AMPD2 is the liver-type ("L") isoform of AMP deaminase, one of three mammalian AMP deaminase paralogs (with muscle-type AMPD1 and erythrocyte-type AMPD3). It is broadly expressed, including in brain and neurons, and is highly expressed in cerebellum. AMPD2 is a cytosolic, zinc-dependent metalloenzyme (binds one Zn2+ per subunit; assembles as a homotetramer) that catalyzes the hydrolytic deamination of AMP to IMP plus ammonia (AMP + H2O + H+ = IMP + NH4+; EC 3.5.4.6). This reaction is the committed entry step of the purine nucleotide cycle and a key point of AMP catabolism, so AMPD2 helps set the cellular adenylate energy charge (AMP/ADP/ATP ratio) and shapes adenine and guanine nucleotide pools. By lowering AMP/adenosine- derived nucleotides, AMPD2 relieves feedback inhibition of de novo purine synthesis and thereby sustains the guanine nucleotide (GTP) pool; this is especially important in neurons and neural progenitors, where GTP is required for translation initiation. Loss-of-function mutations cause severe recessive neurodevelopmental/neurodegenerative disease, including pontocerebellar hypoplasia type 9 (PCH9) and a form of hereditary spastic paraplegia (SPG63); the cellular defect can be partially rescued by purine precursor supplementation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003876 AMP deaminase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of AMPD2: hydrolytic deamination of AMP to IMP + ammonia. This phylogenetically-inferred MF is the well-established, experimentally supported activity of the enzyme and represents the core function of the gene. Reason: AMP deaminase activity is the defining function of AMPD2, confirmed biochemically (patient-cell AMP deaminase assays) and by yeast complementation, and captured by UniProt catalytic activity (EC 3.5.4.6). The IBA is at the correct level of specificity. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Catalyzes the deamination of AMP to IMP and plays an important role in PMID:23911318 which converts AMP to IMP |
| GO:0006188 IMP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IMP is the direct product of the AMP deaminase reaction; UniProt frames this as "IMP biosynthesis via salvage pathway; IMP from AMP: step 1/1". The phylogenetic inference is appropriate and reflects the immediate metabolic role of the enzyme. Reason: Producing IMP from AMP is exactly what AMPD2 does, so this process annotation is well supported and consistent with the pathway assignment in UniProt. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Purine metabolism; IMP biosynthesis via salvage pathway; IMP |
| GO:0046033 AMP metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: AMPD2 consumes AMP (deaminating it to IMP), placing it squarely in AMP metabolism. This higher-level process term is the natural container for the reaction and is a core process for the gene. Reason: Directly supported by the catalyzed reaction (AMP is the substrate). Correct and not over-annotated. Supporting Evidence: PMID:23911318 AMPD2 executes AMP deamination |
| GO:0003876 AMP deaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion (ARBA/RHEA/EC 3.5.4.6/InterPro AMPD family) of the same core AMP deaminase activity. Redundant with the IBA/IGI/NAS annotations but correct. Reason: The InterPro/EC/RHEA mapping to AMP deaminase activity is accurate for AMPD2. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Reaction=AMP + H2O + H(+) = IMP + NH4(+) |
| GO:0006188 IMP biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation of IMP biosynthetic process, consistent with production of IMP from AMP. Redundant with the IBA/IGI evidence but correct. Reason: IMP is the reaction product; the process assignment is appropriate. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Purine metabolism; IMP biosynthesis via salvage pathway; IMP |
| GO:0009168 purine ribonucleoside monophosphate biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to a parent process term (IMP is a purine ribonucleoside monophosphate). Broader than the specific IMP biosynthetic process term but not wrong for this enzyme. Reason: IMP, the product of AMPD2, is a purine ribonucleoside monophosphate, so this higher-level biosynthetic term is consistent. It is more general than GO:0006188 and is retained as non-core context rather than the primary process term. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Purine metabolism; IMP biosynthesis via salvage pathway; IMP |
