DTYMK is thymidylate kinase (dTMP kinase; EC 2.7.4.9), a small cytosolic P-loop nucleotide kinase that catalyses the ATP- and Mg2+-dependent phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP) (dTMP + ATP -> dTDP + ADP). This is the common penultimate step in the synthesis of the DNA building block dTTP: the de novo route (dUMP -> dTMP via thymidylate synthase) and the salvage route (thymidine -> dTMP via thymidine kinase) both converge on dTMP kinase, making it the bottleneck for dTTP biosynthesis; dTDP is subsequently phosphorylated to dTTP by nucleoside diphosphate kinase. Because dTTP cannot be generated by any bypass, the enzyme is essential for DNA replication and genome integrity; its expression and activity peak in S phase. The active enzyme is a homodimer and has been crystallised extensively in complex with dTMP/ATP analogues. It also activates thymidine-analogue prodrugs (e.g. zidovudine/AZT monophosphate). Biallelic loss-of-function variants cause a severe childhood-onset neurodegenerative disorder with progressive microcephaly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004798 dTMP kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred dTMP kinase activity, the defining molecular function of the thymidylate kinase family. This is correct and central for DTYMK and is independently supported by direct human experimental evidence. Reason: dTMP kinase activity is the core, experimentally validated molecular function of the human enzyme, catalysing dTMP + ATP -> dTDP + ADP. The IBA call is consistent with abundant human EXP/IDA evidence. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt Catalyzes the phosphorylation of thymidine monophosphate PMID:34918187 catalyzes the penultimate step in dTTP biosynthesis |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytoplasmic localization. DTYMK is a small soluble kinase with no targeting signal and is described as cytosolic; cytoplasm is a correct, appropriately general compartment. Reason: Consistent with the cytosolic localization of the enzyme reported by Reactome and with GOA cytosol (GO:0005829) annotations. Supporting Evidence: Reactome:R-HSA-73635 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0006233 dTDP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in dTDP biosynthesis. This is the direct product-forming reaction of DTYMK (dTMP -> dTDP) and is a core process for the gene. Reason: The immediate reaction product of DTYMK is dTDP; this is the enzyme's direct biosynthetic contribution and is experimentally supported. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt the immediate precursor for the PMID:34918187 The thymidine de novo and salvage pathways converge at the point of the phosphorylation of dTMP to dTDP by dTMPK |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetically inferred mitochondrial localization. The human enzyme is established as cytosolic, and this IBA call is propagated from a subset of orthologs; it is weakly supported and not the functionally relevant compartment for human DTYMK. Reason: DTYMK is a small soluble protein with no mitochondrial targeting sequence and is described as cytosolic deoxythymidylate kinase (Reactome). The mitochondrial IBA is over-propagated from the PANTHER family; the established and functionally relevant compartment is the cytosol/cytoplasm. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: Reactome:R-HSA-73635 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0006227 dUDP biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred involvement in dUDP biosynthesis, reflecting the enzyme's ability to also phosphorylate dUMP to dUDP. This is a secondary/promiscuous activity, not the biological purpose of DTYMK, which is dTTP synthesis. Reason: Reactome records dUMP as an alternative substrate (dUMP or TMP + ATP -> dUDP or TDP), so dUDP formation is biochemically plausible, but the physiological role of DTYMK is the synthesis of thymidine nucleotides (dTDP/dTTP). Retain as a non-core, secondary activity rather than a core function. Supporting Evidence: Reactome:R-HSA-73635 dUMP or TMP + ATP <=> dUDP or TDP + ADP [DTYMK] |
| GO:0006235 dTTP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in dTTP biosynthesis. DTYMK performs the penultimate, common step of dTTP synthesis (dTMP -> dTDP), and is the essential bottleneck for making dTTP; this is a core biological process for the gene. Reason: Both de novo and salvage routes converge on DTYMK, which is indispensable for dTTP biosynthesis and DNA replication; loss of function completely blocks dTTP synthesis. Supporting Evidence: PMID:34918187 This makes dTMPK the bottleneck for dTTP biosynthesis file:human/DTYMK/DTYMK-uniprot.txt Pyrimidine metabolism; dTTP biosynthesis. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetically inferred nuclear localization, propagated from a subset of orthologs. The human enzyme is characterised as cytosolic, and nuclear localization is weakly supported. Reason: DTYMK has no nuclear-localization signal and is described as cytosolic (Reactome). Although dNTP synthesis serves nuclear DNA replication, the enzyme itself acts in the cytosol; the nuclear IBA is an over-propagation. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: Reactome:R-HSA-73635 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0004798 dTMP kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of dTMP kinase activity from combined IEA methods (ARBA, InterPro, RHEA/EC mapping). This correctly captures the defining molecular function. Reason: Matches the experimentally validated function and the RHEA:13517 / EC:2.7.4.9 reaction; a correct, well-supported electronic call. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt Reaction=dTMP + ATP = dTDP + ADP |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of ATP binding. DTYMK is a P-loop ATP-dependent kinase; ATP binding is directly confirmed by crystal structures. Reason: ATP is the phosphoryl donor and is bound at a defined P-loop site (structurally characterised, PMID:12614151); the electronic call is correct and supported by experimental evidence. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt Reaction=dTMP + ATP = dTDP + ADP |
| GO:0006233 dTDP biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of involvement in dTDP biosynthesis, matching the direct product-forming reaction of DTYMK. Reason: dTDP is the immediate reaction product; the call is consistent with experimental and IBA evidence. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt the immediate precursor for the |
| GO:0006235 dTTP biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic annotation (UniPathway mapping) of involvement in dTTP biosynthesis, matching the UniProt pathway assignment "Pyrimidine metabolism; dTTP biosynthesis". Reason: DTYMK performs the penultimate step of dTTP biosynthesis; the UniPathway-derived call is correct. Supporting Evidence: file:human/DTYMK/DTYMK-uniprot.txt Pyrimidine metabolism; dTTP biosynthesis. |
| GO:0004798 dTMP kinase activity | EXP PMID:2017365 Molecular cloning and expression of the human deoxythymidyla... | ACCEPT | Summary: Human dTMP kinase cDNA cloned by functional complementation of a yeast dTMP kinase temperature-sensitive mutant; expression in yeast produces dTMP kinase activity, experimentally establishing the molecular function. Reason: Direct experimental demonstration that the human gene product has dTMP kinase activity (phosphorylates dTMP to dTDP with ATP and Mg2+). Supporting Evidence: PMID:2017365 the cloned human cDNA, when expressed in yeast, produces dTMP kinase activity. PMID:2017365 (Deoxy)thymidylate (dTMP) kinase is an enzyme which phosphorylates dTMP to dTDP in the presence of ATP and magnesium. |
| GO:0004798 dTMP kinase activity | EXP PMID:34918187 DTYMK is essential for genome integrity and neuronal surviva... | ACCEPT | Summary: dTMPK enzyme activity measured directly in patient fibroblasts (severely reduced in individuals with biallelic DTYMK variants), and the enzyme is defined as catalysing the phosphorylation of dTMP to dTDP, confirming dTMP kinase activity for the human protein. Reason: Provides human experimental (activity assay) evidence for dTMP kinase activity and links loss of this activity to disease; the affected step is the phosphorylation of dTMP to dTDP. Supporting Evidence: PMID:34918187 The thymidine de novo and salvage pathways converge at the point of the phosphorylation of dTMP to dTDP by dTMPK PMID:34918187 dTMPK enzyme activity of the individual is significantly lower than those of the parents |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MARK AS OVER ANNOTATED | Summary: High-throughput mitochondrial proteomics (MitoCoP) call. DTYMK is an established cytosolic enzyme; a proteomics dataset hit likely reflects co-purification or dual/low-level reporting rather than a bona fide mitochondrial function. Reason: DTYMK has no mitochondrial targeting presequence and its characterised, functional compartment is the cytosol (Reactome). A single HTP proteomics localization does not establish the mitochondrion as a functional site for this soluble kinase; treat as an over-annotation relative to the core cytosolic localization. Supporting Evidence: PMID:34800366 high-confidence proteome of >1,100 proteins Reactome:R-HSA-73635 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0004798 dTMP kinase activity | IDA PMID:12614151 Structures of human thymidylate kinase in complex with prodr... | ACCEPT | Summary: Structural and steady-state kinetic characterisation of human thymidylate kinase (TMPK) converting thymidine monophosphate analogues to the corresponding diphosphates, directly demonstrating dTMP kinase activity. Reason: Crystal structures with substrate/product analogues plus steady-state kinetics directly establish the dTMP kinase catalytic activity of the human enzyme. Supporting Evidence: PMID:12614151 the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates |
| GO:0005524 ATP binding | IDA PMID:12614151 Structures of human thymidylate kinase in complex with prodr... | ACCEPT | Summary: Crystal structures solved with ADP or the ATP analogue AppNHp bound at the phosphoryl-donor site, providing direct experimental evidence of ATP binding. Reason: Structures with the ATP analogue at the phosphoryl-donor site directly demonstrate ATP binding by human thymidylate kinase. Supporting Evidence: PMID:12614151 with either ADP or the ATP analogue AppNHp at the phosphoryl donor site |
| GO:0006233 dTDP biosynthetic process | IDA PMID:12614151 Structures of human thymidylate kinase in complex with prodr... | ACCEPT | Summary: Direct assay of the conversion of thymidine monophosphates to the corresponding diphosphates by human thymidylate kinase, supporting involvement in dTDP biosynthesis. Reason: The reaction assayed produces the diphosphate (dTDP) from the monophosphate (dTMP), the direct biosynthetic contribution of DTYMK. Supporting Evidence: PMID:12614151 thymidine monophosphate analogues to the corresponding diphosphates |
| GO:0046105 thymidine biosynthetic process | IDA PMID:12614151 Structures of human thymidylate kinase in complex with prodr... | MARK AS OVER ANNOTATED | Summary: Annotation to thymidine biosynthetic process. This mislabels the biology: DTYMK acts on the nucleotide dTMP (producing dTDP), not on the nucleoside thymidine, and the process it serves is dTDP/dTTP biosynthesis, not thymidine biosynthesis. Reason: The paper characterises phosphorylation of thymidine monophosphate to the diphosphate; it does not establish biosynthesis of thymidine (the nucleoside). The more accurate process terms are dTDP biosynthetic process (GO:0006233) and dTTP biosynthetic process (GO:0006235), both already annotated. Treat this term as an over-annotation relative to the correctly captured dTDP/dTTP processes. Supporting Evidence: PMID:12614151 thymidine monophosphate analogues to the corresponding diphosphates |
| GO:0046105 thymidine biosynthetic process | TAS PMID:8024690 Human dTMP kinase: gene expression and enzymatic activity co... | MARK AS OVER ANNOTATED | Summary: Author-statement annotation to thymidine biosynthetic process. As with the IDA above, the described activity is phosphorylation of dTMP to the diphosphate en route to dTTP, not biosynthesis of the nucleoside thymidine. Reason: DTYMK catalyses dTMP -> dTDP and is essential for dTTP synthesis, not for making thymidine; the correct process terms (dTDP/dTTP biosynthetic process) are already annotated. Over-annotation via a mismatched process term. Supporting Evidence: PMID:8024690 dTMP kinase (E.C.2.7.4.9.) catalyzes the phosphorylation of dTMP to the corresponding diphosphate. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73635 | ACCEPT | Summary: Reactome traceable-author-statement localizing DTYMK to the cytosol, consistent with the enzyme being a small soluble cytosolic kinase. This is the core, functionally relevant compartment. Reason: Reactome explicitly describes cytosolic deoxythymidylate kinase; matches the established localization of the human enzyme. Supporting Evidence: Reactome:R-HSA-73635 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0005829 cytosol | TAS Reactome:R-HSA-75126 | ACCEPT | Summary: Reactome traceable-author-statement (reverse reaction module) localizing DTYMK to the cytosol; duplicate of the cytosol call and equally correct. Reason: Consistent with the cytosolic localization of the human enzyme described by Reactome. Supporting Evidence: Reactome:R-HSA-75126 Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction |
| GO:0004798 dTMP kinase activity | IDA PMID:8845311 Molecular characterization of the murine thymidylate kinase ... | ACCEPT | Summary: Characterisation of the (murine) thymidylate kinase gene, defining TMK as catalysing the essential conversion of dTMP to dTDP; supports the conserved dTMP kinase activity of the orthologous mammalian enzyme. Reason: Establishes thymidylate kinase activity (dTMP -> dTDP) for the mammalian enzyme; the function is directly and abundantly supported for the human protein by other evidence. Supporting Evidence: PMID:8845311 Thymidylate kinase (TMK) catalyzes an essential reaction of converting dTMP to dTDP, leading to formation of the DNA precursor dTTP. |
| GO:0004798 dTMP kinase activity | TAS PMID:8024690 Human dTMP kinase: gene expression and enzymatic activity co... | ACCEPT | Summary: Traceable-author-statement annotation of dTMP kinase activity for the human enzyme, defined as catalysing the phosphorylation of dTMP to the corresponding diphosphate. Reason: Directly states the dTMP kinase catalytic activity of human dTMP kinase; concordant with the EXP/IDA evidence. Supporting Evidence: PMID:8024690 dTMP kinase (E.C.2.7.4.9.) catalyzes the phosphorylation of dTMP to the corresponding diphosphate. |
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