1/CYP8B1-ai-review.yaml
CYP8B1 gene review (human)
The 12-alpha-hydroxylase (cholic-acid branch) step (UniProtKB:Q9UNU6, GO:0008397) matches the completed human CYP8B1 review.
file:human/AKR1D1/AKR1D1-ai-review.yaml
AKR1D1 gene review (human)
The Delta4-3-oxosteroid 5-beta-reductase step (UniProtKB:P51857, GO:0047787) matches the completed human AKR1D1 review.
file:human/AKR1C4/AKR1C4-ai-review.yaml
AKR1C4 gene review (human)
The 3-alpha-hydroxysteroid dehydrogenase step (UniProtKB:P17516, GO:0140169) matches the completed human AKR1C4 review.
file:human/CYP27A1/CYP27A1-ai-review.yaml
CYP27A1 gene review (human)
The sterol 27-hydroxylase (side-chain oxidation) step (UniProtKB:Q02318, GO:0047748) matches the completed human CYP27A1 review.
file:human/CH25H/CH25H-ai-review.yaml
CH25H gene review (human)
The cholesterol 25-hydroxylase (oxysterol) step (UniProtKB:O95992, GO:0001567) matches the completed human CH25H review.
file:human/CYP46A1/CYP46A1-ai-review.yaml
CYP46A1 gene review (human)
The neuronal cholesterol 24-hydroxylase step (UniProtKB:Q9Y6A2, GO:0033781) matches the completed human CYP46A1 review.
file:human/CYP7B1/CYP7B1-ai-review.yaml
CYP7B1 gene review (human)
The 25-/27-oxysterol 7-alpha-hydroxylase step (UniProtKB:O75881, GO:0008396) matches the completed human CYP7B1 review.
file:human/CYP39A1/CYP39A1-ai-review.yaml
CYP39A1 gene review (human)
The 24S-hydroxycholesterol 7-alpha-hydroxylase step (UniProtKB:Q9NYL5, GO:0033782) matches the completed human CYP39A1 review.
file:human/AMACR/AMACR-ai-review.yaml
AMACR gene review (human)
The alpha-methylacyl-CoA racemase (side-chain) step (UniProtKB:Q9UHK6, GO:0008111) matches the completed human AMACR review.
file:human/ACOX2/ACOX2-ai-review.yaml
ACOX2 gene review (human)
The branched-chain acyl-CoA oxidase (side-chain beta-oxidation) step (UniProtKB:Q99424, GO:0003997) matches the completed human ACOX2 review.
file:human/SCP2/SCP2-ai-review.yaml
SCP2 gene review (human)
The bile-acid/branched thiolase step (UniProtKB:P22307, GO:0050632) matches the completed human SCP2 review.
file:human/SLC27A5/SLC27A5-ai-review.yaml
SLC27A5 gene review (human)
The bile acid-CoA ligase (activation) step (UniProtKB:Q9Y2P5, GO:0047747) matches the completed human SLC27A5 review.
file:human/BAAT/BAAT-ai-review.yaml
BAAT gene review (human)
The glycine/taurine bile-acid conjugation step (UniProtKB:Q14032, GO:0047963) matches the completed human BAAT review.
9Nodes
8Parts
0Variant Sets
0Variants
13Annotons
7Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:bile_acid_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 (13/13 grounded genes reviewed)

12 complete review(s) · 0 with deep research · 0 missing review · 13 reviewed but lacking deep research

Gene Review Complete Deep research
AKR1C4 P17516 ✓ ✓ ✗
AKR1D1 P51857 ✓ ✓ ✗
AMACR Q9UHK6 ✓ 38/39 ✗
BAAT Q14032 ✓ ✓ ✗
CH25H O95992 ✓ ✓ ✗
CYP27A1 Q02318 ✓ ✓ ✗
CYP39A1 Q9NYL5 ✓ ✓ ✗
CYP46A1 Q9Y6A2 ✓ ✓ ✗
CYP7A1 P22680 ✓ ✓ ✗
CYP7B1 O75881 ✓ ✓ ✗
CYP8B1 Q9UNU6 ✓ ✓ ✗
HSD3B7 Q9H2F3 ✓ ✓ ✗
SLC27A5 Q9Y2P5 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789 cytosolGO:0005829
Bile-acid biosynthesisMetabolic Pathwaybile_acid_biosynthesis
bile acid biosynthetic processGO:0006699 cholesterol metabolic processGO:0008203
Context
endoplasmic reticulum membraneGO:0005789 cytosolGO:0005829