| GO:0019239 deaminase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO mapping to the generic parent "deaminase activity". The specific and informative child term GO:0003876 (AMP deaminase activity) is already annotated, making this general term uninformative. Reason: Too general; the precise activity (AMP deaminase activity, GO:0003876) is already captured by multiple annotations. Retaining the generic parent adds no information. Proposed replacements: AMP deaminase activity Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Catalyzes the deamination of AMP to IMP and plays an important role in |
| GO:0032264 IMP salvage | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: UniPathway-derived electronic annotation. UniProt assigns AMP->IMP deamination to the "IMP biosynthesis via salvage pathway" (UPA00591), so IMP salvage is a reasonable process context for AMPD2. Reason: Consistent with the UniProt/UniPathway framing of the AMP->IMP step as part of IMP salvage. Retained as non-core process context alongside the more direct AMP/IMP metabolic terms. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Purine metabolism; IMP biosynthesis via salvage pathway; IMP |
| GO:0097009 energy homeostasis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: AMP deaminase sets the cellular adenylate energy charge by regulating AMP levels, linking it to energy homeostasis. Supported by the primary literature framing of purine metabolism as essential for energy homeostasis. Reason: A valid higher-level physiological role that is downstream of the catalytic function rather than the core molecular activity itself; retained as non-core. Supporting Evidence: PMID:23911318 essential for cellular energy homeostasis and nucleic acid synthesis |
| GO:0106380 purine ribonucleotide salvage | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation placing AMPD2 in purine ribonucleotide salvage, consistent with the UniProt/UniPathway assignment of the AMP->IMP step to IMP salvage. Reason: Compatible with the salvage-pathway framing of the AMP->IMP reaction. Broad process context; retained as non-core. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Purine metabolism; IMP biosynthesis via salvage pathway; IMP |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | MARK AS OVER ANNOTATED | Summary: IntAct IPI capturing a binary interaction with TERF1 (P54274) detected in a genome-wide fluorescence-complementation telomere-signaling screen. "protein binding" is uninformative and no functional module for AMPD2 is established by this. Reason: Per curation guidance, bare protein binding (GO:0005515) is uninformative; this is a high-throughput interaction from a telomere-signaling screen with no evidence that it reflects a physiological AMPD2 function. Not removed (experimental IPI), but marked as over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; P54274: TERF1 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: IntAct IPI capturing a binary interaction with CCNDBP1 (O95273) from a proteome-scale human interactome map (yeast two-hybrid). Uninformative bare protein binding. Reason: High-throughput interactome interaction; "protein binding" gives no functional insight and no AMPD2-specific module is established. Retained (experimental IPI) but marked over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; O95273: CCNDBP1 |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: IntAct IPI, again reporting an interaction involving CCNDBP1 (O95273), from a study of variant-mediated disruption of protein interactions. Uninformative bare protein binding. Reason: High-throughput interaction; "protein binding" is uninformative and no functional module is established. Retained (experimental IPI) but marked over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; O95273: CCNDBP1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct IPI reporting an interaction with HIRIP3 (Q9BW71) from a dual proteome-scale interactome (BioPlex) study. Uninformative bare protein binding. Reason: High-throughput interaction; "protein binding" is uninformative and no functional module is established. Retained (experimental IPI) but marked over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; Q9BW71: HIRIP3 |
