BTD

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: Biotinidase is a secreted enzyme; the phylogenetically inferred extracellular localization is correct and represents the canonical site of the serum/plasma form. Reason: UniProt records the subcellular location as secreted/extracellular space, and biotinidase is a well-characterized serum glycoprotein. The IBA is consistent with the direct evidence and represents a core localization for the active enzyme. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Secreted, extracellular space
GO:0006768 biotin metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Biotinidase recycles biotin from biocytin and biotinyl-peptides, a central step in biotin metabolism/salvage. This is a core biological process for the gene. Reason: The enzyme completes the biotin cycle by releasing free biotin from the degradation products of the biotin-dependent carboxylases, making biotin metabolic process the correct high-level BP. Supported by the enzymatic function and by the disease mechanism (loss of recycling causes secondary biotin deficiency). Supporting Evidence: file:human/BTD/BTD-uniprot.txt Catalytic release of biotin from biocytin, the product of Reactome:R-HSA-3076905 As a result, Btn is again available to be used in the biotinylation of apo-carboxylases in the mitochondrion.
GO:0047708 biotinidase activity	IBA GO_REF:0000033	ACCEPT	Summary: Biotinidase activity (biotin-amide amidohydrolase, EC 3.5.1.12) is the defining, core molecular function of BTD. Reason: Direct biochemical characterization establishes hydrolysis of biocytin to biotin and lysine; the IBA correctly identifies the core molecular function and is at the right level of specificity. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Reaction=biocytin + H2O = biotin + L-lysine Reactome:R-HSA-3076905 Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Electronic mapping from the UniProt "Secreted, extracellular space" subcellular location; correct and consistent with the experimental and IBA evidence. Reason: This IEA is derived from the curated UniProt subcellular location (SL-0112) and correctly places the secreted enzyme in the extracellular region. Redundant with the IBA/TAS/HDA extracellular annotations but not incorrect. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Secreted, extracellular space
GO:0016811 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	IEA GO_REF:0000120	ACCEPT	Summary: A correct but broader parent of biotinidase activity, capturing the chemistry (hydrolysis of a non-peptide C-N bond in a linear amide, i.e. the biotin-amide bond). Reason: Biotinidase hydrolyses the amide bond linking biotin to the epsilon-amino group of lysine (biocytin) or to ammonia (biotin amide), a non-peptide carbon-nitrogen bond in a linear amide, so this InterPro/ARBA-based mapping is chemically correct. It is more general than the specific GO:0047708 biotinidase activity term but is not wrong; retained as a broader IEA. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Reaction=biotin amide + H2O = biotin + NH4(+)
GO:0047708 biotinidase activity	IEA GO_REF:0000120	ACCEPT	Summary: Biotinidase activity assigned electronically via RHEA:13081 / EC 3.5.1.12; this is the correct core molecular function. Reason: The EC/RHEA-based electronic mapping matches the experimentally established EC 3.5.1.12 activity of the enzyme. Redundant with the IBA and TAS biotinidase-activity annotations but correct. Supporting Evidence: file:human/BTD/BTD-uniprot.txt EC=3.5.1.12
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: A single high-throughput affinity-purification/mass-spectrometry interaction (BioPlex 2.0; reported partner MYO1D, O94832). "Protein binding" is uninformative about biotinidase function. Reason: This is a bare GO:0005515 "protein binding" term derived from a large-scale AP-MS interactome screen (IntAct) rather than a characterized functional interaction. Per curation guidelines, bare protein binding conveys no useful functional information; the single MYO1D co-purification has no established biological role in biotin recycling. Kept (not removed) as a low-value interaction record, but flagged as over-annotated. Supporting Evidence: PMID:28514442 which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: A second high-throughput AP-MS interactome dataset (BioPlex 3.0; reported partner MYO1D, O94832) supporting the same uninformative "protein binding" term. Reason: As with PMID:28514442, this is a bare protein-binding annotation from a proteome-scale AP-MS screen with no demonstrated functional relevance to biotinidase activity. Retained as a low-value interaction record but flagged as over-annotated per the guideline to avoid uninformative "protein binding" terms. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0006768 biotin metabolic process	TAS Reactome:R-HSA-196780	ACCEPT	Summary: Reactome places biotinidase within biotin transport and metabolism (biotin salvage/recycling); a correct core biological process annotation. Reason: The Reactome pathway "Biotin transport and metabolism" describes biotin uptake, conjugation to apoenzymes and salvage, of which biotinidase-mediated recycling is a key step. Consistent with the IBA biotin metabolic process annotation. Supporting Evidence: Reactome:R-HSA-196780 Its uptake, intracellular translocation, covalent conjugation to apoenzymes, and salvage are described here.
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-3076905	ACCEPT	Summary: Reactome-asserted biotinidase activity for the extracellular hydrolysis of biocytin; the core molecular function. Reason: Reactome reaction "Extracellular BTD hydrolyses BCTN" documents the EC 3.5.1.12 hydrolysis of biocytin to biotin and lysine, matching the core molecular function of the gene. Supporting Evidence: Reactome:R-HSA-3076905 Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine.
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-3325540	ACCEPT	Summary: Biotinidase activity annotation from the Reactome "defective extracellular BTD" disease reaction; the term is the correct core molecular function (its loss is what defines the disease reaction). Reason: This TAS derives from the Reactome disease reaction describing loss of extracellular biotinidase activity in BTD deficiency; the underlying molecular function it references (EC 3.5.1.12 biotinidase activity) is correct and core. Supporting Evidence: Reactome:R-HSA-3325540 Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine.