Bile-acid biosynthesis (GO:0006699 + GO:0008203), grounded to fifteen completed human gene reviews (ten reviewed/merged earlier: CYP7A1/CYP27A1/CYP7B1/HSD3B7/AKR1D1/AMACR/ACOX2/SCP2/BAAT/SLC27A5; five new here: CYP8B1/AKR1C4/CH25H/CYP39A1/CYP46A1). CLASSIC pathway: CYP7A1 (P22680 PTHR24304 GO:0008123, rate-limiting) -> HSD3B7 (Q9H2F3 PTHR10366 GO:0003854) -> CYP8B1 (Q9UNU6 PTHR24306 GO:0008397, 12a-hydroxylase = cholic-acid branch; NB GO:0047749 obsolete) -> AKR1D1 (P51857 GO:0047787 5b-reductase) -> AKR1C4 (P17516 GO:0140169 3a-HSD; both PTHR11732). ALTERNATIVE (acidic) pathway: oxysterols from CYP27A1 (Q02318 PTHR24279 GO:0047748, mito 27-hydroxylase; CTX), CH25H (O95992 PTHR11863 GO:0001567 DI-IRON 25-hydroxylase) and neuronal CYP46A1 (Q9Y6A2 PTHR24293 GO:0033781 24-hydroxylase) -> 7a-hydroxylated by CYP7B1 (O75881 GO:0008396; SPG5) and CYP39A1 (Q9NYL5 GO:0033782; both P450-family-7 PTHR24304). SHARED side-chain shortening: CYP27A1 side-chain oxidation -> AMACR (Q9UHK6 PTHR48228 GO:0008111 racemase) -> peroxisomal beta-oxidation ACOX2 (Q99424 GO:0003997) + SCPx/SCP2 (P22307 GO:0050632) [peroxisomal-beta-oxidation module] -> C24 bile-acyl-CoA. CONJUGATION: SLC27A5 (Q9Y2P5 PTHR43107 GO:0047747 BACS) -> BAAT (Q14032 PTHR10824 GO:0047963 gly/tau conjugation). GO term ids/labels verified against the local go.db. Cholesterol is the substrate; the bile acids feed the enterohepatic bile-salt transport system (SLC10A1/ABCB11, separate). Disorders: CYP27A1 CTX, CYP7B1 SPG5, HSD3B7/AKR1D1/ACOX2/BAAT/SLC27A5 bile-acid-synthesis defects/cholestasis.

Connections

The 7-alpha-hydroxycholesterol made by CYP7A1 is oxidised/isomerised by HSD3B7.
The oxysterols made by CYP27A1/CH25H/CYP46A1 are 7-alpha-hydroxylated by CYP7B1/CYP39A1.
The 7-alpha-hydroxylated oxysterols converge on the shared HSD3B7 3-oxo-Delta4 step.
hsd3b7_step -> sterol_12a_hydroxylation Provides Input For
The 3-oxo-Delta4 intermediate is 12-alpha-hydroxylated by CYP8B1 (cholic-acid branch) or proceeds unhydroxylated (CDCA branch).
The (12-alpha-hydroxylated) 3-oxo-Delta4 intermediate is reduced by AKR1D1 then AKR1C4.
ring_reduction -> side_chain_shortening Provides Input For
The ring-reduced C27 sterol has its side chain oxidised (CYP27A1) and shortened by peroxisomal beta-oxidation.
side_chain_shortening -> conjugation Provides Input For
The C24 bile acid is activated by SLC27A5 and conjugated to glycine/taurine by BAAT.
Part 1: classic-pathway initiation (rate-limiting)
Cholesterol 7-alpha-hydroxylase (CYP7A1)Reactioncholesterol_7a_hydroxylation

Annotons

CYP7A1: cholesterol 7-alpha-monooxygenase
cyp7a1_activity
Participant: Family: CYP7 / cholesterol 7-alpha-hydroxylase family
Family:
CYP7 / cholesterol 7-alpha-hydroxylase familyPANTHER:PTHR24304
Representative Members: CYP7A1 (human)UniProtKB:P22680

Function

cholesterol 7-alpha-monooxygenase activityGO:0008123
Substrates: cholesterol O2 (heme; NADPH-cytochrome P450 reductase)
Products: 7-alpha-hydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

7-alpha-hydroxylate cholesterol (classic-pathway commitment, rate-limiting).

Part 2: alternative-pathway initiation (oxysterol formation)
Side-chain/ring oxysterol synthases (CYP27A1 / CH25H / CYP46A1)Reactionoxysterol_formation

Annotons

CYP27A1: sterol 27-hydroxylase (mitochondrial)
cyp27a1_activity
Participant: Family: CYP27A1 / sterol 27-hydroxylase family
Family:
CYP27A1 / sterol 27-hydroxylase familyPANTHER:PTHR24279
Representative Members: CYP27A1 (human)UniProtKB:Q02318

Function

cholestanetetraol 26-dehydrogenase / sterol 27-hydroxylase activityGO:0047748
Substrates: cholesterol / bile-acid intermediates O2 (mitochondrial P450; adrenodoxin/adrenodoxin reductase)
Products: 27-hydroxycholesterol / C27 bile acid

Locations

mitochondrial inner membraneGO:0005743

27-hydroxylate cholesterol / oxidise side chain (alternative pathway).

