ASS1 encodes argininosuccinate synthase, a predominantly cytosolic homotetrameric ligase that catalyzes the ATP-dependent condensation of L-citrulline and L-aspartate to form argininosuccinate, AMP and diphosphate. Argininosuccinate is then cleaved by ASL to produce arginine and fumarate. ASS1 therefore directly supports hepatic nitrogen disposal through the urea cycle and L-arginine synthesis in other tissues. In endothelial cells, regeneration of arginine from citrulline supports nitric oxide production by nitric oxide synthase. ASS1 activity can be regulated by protein interactions and acetylation, including CLOCK-dependent modification associated with circadian ureagenesis. Peripheral mitochondrial association has been reported in rodent tissues, and nuclear localization has been demonstrated in particular human cell contexts. Pathogenic ASS1 variants cause autosomal recessive citrullinemia type I.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004055 argininosuccinate synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ASS1 catalyzes ATP-dependent argininosuccinate synthesis. Reason: Human recombinant enzyme studies and substrate-bound structures establish ligation of citrulline and aspartate using ATP. The inherited catalytic assignment agrees with direct human biochemistry. The IBA is retained as a phylogenetic judgment; its node/MSA was not independently re-curated. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol is the principal established location of ASS1. Reason: The cytosolic urea-cycle reaction, curated UniProt location and supported human immunofluorescence localization agree. This is not an exclusivity claim: peripheral mitochondrial association and context-dependent nuclear localization are compatible. The PAINT node behind the IBA was not independently re-curated. Supporting Evidence: Reactome:R-HSA-70577 |
| GO:0006526 L-arginine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: ASS1 directly catalyzes a step in L-arginine biosynthesis. Reason: ASS1 synthesizes argininosuccinate, which ASL converts to arginine and fumarate. ASS1 performs the ligation step itself; this is direct pathway participation, not an inference merely from disease or substrate demand. |
| GO:0000050 urea cycle | IBA GO_REF:0000033 | ACCEPT | Summary: ASS1 directly participates in the urea cycle. Reason: Cytosolic condensation of citrulline and aspartate produces the argininosuccinate used by ASL in the hepatic urea cycle. Human ASS1 enzymology supports the inherited pathway annotation. Supporting Evidence: |
| GO:0004055 argininosuccinate synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ASS1 catalyzes ATP-dependent argininosuccinate synthesis. Reason: Human recombinant enzyme studies and substrate-bound structures establish ligation of citrulline and aspartate using ATP. The inherited catalytic assignment agrees with direct human biochemistry. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP is a cosubstrate of the ASS1 ligase reaction. Reason: ATP-dependent substrate activation and human enzyme kinetics establish ATP binding as part of catalysis. This binding annotation does not require a second core function. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol is the principal established location of ASS1. Reason: The cytosolic urea-cycle reaction, curated UniProt location and supported human immunofluorescence localization agree. This is not an exclusivity claim: peripheral mitochondrial association and context-dependent nuclear localization are compatible. Supporting Evidence: Reactome:R-HSA-70577 |
| GO:0006526 L-arginine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: ASS1 directly catalyzes a step in L-arginine biosynthesis. Reason: ASS1 synthesizes argininosuccinate, which ASL converts to arginine and fumarate. ASS1 performs the ligation step itself; this is direct pathway participation, not an inference merely from disease or substrate demand. |
| GO:0005515 protein binding | IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex... | UNDECIDED | Summary: The original ASS1–ARAF interaction record requires target-level inspection. Reason: The Raf interaction-screen abstract and curated pair mapping were read, but the original ASS1-specific construct and target table remain inaccessible. The available evidence does not resolve this particular ASS1–ARAF interaction or support a more specific binding replacement; the row remains UNDECIDED at that target-level evidence boundary. |
| GO:0005515 protein binding | IPI PMID:17496144 Restructuring of the dinucleotide-binding fold in an NADP(H)... | KEEP AS NON CORE | Summary: ASS1 associates with the redox-sensitive regulator NMRAL1/HSCARG. Reason: Targeted original Results, Fig. 4b/c and IP Methods identify ASS in endogenous HeLa HSCARG immunoprecipitates and corroborate association by reciprocal tagged-protein IP in human 293T cells. This supports regulated association without demonstrating a purified binary interface. NMRAL1 is described as an SDR-like sensor lacking a complete catalytic site, so enzyme binding would not be an established refinement. |
