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: The source IBA is linked to PTN000064608; the cached PTHR10609 PAINT table contains the same non-negated extracellular-region IBD with MGI:MGI:1347001 descendant evidence. Curated human UniProt secretion/extracellular location supports the target function. Neither a one-gene donor list nor the broader family label is a defect. The cached table is not a full tree/MSA, so detailed ancestral branching is not independently reconstructed. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Secreted, extracellular space PMID:7509806
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 source IBA joins the non-negated biotin-metabolism IBD at PTN000834762, experimentally seeded by MGI:MGI:1347001 in the cached PAINT record. Human BTD directly hydrolyses biocytin/biotin amide and recycles biotin; it performs a salvage step rather than merely being a consumed substrate. Its placement within the biotinidase subfamily and target chemistry support retaining the broad process without inventing a separate pathway annotation. Full ancestral tree and donor experiment remain outside this bounded reading. Supporting Evidence: file:human/BTD/BTD-uniprot.txt PMID:7509806
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: The source IBA joins the non-negated biotinidase-activity IBD at PTN000834762, with FB:FBgn0029848 and MGI:MGI:1347001 descendants. Human P43251 is explicitly PTHR10609:SF14 in both UniProt and the cached family entry, and its curated EC3.5.1.12 reactions match the annotated activity. The family also includes VNN pantetheinases but their cached functional IBD is a separate node, PTN007449457; family breadth is not evidence of wrong propagation to BTD. The full tree/MSA and original donor experiments were not inspected. Independent human serum enzyme evidence in PMID:7509806 corroborates the target activity. Supporting Evidence: file:human/BTD/BTD-uniprot.txt Reaction=biocytin + H2O = biotin + L-lysine PMID:7509806 PMID:9099842
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: The actual electronic source is UniProtKB-SubCell:SL-0112. The curated human record explicitly places BTD in secreted extracellular space, making this broad location appropriate. This does not imply every cellular pool or alternative product is exclusively extracellular. 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: The actual mapping sources are ARBA:ARBA00026848 and InterPro:IPR012101. Curated biocytin and biotin-amide hydrolysis chemically fit a linear non-peptide amide C–N hydrolase; accept the broad electronic term. The term is broader than GO:0047708 but chemically appropriate. 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 actual electronic mapping carries RHEA:13081 and EC:3.5.1.12. RHEA13081 in this source record is specifically biotin-amide hydrolysis to biotin and ammonium, whereas the separately recorded biocytin-to-biotin/lysine reaction is RHEA77171. The electronic source therefore fits the biotin-amide reaction in the GO definition, while BTD also hydrolyses biocytin. Supporting Evidence: file:human/BTD/BTD-uniprot.txt EC=3.5.1.12 PMID:9099842
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	UNDECIDED	Summary: The source-specific BTD–MYO1D interaction record remains unverified. Reason: The original IPI source assigns UniProtKB:O94832 (MYO1D). The cached abstract, general AP-MS approach and data-availability context were inspected, but the publication-specific BTD–MYO1D bait/prey record was not. Co-purification need not establish purified binary affinity or a role in biotin recycling. This project follows the explicit user instruction documented in projects/CLINGEN_MENDELIAN.md: supported correct generic binding is retained as KEEP_AS_NON_CORE when no justified finer MF exists; inaccessible or unadjudicated interaction evidence remains UNDECIDED. This task-specific instruction overrides the skill’s usual informational-exclusion default and does not verify this uninspected record. Supporting Evidence: PMID:28514442 file:human/BTD/BTD-uniprot.txt
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	UNDECIDED	Summary: The source-specific BTD–MYO1D interaction record remains unverified. Reason: The original IPI source assigns UniProtKB:O94832 (MYO1D). The cache contains Abstract/Introduction/Discussion despite its full-text flag; the publication-specific BTD AP-MS record and Results/Methods were not available in that body. UniProt independently lists the pair without resolving the source-specific record. The explicit user instruction in projects/CLINGEN_MENDELIAN.md retains supported generic binding as KEEP_AS_NON_CORE but leaves unadjudicated evidence UNDECIDED, overriding the skill’s usual informational-exclusion default. No binding verification or more specific MF is inferred here. Supporting Evidence: PMID:33961781 file:human/BTD/BTD-uniprot.txt
GO:0006768 biotin metabolic process	TAS Reactome:R-HSA-196780	ACCEPT	Summary: Biotinidase performs the hydrolytic salvage step in biotin metabolism. Reason: The cached Reactome pathway includes salvage. BTD itself cleaves a biotin amide bond to release reusable biotin, as established for the human serum enzyme; this is direct metabolic participation. Supporting Evidence: Reactome:R-HSA-196780 Its uptake, intracellular translocation, covalent conjugation to apoenzymes, and salvage are described here. PMID:7509806
