Bile acid synthesis II — side-chain oxidation, peroxisomal shortening and amino-acid conjugation; CYP27A1/AMACR/ACOX2/SLC27A5/BAAT

After the sterol nucleus of cholesterol has been hydroxylated (the ring-modification segment: CYP7A1/CYP7B1/HSD3B7/AKR1D1), the C27 side chain must be oxidised and shortened by three carbons to give the mature C24 bile acids, which are then conjugated to an amino acid before secretion. Mitochondrial sterol 27-hydroxylase (CYP27A1) initiates side-chain oxidation, hydroxylating C27 of the 5beta-cholestane-3alpha,7alpha,12alpha-triol (and the 7alpha-hydroxy-diol) and further oxidising it to the C27 bile-acid intermediates 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid (THCA) and its 12-deoxy congener DHCA. These C27 acids are activated to their CoA thioesters and imported into the peroxisome, where alpha-methylacyl-CoA racemase (AMACR) converts the (25R) diastereomer to the (25S) form required for beta-oxidation, and the peroxisomal branched-chain acyl-CoA oxidase ACOX2 catalyses the first (oxidase) step of one round of beta-oxidation; the downstream MFP2/SCPx steps release propionyl-CoA to give the C24 bile-acyl-CoAs choloyl-CoA and chenodeoxychenoyl-CoA. Bile acid-CoA:amino acid N-acyltransferase (BAAT) then transfers the C24 bile acid from CoA onto glycine or taurine, forming the glyco- and tauro-conjugated bile salts that are the major biliary species; the ER-membrane bile acyl-CoA synthetase SLC27A5 (cholate-CoA ligase / FATP5) re-activates free bile acids to their CoA esters, chiefly in the enterohepatic recycling loop, feeding BAAT for re-conjugation. Inherited defects across this segment cause cerebrotendinous xanthomatosis (CYP27A1), AMACR deficiency (an adult sensorimotor neuropathy with bile-acid abnormalities), ACOX2 deficiency (a bile-acid synthesis defect with liver disease/dystonia) and familial hypercholanemia / bile acid conjugation defect (BAAT).

