SLC25A19 is the mitochondrial thiamine pyrophosphate carrier (MTPPT), a multi-pass protein of the SLC25 mitochondrial carrier family embedded in the mitochondrial inner membrane. It imports thiamine pyrophosphate (TPP/ThPP, the activated cofactor form of vitamin B1) from the cytosol into the mitochondrial matrix, operating as an exchanger that couples TPP uptake to thiamine monophosphate efflux. Because mitochondria cannot synthesize TPP, this carrier supplies the essential cofactor for matrix TPP-dependent enzyme complexes, including the pyruvate dehydrogenase, 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase, and branched-chain 2-oxo-acid dehydrogenase complexes, and is thereby required for oxidative energy metabolism and TCA-cycle flux. The gene was originally described as a mitochondrial deoxynucleotide carrier (DNC), but knockout and transport studies established that its physiological substrate is thiamine pyrophosphate rather than deoxynucleotides. Loss-of-function mutations cause Amish lethal microcephaly (with 2-oxoglutaric aciduria) and thiamine metabolism dysfunction syndrome 4 (bilateral striatal necrosis with progressive polyneuropathy).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) localization to mitochondrion. Correct but a broad parent of the specific inner-membrane location; kept as supporting the mitochondrial residence, with the mitochondrial inner membrane annotation carried as the more precise core location. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) localization to the mitochondrial inner membrane. This is the correct, specific location for a functional SLC25 carrier and is consistent with the experimental mitochondrial-membrane and multipass evidence. Core cellular component. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt Multi-pass membrane protein |
| GO:0090422 thiamine pyrophosphate transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the specific molecular function, thiamine pyrophosphate transmembrane transporter activity. This matches the experimentally established physiological function and is the core MF. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt Mitochondrial transporter mediating uptake of thiamine |
| GO:0030974 thiamine pyrophosphate transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the biological process, thiamine pyrophosphate transmembrane transport. Consistent with experimental data; core biological process. Supporting Evidence: PMID:17035501 We conclude that SLC25A19 transports ThPP |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) localization to mitochondrion, matching the UniProt subcellular location. Redundant with the more specific mitochondrial inner membrane location and with experimental mitochondrial annotations, but correct and supporting the core localization. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0015932 nucleobase-containing compound transmembrane transporter activity | IEA GO_REF:0000117 | REMOVE | Summary: Electronic (ARBA) molecular-function prediction of nucleobase-containing compound transmembrane transporter activity. This is a wrong-substrate over-prediction rooted in the obsolete "deoxynucleotide carrier" view of SLC25A19. The physiological substrate is thiamine pyrophosphate, not nucleotides, and GOA carries explicit NOT annotations against deoxynucleotide transporter activity. Remove this electronic annotation. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt Previously identified as the mitochondrial deoxyribonucleotide PMID:15539640 DNC does not play an important role in the delayed |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-location mapping to mitochondrial membrane, matching the UniProt SUBCELLULAR LOCATION and the experimental mitochondrial-membrane annotations. Correct; less precise than mitochondrial inner membrane. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0042723 thiamine-containing compound metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic (ARBA) assignment of the broad process thiamine-containing compound metabolic process. True at a high level (TPP transport is part of thiamine metabolism) but much less informative than the specific TPP transport process; non-core. Supporting Evidence: PMID:17035501 We conclude that SLC25A19 transports ThPP |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Electronic (InterPro2GO) assignment of the generic process transmembrane transport from the mitochondrial carrier domain signature. Correct broad parent of the specific TPP transport process; non-core. Supporting Evidence: PMID:27188525 uptake of TPP by mitochondria |
