TPK1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: TPK1 is a cytosolic enzyme, consistent across the family and confirmed for the human protein by Reactome (TAS) and by ARBA/UniProt annotation. The subcellular location is a genuine feature of where TPK1 acts, so this phylogenetically inferred localization is accepted. Supporting Evidence: Reactome:R-HSA-196761 Cytosolic thiamin pyrophosphokinase (TPK1) catalyzes the reaction of thiamin (THMN) and ATP to form thiamin diphosphate
GO:0036172 thiamine salvage	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phosphorylation of free thiamine to the active cofactor ThDP is the salvage arm of thiamine metabolism (recycling/activation of the intact vitamin, as opposed to de novo pyrimidine/thiazole ring biosynthesis, which humans lack). This is a reasonable phylogenetic characterization of TPK1's role and is compatible with the human data, though it is a broad process term relative to the specific biosynthetic step TPK1 performs. Retained as a non-core contextual process.
GO:0009229 thiamine diphosphate biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: This is the core biological process for TPK1: it carries out the single committed biosynthetic step producing thiamine diphosphate from thiamine. Directly supported experimentally in human (IDA, PMID:38547260 and PMID:11342111) and by the UniProt PATHWAY statement. Phylogenetic support is concordant. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt PATHWAY: Cofactor biosynthesis; thiamine diphosphate biosynthesis; thiamine diphosphate from thiamine: step 1/1.
GO:0004788 thiamine diphosphokinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of TPK1: transfer of a pyrophosphate group to thiamine to form thiamine diphosphate. Directly demonstrated for the human enzyme (IDA, PMID:38547260 and PMID:11342111) and conserved across the thiamine pyrophosphokinase family. Accepted as representing the core function. Supporting Evidence: PMID:11342111 A human thiamine pyrophosphokinase cDNA clone (hTPK1) was isolated and sequenced.
GO:0004788 thiamine diphosphokinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/InterPro-based) assertion of the enzyme's own core catalytic function. Redundant with the experimental IDA annotations but correct, so accepted rather than marked over-annotated.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: TPK1 binds a nucleoside triphosphate phosphodonor; ATP binding is supported by the UniProt ATP-binding keyword and by the in vitro demonstration that TPK1 can use ATP (Km ~5 mM). The InterPro-based inference is correct, though human TPK1 prefers UTP over ATP as the physiological phosphodonor (PMID:38547260). Accepted as a correct, if partial, description of nucleotide binding. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt KM=5 mM for ATP
GO:0005829 cytosol	IEA GO_REF:0000117	ACCEPT	Summary: ARBA/machine-learning cytosol localization, redundant with the Reactome TAS and IBA cytosol annotations and consistent with the known cytosolic site of ThDP synthesis. Accepted.
GO:0006772 thiamine metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Correct but general parent process. TPK1's participation in thiamine metabolism is well established; the more specific and experimentally supported term is thiamine diphosphate biosynthetic process (GO:0009229). Kept as non-core given the more specific annotation is available.
GO:0009229 thiamine diphosphate biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic duplicate of the core biological process, which is also supported experimentally by IDA. Correct; accepted.
GO:0030975 thiamine binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: TPK1 binds thiamine as its acceptor substrate; the protein has a dedicated thiamin-binding domain (InterPro IPR007373, Pfam PF04265). This InterPro-based inference correctly captures substrate binding and is consistent with the enzyme's mechanism. It is a molecular-function component of the catalytic activity rather than an independent function, so kept as non-core. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt DR Pfam; PF04265; TPK_B1_binding; 1.
GO:0141200 UTP thiamine diphosphokinase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-mapped electronic annotation of the UTP-dependent reaction (thiamine + UTP = thiamine diphosphate + UMP + H+, RHEA:79423). This is the physiologically preferred activity of human TPK1 and is also supported experimentally by IDA (PMID:38547260). Correct; accepted. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt Reaction=thiamine + UTP = thiamine diphosphate + UMP + H(+);
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput binary interactome (HuRI) IPI annotation recording an interaction with OPLAH (WITH:O14841). The bare "protein binding" term is experimentally derived but uninformative about TPK1's molecular function, and the OPLAH interaction has no established functional consequence for TPK1. Per policy this experimental IPI is not removed but is flagged as an over-annotation.
GO:0042802 identical protein binding	IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam...	KEEP AS NON CORE	Summary: TPK1 is a homodimer, so self-association (identical protein binding) is a genuine structural property, independently confirmed by the UniProt SUBUNIT statement (homodimer) and by an IntAct self-interaction observed in 8 experiments. This annotation derives from a systematic disease-mutation/interaction pipeline that included TPK1. It correctly reports the homodimeric self-interaction; kept as non-core since homodimerization supports, but is not itself, the catalytic function. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt SUBUNIT: Homodimer.