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-4167509	ACCEPT	Summary: Biotinidase activity annotation from the Reactome "mitochondrial BTD hydrolyses BCTN" reaction; the molecular function is correct and core. Reason: Reactome asserts a mitochondrial pool of biotinidase performing the same EC 3.5.1.12 hydrolysis. Whichever compartment, the molecular function (biotinidase activity) is correct and represents the core function. Supporting Evidence: Reactome:R-HSA-4167509 Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine.
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-4225086	ACCEPT	Summary: Biotinidase activity annotation from the Reactome "defective mitochondrial BTD" disease reaction; the referenced molecular function is correct and core. Reason: As with the other Reactome biotinidase-activity TAS entries, the molecular function referenced (EC 3.5.1.12) is correct. Redundant with the other biotinidase-activity annotations but not incorrect. Supporting Evidence: Reactome:R-HSA-4225086 Human biotinidase (BTD, EC 3.5.1.12) (Cole et al. 1994) catalyzes the hydrolysis of biocytin (BCTN, aka biotinyl-lysine), a product of biotin dependent carboxylase degradation, to biotin (Btn) and lysine.
GO:0005576 extracellular region	TAS Reactome:R-HSA-3325540	ACCEPT	Summary: Reactome localizes the extracellular biotinidase reaction to the extracellular region; consistent with the secreted enzyme. Reason: The secreted/extracellular localization is well supported by UniProt and by the biology of the serum enzyme; this Reactome TAS is correct and represents a core localization. Supporting Evidence: Reactome:R-HSA-3325540 BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005).
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-4225086	KEEP AS NON CORE	Summary: Reactome asserts a mitochondrial pool of biotinidase. This localization is secondary and less well established than the dominant secreted/extracellular form. Reason: The canonical and best-supported localization of biotinidase is secreted/extracellular (serum). Reactome cites Wolf & Jensen 2005 for a mitochondrial pool, but this is a minor, less-characterized localization relative to the serum enzyme; kept as a non-core localization rather than treated as a core site of action. Supporting Evidence: Reactome:R-HSA-4225086 BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005).
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Biotinidase was detected by shotgun proteomics in exosomes from expressed prostatic secretions in urine; consistent with a secreted protein but not a core localization. Reason: This high-throughput proteomic detection in prostatic-secretion exosomes is consistent with biotinidase being a secreted protein that partitions into extracellular vesicles, but the exosome compartment is not a core functional site for the enzyme. Retained as a non-core localization. Supporting Evidence: PMID:23533145 Using expressed prostatic secretions in urine (EPS-urine), exosome preparations were characterized by a shotgun proteomics procedure.
GO:0005576 extracellular region	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	ACCEPT	Summary: Biotinidase was identified among minor proteins of the aqueous phase of human colostrum by proteomics, consistent with its secreted extracellular localization. Reason: Detection in the aqueous phase of colostrum (a secreted body fluid) by mass spectrometry supports the extracellular localization of the secreted enzyme. Consistent with the UniProt-curated secreted location. Supporting Evidence: PMID:16502470 We have investigated the low abundance proteins in the aqueous phase of human colostrum
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-4167509	KEEP AS NON CORE	Summary: Reactome asserts a mitochondrial pool of biotinidase (mitochondrial matrix); secondary and less well established than the secreted form. Reason: As with the other mitochondrial-matrix Reactome TAS, the dominant, best-supported localization is secreted/extracellular. The mitochondrial pool is a minor, less-characterized localization; kept as non-core. Supporting Evidence: Reactome:R-HSA-4167509 BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005).
GO:0005576 extracellular region	TAS Reactome:R-HSA-3076905	ACCEPT	Summary: Reactome localizes the extracellular biotinidase reaction to the extracellular region; consistent with the secreted enzyme and a core localization. Reason: Correct localization of the secreted serum enzyme, consistent with UniProt and the experimental proteomic detections in body fluids. Supporting Evidence: Reactome:R-HSA-3076905 BTD is both secreted from various cells and localised in the mitochondria (Wolf & Jensen 2005).
GO:0007417 central nervous system development	TAS PMID:7550325 Mutational hotspot in the human biotinidase gene causes prof...	MARK AS OVER ANNOTATED	Summary: A legacy ProtInc TAS linking BTD to central nervous system development. The cited paper describes a deficiency-causing mutation and the neurological symptoms of the disorder, not a direct developmental role of the enzyme. Reason: Biotinidase is a metabolic (biotin-recycling) enzyme; it has no direct role in CNS development. The cited reference reports a mutational hotspot causing profound biotinidase deficiency and notes the disorder's neurological symptoms and the need for early treatment to prevent neurological damage. This is a downstream disease phenotype of biotin/carboxylase deficiency, not a developmental function of the gene product. Flagged as over-annotated (phenotype-to-process over-interpretation); not a core function. Supporting Evidence: PMID:7550325 it is important that biotinidase deficiency is diagnosed early so that permanent neurological damage can be prevented.

Gene Description

Existing Annotations Review

Core Functions

Recycling of the vitamin biotin by hydrolysis of biocytin and biotinyl-peptides, releasing free biotin for reuse in biotinylation of apo-carboxylases; occurs in the extracellular/serum compartment.

References

📚 Additional Documentation

Notes

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