CH25H: cholesterol 25-hydroxylase (di-iron)
ch25h_activity
Participant: Family: CH25H / fatty-acid-hydroxylase-superfamily di-iron oxidase family
Family:
CH25H / fatty-acid-hydroxylase-superfamily di-iron oxidase familyPANTHER:PTHR11863
Representative Members: CH25H (human)UniProtKB:O95992

Function

cholesterol 25-hydroxylase activityGO:0001567
Substrates: cholesterol O2 (di-iron; NOT P450)
Products: 25-hydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

25-hydroxylate cholesterol (oxysterol; alternative pathway + immune signalling).

CYP46A1: cholesterol 24-hydroxylase (neuronal)
cyp46a1_activity
Participant: Family: CYP46A1 / cholesterol 24-hydroxylase family
Family:
CYP46A1 / cholesterol 24-hydroxylase familyPANTHER:PTHR24293
Representative Members: CYP46A1 (human)UniProtKB:Q9Y6A2

Function

cholesterol 24-hydroxylase activityGO:0033781
Substrates: cholesterol O2 (heme; NADPH-cytochrome P450 reductase)
Products: 24S-hydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

24-hydroxylate cholesterol (neuronal cholesterol elimination -> alt pathway).

Part 3: oxysterol 7-alpha-hydroxylation (alternative pathway)
Oxysterol 7-alpha-hydroxylases (CYP7B1 / CYP39A1)Reactionoxysterol_7a_hydroxylation

Annotons

CYP7B1: 25-/27-oxysterol 7-alpha-hydroxylase
cyp7b1_activity
Participant: Family: CYP7B1 / oxysterol 7-alpha-hydroxylase family
Family:
CYP7B1 / oxysterol 7-alpha-hydroxylase familyPANTHER:PTHR24304
Representative Members: CYP7B1 (human)UniProtKB:O75881

Function

oxysterol 7-alpha-hydroxylase activityGO:0008396
Substrates: 25- and 27-hydroxycholesterol O2 (heme)
Products: 7-alpha,25/27-dihydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

7-alpha-hydroxylate 25-/27-oxysterols (alternative pathway).

CYP39A1: 24S-hydroxycholesterol 7-alpha-hydroxylase
cyp39a1_activity
Participant: Family: CYP39A1 / 24-hydroxycholesterol 7-alpha-hydroxylase family
Family:
CYP39A1 / 24-hydroxycholesterol 7-alpha-hydroxylase familyPANTHER:PTHR24304
Representative Members: CYP39A1 (human)UniProtKB:Q9NYL5

Function

24S-hydroxycholesterol 7-alpha-hydroxylase activityGO:0033782
Substrates: 24S-hydroxycholesterol (from CYP46A1) O2 (heme)
Products: 7-alpha,24S-dihydroxycholesterol

Locations

endoplasmic reticulum membraneGO:0005789

7-alpha-hydroxylate 24S-oxysterol (alternative pathway).

Part 4: ring 3-oxo-Delta4 formation
3-beta-hydroxy-Delta5-C27-steroid dehydrogenase (HSD3B7)Reactionhsd3b7_step

Annotons

HSD3B7: 3-beta-HSD / Delta5->Delta4 isomerase
hsd3b7_activity
Participant: Family: HSD3B7 / 3-beta-hydroxysteroid dehydrogenase family
Family:
HSD3B7 / 3-beta-hydroxysteroid dehydrogenase familyPANTHER:PTHR10366
Representative Members: HSD3B7 (human)UniProtKB:Q9H2F3

Function

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

Locations

endoplasmic reticulum membraneGO:0005789

Oxidise/isomerise 3-beta-hydroxy-Delta5 to 3-oxo-Delta4 intermediate.

Part 5: 12-alpha-hydroxylation (cholic-acid branch)
Sterol 12-alpha-hydroxylase (CYP8B1)Reactionsterol_12a_hydroxylation

Annotons

CYP8B1: sterol 12-alpha-hydroxylase
cyp8b1_activity
Participant: Family: CYP8B1 / sterol 12-alpha-hydroxylase family
Family:
CYP8B1 / sterol 12-alpha-hydroxylase familyPANTHER:PTHR24306
Representative Members: CYP8B1 (human)UniProtKB:Q9UNU6

Function

sterol 12-alpha-hydroxylase activityGO:0008397
Substrates: 7-alpha-hydroxy-4-cholesten-3-one O2 (heme)
Products: 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one

Locations

endoplasmic reticulum membraneGO:0005789

12-alpha-hydroxylate the 3-oxo-Delta4 intermediate (cholic-acid branch).