| GO:0005515 protein binding | IPI PMID:34819669 A multi-scale map of cell structure fusing protein images an... | MARK AS OVER ANNOTATED | Summary: IntAct IPI reporting an interaction with HIRIP3 (Q9BW71) from a multi-scale cell-structure map (AP-MS/imaging). Uninformative bare protein binding. Reason: High-throughput interaction; "protein binding" is uninformative and no functional module is established. Retained (experimental IPI) but marked over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; Q9BW71: HIRIP3 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IntAct IPI reporting an interaction with HIRIP3 (Q9BW71) from a multimodal cell-map study. Uninformative bare protein binding. Reason: High-throughput interaction; "protein binding" is uninformative and no functional module is established. Retained (experimental IPI) but marked over-annotated. Supporting Evidence: file:human/AMPD2/AMPD2-uniprot.txt Q01433; Q9BW71: HIRIP3 |
| GO:0046033 AMP metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology-based electronic transfer (from mouse Ampd2, Q9DBT5) of AMP metabolic process. Correct, and redundant with the IBA annotation of the same term. Reason: AMP is the substrate of AMPD2; this is a correct core process annotation. Supporting Evidence: PMID:23911318 AMPD2 executes AMP deamination |
| GO:0046034 ATP metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology-based electronic annotation (from mouse Q9DBT5). AMPD2 loss elevates ATP levels, so its activity indirectly influences ATP/adenylate pools, but ATP is neither substrate nor product of the deaminase reaction. Reason: Biologically supported as an indirect/regulatory effect (AMPD2-deficient cells accumulate ATP), not the direct catalyzed reaction. Retained as non-core. Supporting Evidence: PMID:23911318 elevated ATP levels, more striking in AMPD2 homozygous mutant cells |
| GO:0046039 GTP metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology-based electronic annotation (from mouse Q9DBT5). AMPD2 activity is required to sustain the guanine nucleotide (GTP) pool by relieving feedback inhibition of de novo purine synthesis; AMPD2 loss depletes GTP. This is an indirect/regulatory role rather than the direct catalyzed reaction. Reason: Strongly supported biologically as a downstream consequence of AMPD2 activity (GTP halved in patient neural progenitors), but AMPD2 does not directly metabolize GTP. Retained as an important non-core process. Supporting Evidence: PMID:23911318 dramatic reduction in guanine nucleotides, most remarkable for GTP, which was reduced by half |
| GO:0005829 cytosol | TAS Reactome:R-HSA-76590 | ACCEPT | Summary: Cytosolic localization of AMP deaminase, asserted by Reactome. Consistent with the known subcellular distribution of the enzyme. Reason: AMPD is a cytosolic enzyme; the localization is well established and appropriate as the core cellular component. Supporting Evidence: Reactome:R-HSA-76590 Cytosolic AMP deaminase (AMPD) catalyzes the hydrolysis of AMP to yield IMP and ammonia |
| GO:0032263 GMP salvage | IDA PMID:29079593 Hypoxia modulates the purine salvage pathway and decreases r... | MARK AS OVER ANNOTATED | Summary: MGI IDA to GMP salvage citing a red-blood-cell purine-metabolism study. That study centers on the erythrocyte AMPD isoform (AMPD3) and the RBC purine salvage/deamination network; it does not establish AMPD2 specifically in GMP salvage, and mechanistically AMP deaminase produces IMP (not GMP). Reason: The term is a poor fit for AMP deaminase (which acts on AMP->IMP, upstream of, but not within, GMP salvage), and the cited paper foregrounds the erythrocyte AMPD3 isoform and the salvage network generally. Per curation policy this experimental annotation is not removed; the loose acts_upstream_of_or_within qualifier is retained but marked as an over-annotation for AMPD2. Supporting Evidence: PMID:29079593 enhanced purine salvage reactions in human and mouse red blood cells |
| GO:0052652 cyclic purine nucleotide metabolic process | IMP PMID:23911318 AMPD2 regulates GTP synthesis and is mutated in a potentiall... | MARK AS OVER ANNOTATED | Summary: IMP annotation from the AMPD2/PCH9 study. That work demonstrates AMPD2's role in purine (AMP/IMP/GTP) nucleotide metabolism and guanine-nucleotide homeostasis, not in cyclic nucleotide (cAMP/cGMP) metabolism specifically, so the chosen term is a mismatch to the experimental readouts. Reason: The phenotype (guanine/adenine nucleotide pool changes, translation initiation defect) supports purine-nucleotide metabolic terms rather than "cyclic purine nucleotide metabolic process". Experimental annotation, so not removed; marked over-annotated as the AMP/IMP/purine metabolic process terms better capture the finding. Proposed replacements: AMP metabolic process Supporting Evidence: PMID:23911318 we identify AMPD2 as necessary for guanine nucleotide biosynthesis and protein translation |