MODULE:bile_acid_synthesis_sidechain_conjugationDRAFTMetabolic Pathwaymodules/bile_acid_synthesis_sidechain_conjugation.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 side-chain-oxidation, peroxisomal-shortening and amino-acid-conjugation segment that converts C27 sterol-acid intermediates into secreted conjugated C24 bile salts.
Reactome:R-HSA-193368
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
Step order, intermediates and reaction stoichiometries follow the human Reactome "Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol" sub-pathway, including the side-chain-oxidation and conjugation reactions cited on each node.
file:human/CYP27A1/CYP27A1-ai-review.yaml
CYP27A1 gene review (human)
The mitochondrial sterol 27-hydroxylase side-chain-oxidation step (UniProtKB:Q02318, GO:0047748/GO:0031073) matches the human CYP27A1 review, whose status is INITIALIZED: the terms are taken from its GOA rows rather than from a reviewed core function.
file:human/AMACR/AMACR-ai-review.yaml
AMACR gene review (human)
The alpha-methylacyl-CoA racemase step (UniProtKB:Q9UHK6, GO:0008111) that supplies the (25S)-THCA-CoA substrate for beta-oxidation matches the human AMACR review, whose status is INITIALIZED: the term is taken from its GOA rows rather than from a reviewed core function.
file:human/ABCD3/ABCD3-ai-review.yaml
ABCD3 gene review (human)
The peroxisomal C27 bile-acyl-CoA import step (UniProtKB:P28288) matches the human ABCD3 review, whose status is IN_PROGRESS: that review's bile-acid core function pairs GO:0042626 with GO:0015721 and GO:0006699, so the step itself follows a reviewed judgment that is not yet finalized. GO:0015607 ABC-type fatty-acyl-CoA transporter activity, used in this part, is the module's own choice and not that review's. The review's own candidate MF for this step is GO:0015125 bile acid transmembrane transporter activity, proposed NEW/IMP on PMID:25168382; this module prefers GO:0015607 on two grounds. The substrate is a CoA thioester - DHCA-CoA and THCA-CoA - whereas GO:0015125 is defined over bile acids as steroid carboxylic acids present as the glycine or taurine amides, which is the mature conjugate formed two steps later by BAAT. And GO:0015607's definition states the ATP-hydrolysing reaction that an ABC transporter performs, where GO:0015125 is mechanism- neutral. The same term is used for the paralogous activity in the human ABCD1 review, whose status is DRAFT; that is a usage precedent, not a reviewed endorsement, and ABCD1 is cited nowhere else in this module.
file:human/ACOX2/ACOX2-ai-review.yaml
ACOX2 gene review (human)
The peroxisomal branched-chain acyl-CoA oxidase step (UniProtKB:Q99424, GO:0003997/GO:0033791) matches the completed human ACOX2 review.
file:human/SLC27A5/SLC27A5-ai-review.yaml
SLC27A5 gene review (human)
The ER-membrane bile acyl-CoA synthetase (cholate-CoA ligase) step (UniProtKB:Q9Y2P5, GO:0047747) matches the human SLC27A5 review, whose status is INITIALIZED: the term is taken from its GOA rows rather than from a reviewed core function.
file:human/BAAT/BAAT-ai-review.yaml
BAAT gene review (human)
The final glycine/taurine N-acyltransferase conjugation step (UniProtKB:Q14032, GO:0047963) matches the human BAAT review, whose status is INITIALIZED: the term is taken from its GOA rows rather than from a reviewed core function.
7Nodes
6Parts
0Variant Sets
0Variants
6Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:bile_acid_synthesis_sidechain_conjugation 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.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (12 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
cyp27a1_activity CYP27A1 (human)
UniProtKB:Q02318
Family Representative 		cholestanetetraol 26-dehydrogenase activity
GO:0047748 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
abcd3_transport_activity ABCD3 (human)
UniProtKB:P28288
Family Representative 		ABC-type fatty-acyl-CoA transporter activity
GO:0015607 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
amacr_activity AMACR (human)
UniProtKB:Q9UHK6
Family Representative 		alpha-methylacyl-CoA racemase activity
GO:0008111 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acox2_activity ACOX2 (human)
UniProtKB:Q99424
Family Representative 		3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activity
GO:0033791 		Review Disagreement
The review removes, modifies, or marks this term over-annotated and provides no retained/core support. Review the rationale; rejection of an evidence row alone is not a biological NOT.
slc27a5_activity SLC27A5 (human)
UniProtKB:Q9Y2P5
Family Representative 		cholate-CoA ligase activity
GO:0047747 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
baat_activity BAAT (human)
UniProtKB:Q14032
Family Representative 		glycine N-choloyltransferase activity
GO:0047963 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyp27a1_activity Cytochrome P450 family 27 (CYP27A1)
Family 		cholestanetetraol 26-dehydrogenase activity
GO:0047748 		Family Id Missing
The family has no identifier linking it to a curated family review.
abcd3_transport_activity Peroxisomal ABC half-transporter family (ABCD3)
PANTHER:PTHR11384:SF62
Family 		ABC-type fatty-acyl-CoA transporter activity
GO:0015607 		Family Supported
Family review supports GO:0015607 for PANTHER:PTHR11384:SF62. Peroxisomal ABCD subfamilies, as peroxisomal_beta_oxidation asserts on the base family.
amacr_activity Alpha-methylacyl-CoA racemase family (AMACR)
PANTHER:PTHR48228
Family 		alpha-methylacyl-CoA racemase activity
GO:0008111 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR48228.
acox2_activity Acyl-CoA oxidase family (ACOX2)
PANTHER:PTHR10909
Family 		3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activity
GO:0033791 		Family Scope Restricted
GO:0033791 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. ACOX2 only (SF344), as bile_acid_synthesis_sidechain_conjugation asserts; that module selects the base family.
slc27a5_activity Long-chain fatty-acid transport/CoA ligase family (SLC27/FATP)
PANTHER:PTHR43107
Family 		cholate-CoA ligase activity
GO:0047747 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR43107.
baat_activity Bile acid-CoA:amino acid N-acyltransferase family (BAAT)
PANTHER:PTHR10824
Family 		glycine N-choloyltransferase activity
GO:0047963 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10824.