Part 6: A/B-ring reduction (5-beta then 3-alpha)
Ring reductases (AKR1D1 5-beta-reductase, AKR1C4 3-alpha-HSD)Reactionring_reduction

Annotons

AKR1D1: Delta4-3-oxosteroid 5-beta-reductase
akr1d1_activity
Participant: Family: AKR1D1 / steroid 5-beta-reductase family
Family:
AKR1D1 / steroid 5-beta-reductase familyPANTHER:PTHR11732
Representative Members: AKR1D1 (human)UniProtKB:P51857

Function

Delta4-3-oxosteroid 5-beta-reductase activityGO:0047787
Substrates: 3-oxo-Delta4 bile-acid intermediate NADPH
Products: 3-oxo-5-beta intermediate NADP+

Locations

cytosolGO:0005829

Reduce the Delta4 double bond (5-beta configuration).

AKR1C4: 3-alpha-hydroxysteroid dehydrogenase
akr1c4_activity
Participant: Family: AKR1C4 / 3-alpha-hydroxysteroid dehydrogenase family
Family:
AKR1C4 / 3-alpha-hydroxysteroid dehydrogenase familyPANTHER:PTHR11732
Representative Members: AKR1C4 (human)UniProtKB:P17516

Function

3-alpha-hydroxysteroid 3-dehydrogenase [NAD(P)+] activityGO:0140169
Substrates: 3-oxo-5-beta bile-acid intermediate NADPH
Products: 3-alpha-hydroxy-5-beta intermediate NADP+

Locations

cytosolGO:0005829

Reduce the 3-oxo group to 3-alpha-hydroxy (bile-acid ring completion).

Part 7: side-chain shortening (27-oxidation + peroxisomal beta-oxidation)
Side-chain oxidation + shortening (CYP27A1, AMACR, ACOX2, SCP2)Reactionside_chain_shortening

Annotons

AMACR: alpha-methylacyl-CoA racemase
amacr_activity
Participant: Family: AMACR / alpha-methylacyl-CoA racemase family
Family:
AMACR / alpha-methylacyl-CoA racemase familyPANTHER:PTHR48228
Representative Members: AMACR (human)UniProtKB:Q9UHK6

Function

alpha-methylacyl-CoA racemase activityGO:0008111
Substrates: (25R)-THCA-CoA / DHCA-CoA
Products: (25S)-THCA-CoA / DHCA-CoA

Locations

peroxisomal matrixGO:0005782

CYP27A1 (GO:0047748) oxidises the C27 side chain to a bile-acyl-CoA; AMACR (GO:0008111) racemises it; ACOX2 (Q99424, GO:0003997) then the D-bifunctional protein and SCPx thiolase (SCP2, P22307, GO:0050632; curated in the peroxisomal beta-oxidation module) remove a propionyl unit to give the C24 bile-acyl-CoA.

Part 8: activation + amino-acid conjugation
Bile-acid CoA ligase + amino-acid conjugation (SLC27A5, BAAT)Reactionconjugation

Annotons

SLC27A5: bile acid-CoA ligase (BACS)
slc27a5_activity
Participant: Family: SLC27A5 / very-long-chain acyl-CoA synthetase (bile-acid CoA ligase) family
Family:
SLC27A5 / very-long-chain acyl-CoA synthetase (bile-acid CoA ligase) familyPANTHER:PTHR43107
Representative Members: SLC27A5 (human)UniProtKB:Q9Y2P5

Function

cholate-CoA ligase activityGO:0047747
Substrates: (unconjugated) bile acid (cholate/CDCA) ATP + CoA
Products: bile acyl-CoA (choloyl-CoA) AMP + diphosphate

Locations

endoplasmic reticulum membraneGO:0005789

Activate the bile acid to bile-acyl-CoA (ATP/CoA).

BAAT: bile acid-CoA:amino acid N-acyltransferase
baat_activity
Participant: Family: BAAT / bile acid-CoA:amino acid N-acyltransferase family
Family:
BAAT / bile acid-CoA:amino acid N-acyltransferase familyPANTHER:PTHR10824
Representative Members: BAAT (human)UniProtKB:Q14032

Function

glycine N-choloyltransferase activityGO:0047963
Substrates: choloyl-CoA / bile-acyl-CoA glycine or taurine
Products: glyco-/tauro-conjugated bile acid CoA

Locations

cytosolGO:0005829

Conjugate the bile-acyl-CoA to glycine/taurine (final step).