PPAT is human amidophosphoribosyltransferase (ATase; glutamine phosphoribosylpyrophosphate amidotransferase, GPAT; EC 2.4.2.14), the enzyme that catalyses the first committed and rate-limiting step of de novo purine nucleotide biosynthesis. It transfers the amide nitrogen of L-glutamine to 5-phospho-alpha-D-ribose 1-diphosphate (PRPP), producing 5-phospho-beta-D- ribosylamine (PRA) plus L-glutamate and diphosphate; PRA is the entry metabolite for the entire de novo purine branch leading to IMP and thence to AMP and GMP. The protein has an N-terminal type-2 glutamine amidotransferase domain (with an N-terminal-nucleophile cysteine exposed only after removal of an 11-residue propeptide) and a C-terminal phosphoribosyltransferase domain, binds Mg2+, and carries a [4Fe-4S] cluster required for activity. As the pathway's committed entry point it is allosterically feedback-inhibited by the purine mononucleotide end products AMP, GMP and IMP (which promote an inactive tetramer) and activated by its substrate PRPP (which favours the active dimer). It acts in the cytosol.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004044 amidophosphoribosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. PPAT is amidophosphoribosyltransferase (EC 2.4.2.14), transferring the L-glutamine amide nitrogen to PRPP to give 5-phospho-beta-D-ribosylamine. This IBA is well supported across the orthologous family (E. coli PurF, B. subtilis, yeast ADE4, etc.) and matches direct human evidence. Reason: Phylogenetically conserved and experimentally established core catalytic activity of the gene product. Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt Catalyzes the formation of phosphoribosylamine from |
| GO:0006164 purine nucleotide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PPAT catalyses the committed step of de novo purine nucleotide synthesis, so the general process "purine nucleotide biosynthetic process" correctly captures its biological role at an appropriate level. Reason: Accurate, appropriately general process annotation supported by the conserved catalytic role and human literature. Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt IMP biosynthesis via de novo pathway |
| GO:0004044 amidophosphoribosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of the core amidophosphoribosyltransferase activity, backed by the RHEA:14905 / EC 2.4.2.14 reaction and InterPro PurF signature. Consistent with the IBA/ISS/TAS evidence for the same term. Reason: Correct MF; duplicate of the core catalytic activity supported by additional evidence codes. Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt Catalyzes the formation of phosphoribosylamine from |
| GO:0009113 purine nucleobase biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO maps the PurF signature to "purine nucleobase biosynthetic process". PPAT actually produces the ribonucleotide precursor 5-phospho-beta-D-ribosylamine, not a free purine nucleobase, so nucleobase biosynthesis is a slightly imprecise process; the accurate downstream process is de novo IMP biosynthesis. Reason: The essence (purine biosynthesis) is correct but the branch (nucleobase vs nucleotide) is imprecise for this enzyme, which makes the nucleotide precursor PRA. Replace with the accurate de novo IMP biosynthetic process. Proposed replacements: 'de novo' IMP biosynthetic process Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt IMP biosynthesis via de novo pathway |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput AP-MS interactome screen (BioPlex; IntAct-derived interaction with NUDT5, Q9UKK9). This term is uninformative about PPAT's molecular function and the interaction has no established functional consequence for the enzyme. Reason: Uninformative "protein binding" from a proteome-scale screen; retained (an experimental IPI) but flagged as over-annotation because it does not convey a meaningful molecular function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the second BioPlex proteome-scale interactome (again the NUDT5 interaction, Q9UKK9). Uninformative regarding PPAT's catalytic function. Reason: Uninformative high-throughput "protein binding"; retained as an experimental IPI but flagged as over-annotation. |
| GO:0006177 GMP biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transfer (Ensembl Compara) annotation to the GMP-specific branch. PPAT catalyses only the single committed step producing PRA, upstream of IMP; the GMP-specific conversions are carried out by dedicated downstream enzymes (IMPDH, GMP synthase). Annotating PPAT directly to GMP biosynthesis over-states its involvement. Reason: Downstream branch-specific process; PPAT contributes only the shared upstream precursor. Over-propagated automated ortholog transfer rather than a directly supported role (kept, not removed). |