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-3076905	ACCEPT	Summary: Biotinidase activity is the established molecular function of human BTD. Reason: The reaction names the established hydrolysis performed by BTD. Human serum enzyme characterization and the curated EC/Rhea reactions support retaining the molecular function. Supporting Evidence: Reactome:R-HSA-3076905 catalyzes the hydrolysis of biocytin PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-3325540	ACCEPT	Summary: Biotinidase activity is the established molecular function of human BTD. Reason: The source disease reaction describes loss of this normal activity; it does not make the unnegated wild-type molecular-function assertion incorrect. Human serum enzyme characterization and the curated EC/Rhea reactions support retaining the molecular function. Supporting Evidence: Reactome:R-HSA-3325540 catalyzes the hydrolysis of biocytin PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-4167509	ACCEPT	Summary: Biotinidase activity is the established molecular function of human BTD. Reason: The reaction names the established hydrolysis performed by BTD. Its mitochondrial reaction context is not independently established: the source-specific localization uncertainty is assessed separately in rows carrying mitochondrial matrix. Human serum enzyme characterization and the curated EC/Rhea reactions support retaining the molecular function. Supporting Evidence: Reactome:R-HSA-4167509 catalyzes the hydrolysis of biocytin PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0047708 biotinidase activity	TAS Reactome:R-HSA-4225086	ACCEPT	Summary: Biotinidase activity is the established molecular function of human BTD. Reason: The source disease reaction describes loss of this normal activity; it does not make the unnegated wild-type molecular-function assertion incorrect. Its mitochondrial reaction context is not independently established: the source-specific localization uncertainty is assessed separately in rows carrying mitochondrial matrix. Human serum enzyme characterization and the curated EC/Rhea reactions support retaining the molecular function. Supporting Evidence: Reactome:R-HSA-4225086 catalyzes the hydrolysis of biocytin PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0005576 extracellular region	TAS Reactome:R-HSA-3325540	ACCEPT	Summary: Extracellular localization is supported for the active serum enzyme. Reason: The Reactome extracellular reaction agrees with the purified human serum enzyme and UniProt secretion annotation. Acceptance of this extracellular location does not validate the separate mitochondrial statement in the same Reactome summary. Supporting Evidence: Reactome:R-HSA-3325540 BTD is both secreted from various cells PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-4225086	UNDECIDED	Summary: The human mitochondrial-matrix localization remains unresolved. Reason: Reactome asserts this compartment. PMID:15059618 reports an inactive, anti-BTD-reactive 48-kDa mitochondrial protein in rat liver with unresolved identity; human immunofluorescence was not matrix-specific. PMID:16150625 reports inconsistent mitochondrial targeting predictions. These accessible abstracts do not establish an active human matrix pool, and the complete localization experiments were not inspected. Supporting Evidence: Reactome:R-HSA-4225086 PMID:15059618 PMID:16150625
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent. Reason: Secreted biotinidase. Secreted or lumenal protein (UniProt). MISEV2018 (PMID:30637094) category 5 allows such proteins onto EVs through specific or promiscuous (proteoglycan, lipid) receptors on the EV surface, but asks that their identification be backed by evidence of that association. A bulk EV proteome cannot separate surface binding from co-isolation, and this protein's annotations record no experimental proteoglycan, heparin or lipid binding, and its own review keeps no experimental cell-surface or plasma-membrane pool. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.) 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: The broad extracellular location agrees with established human serum BTD. Reason: The original colostrum proteomics reference is abstract-only locally and its BTD target table was not inspected. The broad extracellular annotation is independently supported by purification and cloning of human serum biotinidase; acceptance does not claim that the colostrum detection itself was reverified. Supporting Evidence: PMID:16502470 We have investigated the low abundance proteins in the aqueous phase of human colostrum PMID:7509806
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-4167509	UNDECIDED	Summary: The human mitochondrial-matrix localization remains unresolved. Reason: Reactome asserts this compartment. PMID:15059618 reports an inactive, anti-BTD-reactive 48-kDa mitochondrial protein in rat liver with unresolved identity; human immunofluorescence was not matrix-specific. PMID:16150625 reports inconsistent mitochondrial targeting predictions. These accessible abstracts do not establish an active human matrix pool, and the complete localization experiments were not inspected. Supporting Evidence: Reactome:R-HSA-4167509 PMID:15059618 PMID:16150625
GO:0005576 extracellular region	TAS Reactome:R-HSA-3076905	ACCEPT	Summary: Extracellular localization is supported for the active serum enzyme. Reason: The Reactome extracellular reaction agrees with the purified human serum enzyme and UniProt secretion annotation. Acceptance of this extracellular location does not validate the separate mitochondrial statement in the same Reactome summary. Supporting Evidence: Reactome:R-HSA-3076905 BTD is both secreted from various cells PMID:7509806 file:human/BTD/BTD-uniprot.txt
GO:0007417 central nervous system development	TAS PMID:7550325 Mutational hotspot in the human biotinidase gene causes prof...	UNDECIDED	Summary: A specific role in central nervous system development is not resolved by the accessible evidence. Reason: This is a legacy ProtInc TAS, not an experimental annotation. The complete cached abstract and publisher preview describe loss of biotin recycling and prevention of neurological injury by biotin treatment. This establishes metabolic necessity; it does not identify a developmental step performed by BTD and is insufficient to affirm the CNS-development term. The full paper and exact source-to-term rationale remain unavailable, however, so the universal instruction to use UNDECIDED for inaccessible relevant evidence applies. This decision does not rely on the special rule for experimental curators, and does not turn missing participation evidence into proof that the complete reference is miscited or that BTD has no developmental role. Supporting Evidence: PMID:7550325 it is important that biotinidase deficiency is diagnosed early so that permanent neurological damage can be prevented.