| GO:0005515 protein binding | IPI PMID:28587924 PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrup... | MODIFY | Summary: ASS1 binds the enzyme PRMT7. Reason: The original abstract reports yeast two-hybrid identification, direct pull-down confirmation and interface mutagenesis for ASS1–PRMT7. Enzyme binding describes the known catalytic partner more precisely than generic protein binding; it does not assign methyltransferase activity to ASS1 or prove methylation of ASS1. Full assay panels were not inspected. Proposed replacements: enzyme binding Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: ASS1 self-association is consistent with its homotetrameric assembly. Reason: The original interactome-specific target tables were not independently inspected. The identical-protein partner assignment is retained with curator deference because independent purified human enzyme work and human structural evidence establish a homotetramer. This does not claim to re-verify each screen or create a separate binding core. |
| GO:0042802 identical protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | KEEP AS NON CORE | Summary: ASS1 self-association is consistent with its homotetrameric assembly. Reason: The original interactome-specific target tables were not independently inspected. The identical-protein partner assignment is retained with curator deference because independent purified human enzyme work and human structural evidence establish a homotetramer. This does not claim to re-verify each screen or create a separate binding core. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: ASS1 self-association is consistent with its homotetrameric assembly. Reason: The original interactome-specific target tables were not independently inspected. The identical-protein partner assignment is retained with curator deference because independent purified human enzyme work and human structural evidence establish a homotetramer. This does not claim to re-verify each screen or create a separate binding core. |
| GO:0000050 urea cycle | IEA GO_REF:0000120 | ACCEPT | Summary: ASS1 directly participates in the urea cycle. Reason: Cytosolic condensation of citrulline and aspartate produces the argininosuccinate used by ASL in the hepatic urea cycle. Human ASS1 enzymology supports the inherited pathway annotation. Supporting Evidence: |
| GO:0001822 kidney development | IEA GO_REF:0000107 | UNDECIDED | Summary: Developmental ASS expression is established; its role in kidney maturation remains unresolved. Reason: PMID:10473900 reports rat perinatal ASS/ASL expression and transcriptional activation alongside acquisition of arginine-synthesis capacity. Kidney development includes progression to a mature organ, not only morphogenesis. The inspected abstract leaves unresolved whether the assigned role is metabolic maturation within that process or an expression marker; the full study was inaccessible. Retain UNDECIDED rather than infer absence of a developmental role from an unread experiment. |
| GO:0001889 liver development | IEA GO_REF:0000107 | UNDECIDED | Summary: Developmental and hormonal ASS regulation is established; the liver-development assignment remains unresolved. Reason: PMID:10473900 and PMID:9395312 describe perinatal rat hepatic ASS expression, enzyme activity and hormonal transcriptional regulation. Liver development includes maturation and is broader than liver morphogenesis. These observations document metabolic maturation, but the complete evidence connecting ASS to the annotated organ-development process was not inspected. The inference remains UNDECIDED; expression alone is neither accepted as participation nor treated as proof that the developmental role is false. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Peripheral mitochondrial association is compatible with primarily cytosolic ASS1. Reason: The original mouse donor experiment (PMID:14701727) was not independently inspected. Independent rat liver fractionation and immunoelectron microscopy place ASS activity/protein at the cytoplasmic surface of the mitochondrial outer membrane. With this corroboration the broader curated mammalian association is retained by curator deference, without asserting matrix import, an integral membrane protein, or direct human mitochondrial imaging. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rodent studies support a peripheral mitochondrial association, with attachment unresolved by proximity imaging alone. Reason: The rat donor PMID:8867809 reports ASS predominantly near the cytoplasmic face of the outer mitochondrial membrane; proximity alone does not prove attachment. The separate rat biochemical study PMID:7845368 reports membrane-associated ASS activity and provides corroboration for the transferred peripheral localization. Retain the existing term non-core with this combined-source limitation. GO permits extrinsic membrane components, but neither integral insertion nor direct human localization is established, and the complete rodent Methods were not inspected. The mitochondria-associated pool predominates in fetal/newborn rat liver, whereas the cytoplasmic pool predominates in adults (PMID:7845368). |