| GO:0006189 'de novo' IMP biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: PPAT's product 5-phospho-beta-D-ribosylamine is the first intermediate of the de novo IMP biosynthetic pathway (UniPathway UPA00074, step 1). This is the accurate de novo purine process for the enzyme. Reason: Correct and precise process annotation; PPAT performs step 1/2 of the de novo IMP pathway per UniProt/UniPathway. Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt IMP biosynthesis via de novo pathway |
| GO:0044208 'de novo' AMP biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transfer annotation to the AMP-specific de novo branch. As with the GMP branch, PPAT only provides the shared upstream precursor (PRA -> IMP); the AMP-specific steps use adenylosuccinate synthase/lyase. Reason: Downstream branch-specific process beyond PPAT's single committed step; over-propagated automated ortholog transfer (kept, not removed). |
| GO:0097294 'de novo' XMP biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transfer annotation to the XMP-specific de novo branch. XMP is produced from IMP by IMPDH, several steps downstream of PPAT's committed reaction; PPAT does not itself act in XMP-specific synthesis. Reason: Downstream branch-specific process; PPAT contributes only the shared precursor. Over-propagated automated ortholog transfer (kept, not removed). |
| GO:0004044 amidophosphoribosyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the core amidophosphoribosyltransferase activity from rat ortholog (UniProtKB:P35433). Concordant with the IBA/IEA/TAS evidence for the same MF. Reason: Correct core catalytic activity supported by ortholog similarity and direct human evidence. Supporting Evidence: file:human/PPAT/PPAT-uniprot.txt Catalyzes the formation of phosphoribosylamine from |
| GO:0005829 cytosol | TAS Reactome:R-HSA-111285 | ACCEPT | Summary: PPAT is a cytosolic enzyme. Reactome describes cytosolic PPAT and its allosteric assembly, in which AMP, GMP and IMP promote dimer-to-tetramer association (the feedback-inhibited state). Reason: Correct subcellular localization, consistent across Reactome and UniProt. Supporting Evidence: Reactome:R-HSA-111285 Cytosolic AMP, GMP, and IMP stimulate the association of phosphoribosyl pyrophosphate amidotransferase (PPAT) dimers to form tetramers |
| GO:0005829 cytosol | TAS Reactome:R-HSA-111289 | ACCEPT | Summary: Cytosolic localization. Reactome documents that the substrate PRPP drives dissociation of the inactive tetramer into the active dimer, part of PPAT's cytosolic allosteric regulation. Reason: Correct subcellular localization. Supporting Evidence: Reactome:R-HSA-111289 PRPP stimulates the dissociation of phosphoribosyl pyrophosphate amidotransferase tetramers to form dimers |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73815 | ACCEPT | Summary: Cytosolic localization tied to the catalytic reaction itself. Reactome states that cytosolic PPAT catalyses the committed step of de novo purine synthesis, pulled forward by pyrophosphate hydrolysis. Reason: Correct subcellular localization, from the reaction event where PPAT acts. Supporting Evidence: Reactome:R-HSA-73815 This event is the committed step in de novo purine synthesis. |
| GO:0004044 amidophosphoribosyltransferase activity | TAS PMID:8106516 Two genes for de novo purine nucleotide synthesis on human c... | ACCEPT | Summary: Human GPAT/PPAT cDNA was cloned and expressed to yield functional enzyme catalysing step one of de novo purine nucleotide synthesis, directly supporting the amidophosphoribosyltransferase activity for the human protein. Reason: Author statement (TAS) directly establishing the enzyme's identity and catalytic role in human. Supporting Evidence: PMID:8106516 A cDNA encoding human glutamine phosphoribosylpyrophosphate amidotransferase for |
| GO:0006164 purine nucleotide biosynthetic process | TAS PMID:8106516 Two genes for de novo purine nucleotide synthesis on human c... | ACCEPT | Summary: The cloned human enzyme performs step one in de novo purine nucleotide synthesis, supporting involvement in the purine nucleotide biosynthetic process. Reason: Author statement directly supporting the process role in human. Supporting Evidence: PMID:8106516 step one in de novo purine nucleotide synthesis was cloned, sequenced, and |
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