Gene-review completeness (6/6 grounded genes reviewed)

5 complete review(s) · 1 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
ABCD3 P28288 ✓ ✓ ✓
ACOX2 Q99424 ✓ 37/40 ✗
AMACR Q9UHK6 ✓ ✓ ✗
BAAT Q14032 ✓ ✓ ✗
CYP27A1 Q02318 ✓ ✓ ✗
SLC27A5 Q9Y2P5 ✓ ✓ ✗

Details

Context
mitochondrionGO:0005739 peroxisomal matrixGO:0005782 endoplasmic reticulum membraneGO:0005789
Bile acid side-chain oxidation and conjugationMetabolic Pathwaybile_acid_synthesis_sidechain_conjugation
bile acid biosynthetic processGO:0006699
Context
mitochondrionGO:0005739 peroxisomal matrixGO:0005782 endoplasmic reticulum membraneGO:0005789

Side-chain-oxidation/conjugation segment of bile-acid synthesis, grounded to the human enzymes CYP27A1 (UniProtKB:Q02318, GO:0047748/GO:0031073, EC 1.14.15.15), AMACR (Q9UHK6, GO:0008111, EC 5.1.99.4), ACOX2 (Q99424, GO:0033791/GO:0003997, EC 1.17.99.3), SLC27A5 (Q9Y2P5, GO:0047747, EC 6.2.1.7) and BAAT (Q14032, GO:0047963, EC 2.3.1.65). GO molecular-function and location terms were taken from the human gene reviews and verified against the local go.db; Reactome reaction ids/titles were verified against the local reactome cache. Of those reviews only ACOX2 and SCP2 are COMPLETE: ABCD3 is IN_PROGRESS, and CYP27A1, AMACR, SLC27A5, BAAT and HSD17B4 are INITIALIZED, so for those the terms come from GOA rows rather than from a reviewed core function, as each evidence statement now says. Each step uses a PANTHER family selector with the human enzyme as representative so the module generalises across orthologs/paralogs. Upstream is the ring-modification module (CYP7A1/CYP7B1/HSD3B7/AKR1D1 -> the 5beta-cholestane-triol/diol); ABCD3 (P28288, GO:0015607) imports the CoA-activated C27 acids into the peroxisome. The C27-acid CoA activation and the downstream MFP2 (HSD17B4) and SCPx (SCP2) thiolytic steps that release propionyl-CoA are not represented as separate mapping genes here. The SCPx half of that pair is now modellable: SCP2 became COMPLETE in this change, and its reviewed thiolase activity would support a part. HSD17B4 is still INITIALIZED, so adding only SCP2 would leave the round of beta-oxidation half-represented; both steps should be added together once HSD17B4 is reviewed. SLC27A5 and BAAT together constitute the conjugation/recycling node feeding conjugated bile salts into biliary secretion (BSEP/ABCB11) and the enterohepatic circulation. Disorders span the segment: cerebrotendinous xanthomatosis (CYP27A1), AMACR deficiency, ACOX2 deficiency and familial hypercholanemia / bile acid conjugation defect (BAAT).

Connections

cyp27a1_step -> abcd3_import Provides Input For
The C27 acid (THCA/DHCA) from CYP27A1 is activated to its CoA ester, which ABCD3 imports into the peroxisome.
abcd3_import -> amacr_step Provides Input For
Imported (25R)-THCA-CoA/DHCA-CoA is racemized by AMACR to the (25S) form.
amacr_step -> acox2_step Provides Input For
(25S)-THCA-CoA from AMACR is the substrate for ACOX2-initiated beta-oxidation.
acox2_step -> baat_step Provides Input For
Peroxisomal beta-oxidation (ACOX2 + MFP2/SCPx) shortens the side chain to the C24 choloyl-CoA that BAAT conjugates.
slc27a5_step -> baat_step Provides Input For
SLC27A5 re-activates free bile acids to choloyl-CoA, supplying BAAT for re-conjugation during enterohepatic recycling.
Part 1: side-chain oxidation (C27 -> C27 bile-acid intermediate)
sterol side-chain 27-hydroxylation/oxidation to THCA/DHCAReactioncyp27a1_step

Annotons

CYP27A1: sterol 27-hydroxylase
cyp27a1_activity
Participant: Family: Cytochrome P450 family 27 (CYP27A1)
Family:
Cytochrome P450 family 27 (CYP27A1)
Representative Members: CYP27A1 (human)UniProtKB:Q02318

Function

cholestanetetraol 26-dehydrogenase activityGO:0047748
Substrates: 5beta-cholestane-3alpha,7alpha,12alpha-triol O2 NADPH (via adrenodoxin/adrenodoxin reductase)
Products: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid (THCA)

Locations

mitochondrial inner membraneGO:0005743

Mitochondrial initiation of side-chain oxidation; also the sole enzyme of the acidic (alternative) bile-acid pathway. Deficiency = cerebrotendinous xanthomatosis.