| GO:0006953 acute-phase response | IEA GO_REF:0000107 | UNDECIDED | Summary: ASS is measured during the acute-phase response, but its specific contribution remains unresolved. Reason: PMID:15698416 measures rat urea-synthesis capacity and ASS mRNA after LPS. ASS transcript decreases while low-dose LPS increases synthesis capacity. Thus the target was studied, but the inspected abstract does not resolve its specific contribution to the acute-phase program or conservation of that regulation in human ASS1. |
| GO:0007494 midgut development | IEA GO_REF:0000107 | UNDECIDED | Summary: Perinatal intestinal ASS expression and zonation do not yet resolve the developmental assignment. Reason: PMID:9544996 describes spatiotemporal ornithine-cycle expression in rat intestine, including ASS protein in upper-villus enterocytes. This supports neonatal arginine metabolism. The full developmental experiments and images were not read, so the relationship to midgut development remains unresolved. A lack of a described morphogenesis assay in the abstract does not alone establish that the broader developmental annotation is incorrect. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | UNDECIDED | Summary: Salt-associated transcript changes do not yet resolve a nutrient-response mechanism. Reason: PMID:15257170 reports salt- and strain-dependent ASS transcript changes in Dahl rat liver. The inspected abstract establishes regulated expression, while an ASS1 contribution to the adaptive nutrient-response mechanism beyond altered abundance or arginine demand remains unresolved. |
| GO:0007623 circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Circadian control modulates ASS1 activity and ureagenesis. Reason: CLOCK-dependent acetylation of ASS1 K165/K176 and rhythmic interaction were reported in human cells and mouse liver. The existing circadian annotation is retained for this metabolic context; ASS1 is not thereby established as a core oscillator or a general clock-setting protein. Supporting Evidence: |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: Xenobiotic-associated ASS transcript changes are established; their functional interpretation remains unresolved. Reason: PMID:9252090 measures rat hepatic ASS transcripts after allyl alcohol and acetaminophen exposure. Differential expression after injury, including induction after nonlethal acetaminophen, does not by itself establish an ASS1 detoxification step. The full functional response context and its human conservation were not established from the inspected abstract. |
| GO:0009636 response to toxic substance | IEA GO_REF:0000107 | UNDECIDED | Summary: PFOA changes ASS abundance, without establishing a protective or detoxifying role. Reason: PMID:20452409 reports reduced hepatic ASS mRNA and protein after 28 days of PFOA exposure in rats. This is a target-specific toxicant-associated expression result. The inspected abstract does not determine whether ASS1 contributes to the response mechanism or is a regulated consequence of exposure; injury resistance and detoxification remain unestablished. |
| GO:0010043 response to zinc ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASS activity responds to dietary zinc status in the rat donor experiment. Reason: The historical rat donor maps to PMID:11686784. Its official abstract reports increased cytosolic liver ASS activity in force-fed zinc-deficient rats. Retain the curated conserved response as contextual, without claiming zinc binding, a zinc cofactor, or a direct human dietary experiment. |
| GO:0010046 response to mycotoxin | IEA GO_REF:0000107 | UNDECIDED | Summary: In-vitro fumonisin inhibition does not by itself close the cellular mycotoxin-response assertion. Reason: The rat donor maps to PMID:11083085. The abstract demonstrates affinity capture and enzyme inhibition but explicitly leaves cellular/toxicological importance unresolved. GO:0010046 concerns a cell or organism response; the needed cellular scope has not been established from the inspected material. This is uncertainty about the process assignment, not rejection of inhibitor binding. Supporting Evidence: |
| GO:0014075 response to amine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The supported cellular amine response also entails the broader amine-response term. Reason: The mapped spermine study PMID:16168957 reports regulated ASS expression in suckling rats. Independently, the retained cellular amine-response annotation is supported by ASS induction in the arginine/NO-cycle context of PMID:18457831. GO:0071418 is a child of GO:0014075, so that accepted cellular context supports this broader term. Retain the parent as non-core without claiming that the spermine-specific mechanism is resolved or that either rat experiment was performed in humans. |
