Biotin cycle — holocarboxylase synthetase and biotinidase (multiple carboxylase deficiency)

The biotin cycle activates and recycles the cofactor biotin for the five human biotin-dependent carboxylases, and its two enzymes are the causes of multiple carboxylase deficiency. Holocarboxylase synthetase (HLCS, biotin-protein ligase) covalently attaches biotin to a specific lysine in the biotin-carboxyl-carrier domain of each apo-carboxylase — pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCCA/PCCB), 3-methylcrotonyl-CoA carboxylase (MCCC1/MCCC2) and the cytosolic and mitochondrial acetyl-CoA carboxylases (ACACA, ACACB) — via a two-step reaction (biotin + ATP -> biotinyl-5'-AMP, then transfer to the carrier lysine), converting inactive apo-enzymes to active holo-carboxylases. When these holo-carboxylases are proteolytically degraded, the biotin remains bound as biocytin (biotinyl-lysine) or short biotinyl-peptides; biotinidase (BTD) hydrolyses these to liberate free biotin for reuse, and also releases dietary protein-bound biotin, making it bioavailable. Free biotin then re-enters the cycle as the HLCS substrate. Inherited deficiency of either enzyme produces multiple carboxylase deficiency (simultaneous functional loss of all biotin carboxylases, with lactic acidosis and organic aciduria): HLCS deficiency is the early-onset (neonatal) form, and BTD (biotinidase) deficiency is the late-onset form — a classic treatable, newborn-screened disorder rescued by biotin supplementation.

MODULE:biotin_cycleDRAFTMetabolic Pathwaymodules/biotin_cycle.yaml
biotin metabolic processGO:0006768
GO:0006768
biotin metabolic process
The module is grounded in the GO biotin metabolic process (GO:0006768): HLCS uses biotin to activate the carboxylases and BTD recycles it.
Reactome:R-HSA-196780
Biotin transport and metabolism
Reactions follow the human Reactome "Biotin transport and metabolism" pathway (R-HSA-196780): HLCS biotinylation of the apo-carboxylases (R-HSA-2993447, R-HSA-2993799, ...) and BTD hydrolysis of biocytin (R-HSA-3076905).
file:human/HLCS/HLCS-ai-review.yaml
HLCS gene review (human)
The biotinylation step grounding (UniProtKB:P50747, GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity) matches the completed human HLCS review.
file:human/BTD/BTD-ai-review.yaml
BTD gene review (human)
The biotin-recycling step grounding (UniProtKB:P43251, GO:0047708 biotinidase activity) matches the completed human BTD review.
file:human/PC/PC-ai-review.yaml
PC gene review (human)
One of the biotin-dependent carboxylase clients activated by HLCS (pyruvate carboxylase; see the pyruvate_metabolism module).
file:human/PCCA/PCCA-ai-review.yaml
PCCA gene review (human)
A biotin-dependent carboxylase client of HLCS (propionyl-CoA carboxylase; see the propionyl_coa_catabolism module).
file:human/MCCC1/MCCC1-ai-review.yaml
MCCC1 gene review (human)
A biotin-dependent carboxylase client of HLCS (3-methylcrotonyl-CoA carboxylase; see the leucine_catabolism module).
3Nodes
2Parts
0Variant Sets
0Variants
2Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:biotin_cycle 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 (2/2 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
BTD P43251 ✓ ✓ ✗
HLCS P50747 ✓ ✓ ✗

Details

Biotin cycle (HLCS + biotinidase)Metabolic Pathwaybiotin_cycle
biotin metabolic processGO:0006768

The biotin cofactor cycle grounded to the human enzymes HLCS (UniProtKB:P50747, GO:0004077, EC 6.3.4.10) and BTD (P43251, GO:0047708, EC 3.5.1.12). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over paralogs and orthologs) plus a concrete human representative member. HLCS activates all five human biotin-dependent carboxylases — pyruvate carboxylase (PC; pyruvate_metabolism module), propionyl-CoA carboxylase (PCCA/PCCB; propionyl_coa_catabolism module), 3-methylcrotonyl-CoA carboxylase (MCCC1/MCCC2; leucine_catabolism module) and the acetyl-CoA carboxylases (ACACA/ACACB, of fatty-acid synthesis, not yet reviewed) — so deficiency of either HLCS or BTD produces MULTIPLE carboxylase deficiency affecting all of those pathways simultaneously. The reported nuclear/histone- biotinylation moonlighting role of HLCS is kept out of this metabolic module (it is captured non-core in the HLCS gene review).

Connections

btd_step -> hlcs_step Provides Input For
Free biotin liberated by BTD (from biocytin/dietary sources) is the substrate HLCS uses to re-biotinylate the apo-carboxylases, closing the biotin cycle.
Part 1: biotin attachment to the apo-carboxylases (activation)
apo-carboxylase + biotin + ATP to holo-carboxylase (biotinylated) + AMP + PPiReactionhlcs_step

Annotons

HLCS: holocarboxylase synthetase (biotin-protein ligase)
hlcs_activity
Participant: Family: Biotin-protein ligase family (HLCS)
Family:
Biotin-protein ligase family (HLCS)PANTHER:PTHR12835
Representative Members: HLCS (human)UniProtKB:P50747

Function

biotin--[biotin carboxyl-carrier protein] ligase activityGO:0004077
Substrates: apo-carboxylase (PC / PCC / MCC / ACC) biotin ATP
Products: holo-(biotinylated) carboxylase AMP diphosphate

Locations

cytosolGO:0005829

Biotin-protein ligase that (via a biotinyl-5'-AMP intermediate) attaches biotin to the carrier lysine of all five human biotin- dependent carboxylases (PC, PCCA, MCCC1, ACACA, ACACB), converting apo- to holo-enzymes. Deficiency causes early-onset (neonatal) multiple carboxylase deficiency (biotin-responsive).

Part 2: biotin recycling / salvage (regenerates free biotin)
biocytin (biotinyl-lysine) + H2O to biotin + L-lysineReactionbtd_step

Annotons

BTD: biotinidase
btd_activity
Participant: Family: Biotinidase / nitrilase-like amidohydrolase family (BTD)
Family:
Biotinidase / nitrilase-like amidohydrolase family (BTD)PANTHER:PTHR10609
Representative Members: BTD (human)UniProtKB:P43251

Function

biotinidase activityGO:0047708
Substrates: biocytin (biotinyl-L-lysine) water
Products: biotin L-lysine

Locations

extracellular regionGO:0005576

Secreted glycoprotein that hydrolyses biocytin and biotinyl-peptides (from holo-carboxylase turnover) and dietary protein-bound biotin, liberating free biotin for reuse. Deficiency causes late-onset multiple carboxylase deficiency — a treatable, newborn-screened disorder (biotin supplementation).