| GO:0090422 thiamine pyrophosphate transmembrane transporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) assignment of the specific molecular function, matching the experimentally established TPP transporter activity. Correct; the experimental (IDA) instance of this same term is the core annotation. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt Mitochondrial transporter mediating uptake of thiamine |
| GO:0042723 thiamine-containing compound metabolic process | TAS Reactome:R-HSA-196819 | KEEP AS NON CORE | Summary: Reactome (TAS) placement of SLC25A19 within vitamin B1 (thiamin) metabolism. Correct pathway context but a broad process relative to the specific TPP transport function; non-core. Supporting Evidence: Reactome:R-HSA-196819 thiamin is converted into the coenzyme thiamin pyrophosphate |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence (IDA) localization to mitochondrion. Consistent with the established mitochondrial residence. Correct but less precise than the inner-membrane location; supports the core localization. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0031966 mitochondrial membrane | EXP PMID:15539640 Expression of deoxynucleotide carrier is not associated with... | ACCEPT | Summary: Experimental localization to the mitochondrial membrane. Consistent with SLC25A19 being an inner-membrane carrier. Correct; less precise than mitochondrial inner membrane. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0031966 mitochondrial membrane | EXP PMID:27188525 Structure-function characterization of the human mitochondri... | ACCEPT | Summary: Experimental localization to the mitochondrial membrane (GFP-tagged hMTPPT delivered to mitochondria in HepG2 cells; TPP uptake by isolated mitochondria). Correct; less precise than mitochondrial inner membrane. Supporting Evidence: PMID:27188525 delivery of the protein to mitochondria |
| GO:0031966 mitochondrial membrane | EXP PMID:31506564 Functional analysis of the third identified SLC25A19 mutatio... | ACCEPT | Summary: Experimental localization to the mitochondrial membrane (WT and Q192H hMTPPT expression and mitochondrial isolation in HepG2 cells). Correct; less precise than mitochondrial inner membrane. Supporting Evidence: PMID:31506564 Mitochondria were isolated from HepG2 cells stably expressing WT hMTPPT |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteomics places SLC25A19 in the high-confidence human mitochondrial proteome (MitoCoP). Corroborates the mitochondrial localization. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) |
| GO:0005739 mitochondrion | IDA PMID:15539640 Expression of deoxynucleotide carrier is not associated with... | ACCEPT | Summary: Direct experimental (IDA) mitochondrial localization. Supports the core mitochondrial residence; less precise than the inner-membrane location. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane |
| GO:0030233 deoxynucleotide transmembrane transporter activity | IDA NOT PMID:15539640 Expression of deoxynucleotide carrier is not associated with... | ACCEPT | Summary: NOT annotation: experimental evidence shows SLC25A19 (DNC) does not function physiologically as a deoxynucleotide transporter. Reconstituted DNC transported dNTPs only at millimolar Km (~1000x above physiological), and DNC over-expression/knockdown did not affect mitochondrial dNTP uptake or mtDNA depletion. Correctly recorded as a negated annotation. Supporting Evidence: PMID:15539640 DNC does not play an important role in the delayed PMID:15539640 which is a thousandfold higher than that of the |
| GO:0030233 deoxynucleotide transmembrane transporter activity | IDA NOT PMID:17035501 Knockout of Slc25a19 causes mitochondrial thiamine pyrophosp... | ACCEPT | Summary: NOT annotation supported by the Slc25a19 knockout mouse: mitochondrial ribo- and deoxyribonucleoside triphosphate levels were normal and no mtDNA depletion occurred, showing deoxynucleotide transport is not the primary function. Correctly recorded as negated. Supporting Evidence: PMID:17035501 normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels |
| GO:0030302 deoxynucleotide transport | IDA NOT PMID:15539640 Expression of deoxynucleotide carrier is not associated with... | ACCEPT | Summary: NOT annotation: SLC25A19 is not physiologically involved in deoxynucleotide transport (no effect on mitochondrial dNTP uptake or mtDNA maintenance). Correctly recorded as negated. Supporting Evidence: PMID:15539640 DNC does not play an important role in the delayed |
| GO:0030974 thiamine pyrophosphate transmembrane transport | IDA PMID:17035501 Knockout of Slc25a19 causes mitochondrial thiamine pyrophosp... | ACCEPT | Summary: Direct experimental evidence that SLC25A19 mediates thiamine pyrophosphate transport: reconstituted protein exchanged TPP, and knockout cells had undetectable mitochondrial ThPP. Core biological process. Supporting Evidence: PMID:17035501 We conclude that SLC25A19 transports ThPP |
| GO:0090422 thiamine pyrophosphate transmembrane transporter activity | IDA PMID:17035501 Knockout of Slc25a19 causes mitochondrial thiamine pyrophosp... | ACCEPT | Summary: Direct experimental evidence for TPP transmembrane transporter activity (reconstituted recombinant protein exchange assay; ThPP transport confirmed). This is the core molecular function of SLC25A19. Supporting Evidence: PMID:17035501 confirmed it by using transport assays of the recombinant reconstituted protein |
| GO:0005739 mitochondrion | IDA PMID:31506564 Functional analysis of the third identified SLC25A19 mutatio... | ACCEPT | Summary: Direct experimental (IDA) mitochondrial localization from the THMD4 functional study (WT and mutant hMTPPT expression and mitochondrial isolation). Supports the core mitochondrial localization. Supporting Evidence: PMID:31506564 expression of the mutant hMTPPT protein in mitochondria |
| GO:0090422 thiamine pyrophosphate transmembrane transporter activity | TAS Reactome:R-HSA-8875838 | ACCEPT | Summary: Reactome (TAS) assertion of the core TPP transporter activity, describing transport of ThDP from cytosol to the mitochondrial matrix. Consistent with the experimental evidence; supports the core MF. Supporting Evidence: Reactome:R-HSA-8875838 transporter of thiamine pyrophosphate (ThDP) into mitochondria |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-8875838 | ACCEPT | Summary: Reactome (TAS) localization to the mitochondrial inner membrane, the specific and correct location for this SLC25 carrier. Core cellular component. Supporting Evidence: Reactome:R-HSA-8875838 transporter of thiamine pyrophosphate (ThDP) into mitochondria |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | KEEP AS NON CORE | Summary: High-throughput (HDA) nucleus assignment from a human sperm-nucleus proteome. For a mitochondrial inner-membrane carrier this is almost certainly a proteomic contaminant rather than a functional nuclear localization, and it is not supported by any targeted evidence. Retained as non-core (high-throughput, not removed) but flagged as unlikely to be biologically meaningful. Supporting Evidence: PMID:21630459 several chromatin-related proteins, such as zinc fingers and |
| GO:0030302 deoxynucleotide transport | NAS PMID:11226231 The human mitochondrial deoxynucleotide carrier and its role... | MARK AS OVER ANNOTATED | Summary: Author-statement (NAS) that SLC25A19/DNC mediates deoxynucleotide transport, from the original characterization paper. This reflects the obsolete "deoxynucleotide carrier" interpretation that was subsequently overturned; GOA now records explicit NOT annotations against deoxynucleotide transport. Over-annotated relative to the corrected physiological function (TPP transport). Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt Previously identified as the mitochondrial deoxyribonucleotide PMID:17035501 normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels |
| GO:0030233 deoxynucleotide transmembrane transporter activity | TAS PMID:11226231 The human mitochondrial deoxynucleotide carrier and its role... | MARK AS OVER ANNOTATED | Summary: Author/TAS assignment of deoxynucleotide transmembrane transporter activity from the original DNC characterization. Reconstituted transport was observed in vitro but only at non-physiological (millimolar) Km, and the physiological function was later established as TPP transport; GOA carries explicit NOT annotations against this activity. Over-annotated; not the physiological molecular function. Supporting Evidence: file:human/SLC25A19/SLC25A19-uniprot.txt SLC25A19 is a thiamine diphosphate transporter and not a PMID:15539640 which is a thousandfold higher than that of the |
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