| GO:0015643 toxic substance binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fumonisin B1 affinity capture and inhibition support a limited in-vitro interaction. Reason: Rat liver ASS was affinity-captured on immobilized fumonisin B1, and recombinant human ASS showed mixed inhibition in vitro (Ki-prime approximately 6 mM; crude rat enzyme approximately 35 mM). Two tested fumonisin-related compounds did not inhibit the recombinant enzyme. Retain this existing inhibitor-binding transfer as non-core, while distinguishing rat capture from human inhibition and leaving physiological binding strength, cellular toxicity and detoxification unresolved. Supporting Evidence: |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | UNDECIDED | Summary: The estradiol proteomic study identifies ASS, but does not resolve its physiological response role. Reason: PMID:16339744 Table 1 explicitly identifies two rat ASS protein spots, with reported fold changes of 2.23 and 1.68 in the ovariectomy/estradiol experiment. The parsed table and adjacent Methods/Results were inspected. The target is therefore verified, while its physiological contribution to the hormone response and conservation in humans remain unresolved; no raw spectra or table images were examined. |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASS induction accompanies arginine/NO metabolism under combined inflammatory stimulation. Reason: PMID:12589771 studies rat RPE-J cells exposed to combined interferon-gamma, TNF and LPS, with ASS mRNA/protein induction and citrulline/arginine-supported NO production. Retain the existing response as contextual, without claiming LPS-alone sufficiency or direct human validation. This is a different donor experiment from the macrophage study PMID:9879717 underlying the cellular LPS row. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat gastric neurons support a contextual neuronal cell-body localization. Reason: PMID:12445581 places ASS together with ASL/nNOS in rat gastric myenteric neurons and nerve fibers. The abstract and accessible publisher passages support retaining the curated neuronal cell-body location as a qualified ortholog transfer. Complete antibody controls and image pixels were not examined. This is not direct human neuronal imaging or a claim that all neurons express ASS1. |
| GO:0043200 response to amino acid | IEA GO_REF:0000107 | UNDECIDED | Summary: Citrulline supplementation improves rat renal endpoints, but the ASS-specific response remains unresolved. Reason: PMID:17938381 reports improved renal NO/blood-pressure endpoints after maternal citrulline supplementation in the rat model, alongside ASS expression in strain comparisons. The inspected abstract does not isolate an ASS1-mediated response to the amino-acid intervention. A plausible metabolic connection alone does not close this transferred process assignment. |
| GO:0043204 perikaryon | IEA GO_REF:0000107 | UNDECIDED | Summary: Neuronal ASS localization is reported, but the narrower perikaryon compartment remains unresolved. Reason: PMID:17900569 examines ASS localization in rat neurons and activated microglia after transient ischemia. The complete accessible abstract does not resolve the nucleus-excluding cytoplasmic compartment specified by perikaryon. Full images were unavailable, so this narrower localization transfer remains undecided without implying that neuronal ASS is absent. |
| GO:0043434 response to peptide hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Growth-hormone treatment regulates ASS expression in a measured ureagenic response. Reason: PMID:9688877 studies female rats treated with growth hormone and/or prednisolone. Target-specific publisher passages identify the ASS transcript measurement and its regulation alongside functional urea-synthesis capacity in identically treated groups. Retain the existing peptide-hormone response as non-core. The evidence is contextual metabolic regulation, not an isolated ASS intervention, direct receptor interaction or human experiment. |
| GO:0048545 response to steroid hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Prednisolone regulates ASS expression alongside the rat ureagenic response. Reason: PMID:9688877 reports prednisolone-associated ASS transcript regulation and measured changes in urea-synthesis capacity in rats. The target transcript was verified in accessible publisher Methods/Results passages, resolving the earlier target-identification gap. Retain this steroid-hormone response as non-core, with no claim that an ASS-specific perturbation establishes causality or that the regulation was tested in humans. |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glucocorticoid treatment increases ASS activity in rat astrocytes. Reason: PMID:8923475 reports dexamethasone-induced ASS enzyme activity in rat astrocytes, supporting a contextual conserved response. This differs from the fetal-hepatocyte transcription experiment PMID:9395312 underlying the cellular dexamethasone row. Neither is a direct human experiment, and the variable cAMP result in the astrocyte paper is not generalized as uniform induction. |