| GO:0003876 AMP deaminase activity | IGI PMID:23911318 AMPD2 regulates GTP synthesis and is mutated in a potentiall... | ACCEPT | Summary: Experimental (IGI) support for AMP deaminase activity: human AMPD2 functionally complements the yeast amd1 (AMP deaminase) mutant, and patient cells lacking AMPD2 lose 80-90% of AMP deaminase activity. Core molecular function. Reason: Directly demonstrates AMP deaminase activity for AMPD2 via cross-species genetic interaction/complementation and enzymatic assay of patient cells. This is the core function. Supporting Evidence: PMID:23911318 which converts AMP to IMP |
| GO:0006188 IMP biosynthetic process | IGI PMID:23911318 AMPD2 regulates GTP synthesis and is mutated in a potentiall... | ACCEPT | Summary: Experimental (IGI, yeast amd1 complementation) support that AMPD2 acts in production of IMP from AMP. Consistent with the core metabolic role of the enzyme. Reason: Supported by functional complementation and by the direct chemistry of the reaction (AMP->IMP). Correct process for the gene. Supporting Evidence: PMID:23911318 which converts AMP to IMP |
| GO:0097009 energy homeostasis | IGI PMID:23911318 AMPD2 regulates GTP synthesis and is mutated in a potentiall... | KEEP AS NON CORE | Summary: Experimental (IGI) support linking AMPD2 to cellular energy/purine homeostasis via the yeast amd1 complementation system and the demonstrated regulation of adenine/guanine nucleotide pools. A valid higher-level physiological role. Reason: Downstream physiological role (setting the adenylate energy charge / purine pools) rather than the direct catalytic activity; retained as non-core. Supporting Evidence: PMID:23911318 essential for cellular energy homeostasis and nucleic acid synthesis |
| GO:0003876 AMP deaminase activity | NAS PMID:8764830 Cloning, sequence and characterization of the human AMPD2 ge... | ACCEPT | Summary: Author statement (NAS) of AMP deaminase activity from the AMPD2 gene cloning and characterization paper, which describes AMPD2 as a member of the AMP deaminase multigene family. Same core function as the IBA/IGI/IEA annotations. Reason: Correct core molecular function; the cloning paper explicitly identifies AMPD2 as an AMP deaminase family gene. Redundant with stronger experimental evidence but accurate. Supporting Evidence: PMID:8764830 AMP deaminase (AMPD) is manifest through a multigene family in higher |
| GO:0006196 AMP catabolic process | IDA PMID:23911318 AMPD2 regulates GTP synthesis and is mutated in a potentiall... | NEW | Summary: Proposed annotation for the most precise process term describing the AMPD2 reaction: catabolic breakdown of AMP (AMP -> IMP + ammonia). Directly supported by the demonstrated AMP deaminase activity and loss of that activity in patient cells. Reason: The AMP->IMP deamination is a breakdown of AMP and is best captured by AMP catabolic process. Existing annotations use the broader parent (AMP metabolic process, GO:0046033) and product-oriented terms (IMP biosynthetic process); adding the specific catabolic term makes the substrate-consuming role explicit. Supported experimentally. Supporting Evidence: PMID:23911318 which converts AMP to IMP file:human/AMPD2/AMPD2-uniprot.txt Catalyzes the deamination of AMP to IMP and plays an important role in |
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Download this section (compressed HTML)Q: Do the four AMPD2 splice isoforms (differing mainly in N-terminal extension) differ in catalytic regulation, subcellular targeting, or tissue distribution?
Q: In post-mitotic neurons, where de novo purine synthesis is low, what is the precise mechanism by which AMPD2 loss depletes GTP and impairs translation initiation?
Experiment: Isoform-resolved enzyme kinetics and allosteric regulation (by ATP, GTP, phosphate) of the four AMPD2 splice variants expressed and purified in parallel.
Experiment: Metabolic-flux (labeled-adenosine) analysis in AMPD2-null vs rescued human neurons to map how the AMP->IMP block redistributes purine flux toward or away from the guanine branch.
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