Part 2: peroxisomal import of the C27 bile-acyl-CoA
THCA-CoA/DHCA-CoA import across the peroxisomal membraneTransport Stepabcd3_import

Annotons

ABCD3 (PMP70): peroxisomal ABC acyl-CoA transporter
abcd3_transport_activity
Participant: Family: Peroxisomal ABC half-transporter family (ABCD3)
Family:
Peroxisomal ABC half-transporter family (ABCD3)PANTHER:PTHR11384:SF62
Representative Members: ABCD3 (human)UniProtKB:P28288

Function

ABC-type fatty-acyl-CoA transporter activityGO:0015607
Substrates: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA (THCA-CoA) and DHCA-CoA (cytosolic face) ATP
Products: THCA-CoA/DHCA-CoA in the peroxisomal matrix ADP phosphate

Locations

peroxisomal membraneGO:0005778

Delivers the CoA-activated C27 bile-acid intermediates into the peroxisome for racemization and beta-oxidation. Deficiency = congenital bile acid synthesis defect 5 (CBAS5).

Part 3: racemization of the C27 acyl-CoA for beta-oxidation
(25R)-THCA-CoA to (25S)-THCA-CoAReactionamacr_step

Annotons

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

Function

alpha-methylacyl-CoA racemase activityGO:0008111
Substrates: (25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA
Products: (25S)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA

Locations

peroxisomal matrixGO:0005782

Chiral inversion at C25 that converts the (25R) product of side-chain oxidation into the (25S) substrate for ACOX2. Deficiency = adult AMACR-deficiency neuropathy.

Part 4: peroxisomal beta-oxidation (side-chain shortening, first step)
(25S)-THCA-CoA to 24-ene-THCA-CoA (leading to choloyl-CoA)Reactionacox2_step

Annotons

ACOX2: branched-chain acyl-CoA oxidase
acox2_activity
Participant: Family: Acyl-CoA oxidase family (ACOX2)
Family:
Acyl-CoA oxidase family (ACOX2)PANTHER:PTHR10909
Representative Members: ACOX2 (human)UniProtKB:Q99424

Function

3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activityGO:0033791
Substrates: (25S)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA O2
Products: (24E)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA H2O2

Locations

peroxisomal matrixGO:0005782

Rate-limiting oxidase step of side-chain beta-oxidation; downstream MFP2 and SCPx complete one round, releasing propionyl-CoA to yield the C24 bile-acyl-CoAs. Deficiency = ACOX2-related bile-acid synthesis defect.

Part 5: bile-acid CoA activation (enterohepatic recycling/activation)
cholate + CoA + ATP to choloyl-CoAReactionslc27a5_step

Annotons

SLC27A5: bile acyl-CoA synthetase (cholate-CoA ligase)
slc27a5_activity
Participant: Family: Long-chain fatty-acid transport/CoA ligase family (SLC27/FATP)
Family:
Long-chain fatty-acid transport/CoA ligase family (SLC27/FATP)PANTHER:PTHR43107
Representative Members: SLC27A5 (human)UniProtKB:Q9Y2P5

Function

cholate-CoA ligase activityGO:0047747
Substrates: cholate (or chenodeoxycholate) ATP CoA
Products: choloyl-CoA (or chenodeoxycholoyl-CoA) AMP diphosphate

Locations

endoplasmic reticulum membraneGO:0005789

Regenerates bile-acyl-CoA from free bile acids (also a long-chain-fatty-acid-CoA ligase); supplies the CoA-thioester substrate for BAAT during enterohepatic recycling.

Part 6: amino-acid conjugation (final, secreted product)
choloyl-CoA + glycine/taurine to glyco-/tauro-cholateReactionbaat_step

Annotons

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

Function

glycine N-choloyltransferase activityGO:0047963
Substrates: choloyl-CoA (or chenodeoxycholoyl-CoA) glycine (or taurine)
Products: glycocholate (or taurocholate) CoA

Locations

peroxisomeGO:0005777 cytosolGO:0005829

Produces the mature, secreted glyco-/tauro-conjugated bile salts. Deficiency = familial hypercholanemia / bile acid conjugation defect.