GO:0042802 identical protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	KEEP AS NON CORE	Summary: Additional IPI evidence for TPK1 self-association from a systematic interactome-perturbation study. Consistent with the homodimeric structure documented in UniProt. Kept as non-core (structural self-interaction, not the core catalytic function). Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt SUBUNIT: Homodimer.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: Further IPI evidence for TPK1 homodimerization from a large-scale variant/interaction study, consistent with the UniProt homodimer subunit annotation. Kept as non-core. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt SUBUNIT: Homodimer.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Self-interaction detected in the HuRI binary interactome map, matching the IntAct TPK1-TPK1 self-interaction (NbExp=8) and the documented homodimeric state. Kept as non-core structural self-association. Supporting Evidence: file:human/TPK1/TPK1-uniprot.txt SUBUNIT: Homodimer.
GO:0141200 UTP thiamine diphosphokinase activity	IDA PMID:38547260 Pyrimidines maintain mitochondrial pyruvate oxidation to sup...	ACCEPT	Summary: Direct experimental demonstration that purified human TPK1 uses UTP as its preferred phosphodonor to synthesize thiamine diphosphate, with ~10-fold higher affinity for UTP than ATP. This is a core, physiologically relevant molecular function of human TPK1 and is accepted as core. Supporting Evidence: PMID:38547260 UTP was the preferred substrate for TPK1 in producing TPP
GO:0004788 thiamine diphosphokinase activity	IDA PMID:38547260 Pyrimidines maintain mitochondrial pyruvate oxidation to sup...	ACCEPT	Summary: Direct assay of purified human TPK1 catalyzing thiamine diphosphate synthesis (from UTP, ATP, or CTP). This is the core catalytic function of the enzyme; accepted. Supporting Evidence: PMID:38547260 To determine the phosphodonor preference of TPK1 for thiamine phosphorylation, we incubated purified human TPK1 with thiamine, UTP, ATP, or CTP.
GO:0009229 thiamine diphosphate biosynthetic process	IDA PMID:38547260 Pyrimidines maintain mitochondrial pyruvate oxidation to sup...	ACCEPT	Summary: Cellular TPP synthesis is TPK1-dependent: genetic depletion of TPK1 decreased TPP abundance, and reconstitution with wild-type TPK1 restored TPP synthesis. Directly supports TPK1's role in the thiamine diphosphate biosynthetic process. Core process; accepted. Supporting Evidence: PMID:38547260 Genetic depletion of TPK1 decreased abundance of TPP
GO:0010510 regulation of pyruvate decarboxylation to acetyl-CoA	IMP PMID:38547260 Pyrimidines maintain mitochondrial pyruvate oxidation to sup...	KEEP AS NON CORE	Summary: By producing ThDP, the essential cofactor of the pyruvate dehydrogenase E1 subunit, TPK1 governs pyruvate decarboxylation to acetyl-CoA. TPK1 depletion decreased pyruvate catabolism, and expression of catalytically impaired TPK1 (D100A) reduced pyruvate catabolism relative to wild type (IMP). This is a downstream regulatory consequence of TPK1's cofactor-biosynthetic activity rather than TPK1's direct enzymatic function, so it is kept as a valid non-core process. Supporting Evidence: PMID:38547260 cells expressing D100A TPK1 displayed decreased pyruvate catabolism compared to that of sgTPK1 cells reconstituted with wild-type TPK1
GO:0004788 thiamine diphosphokinase activity	IDA PMID:11342111 Isolation and characterization of a human thiamine pyrophosp...	ACCEPT	Summary: The founding characterization of human TPK1: the cloned hTPK1 open reading frame expressed in E. coli showed marked thiamine pyrophosphokinase enzyme activity, directly establishing the core molecular function. Accepted as core. Supporting Evidence: PMID:11342111 When the intact hTPK1 open reading frame was expressed as a histidine-tag fusion protein in Escherichia coli, marked enzyme activity was detected in the bacterial cells.
GO:0009229 thiamine diphosphate biosynthetic process	IDA PMID:11342111 Isolation and characterization of a human thiamine pyrophosp...	ACCEPT	Summary: The demonstrated thiamine pyrophosphokinase activity of the cloned human enzyme establishes its role in ThDP biosynthesis. Consistent with the core process; accepted. Supporting Evidence: PMID:11342111 When the intact hTPK1 open reading frame was expressed as a histidine-tag fusion protein in Escherichia coli, marked enzyme activity was detected in the bacterial cells.
GO:0005829 cytosol	TAS Reactome:R-HSA-196761	ACCEPT	Summary: Reactome traceable-author statement placing TPK1 in the cytosol, where it phosphorylates thiamine. Consistent with all other localization evidence; accepted. Supporting Evidence: Reactome:R-HSA-196761 Cytosolic thiamin pyrophosphokinase (TPK1) catalyzes the reaction of thiamin (THMN) and ATP to form thiamin diphosphate

Gene Description

Existing Annotations Review

Core Functions

Thiamine diphosphokinase (thiamine pyrophosphokinase) activity: transfer of a pyrophosphate group from a nucleoside triphosphate to thiamine, forming thiamine diphosphate (the active vitamin B1 cofactor); the single committed step of ThDP biosynthesis from thiamine.

UTP-dependent thiamine diphosphokinase activity: human TPK1's preferred physiological reaction, thiamine + UTP -> thiamine diphosphate + UMP, coupling pyrimidine nucleotide availability to ThDP synthesis.

References

📚 Additional Documentation

Notes

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