| GO:0060416 response to growth hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Growth hormone changes ASS expression in a functional ureagenic context. Reason: PMID:9688877 reports growth-hormone repression of ASS transcripts and coordinated changes in rat urea-synthesis capacity. Accessible publisher Methods/Results passages identify the target measurement. A decrease is still a response, so retain the existing term as non-core. No isolated ASS causal intervention, universal direction of regulation or direct human experiment is claimed. |
| GO:0060539 diaphragm development | IEA GO_REF:0000107 | UNDECIDED | Summary: The developmental role of the diaphragm ASS pool remains unresolved. Reason: PMID:9618389 reports perinatal rat diaphragm ASS/ASL expression and NOS-directed force experiments. Diaphragm development includes maturation of the organ, not only its initial morphogenesis. The inspected evidence establishes a metabolic and contractile context, while the full study connecting ASS to development was not read. Retain UNDECIDED without claiming that expression or an unread functional experiment disproves developmental participation. |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | UNDECIDED | Summary: Maternal dietary fatty acids alter neonatal rat ASS abundance; its response role remains unresolved. Reason: PMID:19651254 reports liver proteomic changes, including ASS, in rat pups after maternal dietary unsaturated-fatty-acid exposure. The complete abstract was inspected, but the target table and complete Methods were not. An ASS-specific functional contribution to the fatty-acid response and its conservation in humans remain unresolved. |
| GO:0070852 cell body fiber | IEA GO_REF:0000107 | MODIFY | Summary: Neuron projection captures the observed nerve-fiber localization without asserting a specific unipolar-neuron segment. Reason: The original publisher Discussion for PMID:12445581 explicitly places ASS with nNOS in rat myenteric neurons and smooth-muscle-layer nerve fibers. GO:0043005 neuron projection includes such nerve fibers. GO:0070852 additionally specifies the prebranch projection segment of a unipolar neuron, which was not established in the inspected material. Generalize this electronic transfer to the supported compartment; this does not assert that the narrower location is experimentally disproved or relabel the rat evidence as human IDA. Proposed replacements: neuron projection |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | UNDECIDED | Summary: LPS induces macrophage ASS, but the functional cellular response remains unresolved. Reason: PMID:9879717 measures ASS mRNA/protein induction after LPS in rat alveolar macrophages, so cellular resolution is present. It reports no significant labeled-citrulline recycling, leaving the ASS contribution to the proposed arginine/NO response unresolved in the inspected abstract. This does not exclude every possible cellular response. The parent LPS row uses the different RPE-J study PMID:12589771, not this experiment. |
| GO:0071230 cellular response to amino acid stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: The cited review discusses amino-acid regulation, but the primary ASS assay remains unverified. Reason: PMID:9893939 is a review of glutamine regulation and cell swelling in rat hepatocytes. Its complete abstract was inspected, but the underlying primary target-specific ASS experiment was not. The transferred cellular amino-acid response remains undecided pending that evidence. |
| GO:0071242 cellular response to ammonium ion | IEA GO_REF:0000107 | UNDECIDED | Summary: Ammonium induces ASS transcripts in rat brain cultures; the functional response remains unresolved. Reason: PMID:10353334 examines fetal rat brain aggregates and reports ammonium-associated ASS/ASL transcript induction in astrocytes. The abstract proposes citrulline/arginine recycling, but does not demonstrate the corresponding flux or establish the ASS-specific adaptive mechanism. The positive expression result is retained as context while the process transfer remains unresolved. |
| GO:0071320 cellular response to cAMP | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat astrocyte study reports a variable ASS response to cAMP. Reason: PMID:8923475 reports a variable cAMP effect on ASS in rat astrocytes. The stronger ASL response cannot be assigned to ASS. The abstract is available, but the full condition-specific ASS results needed to adjudicate this cellular-response transfer were not inspected. |
| GO:0071346 cellular response to type II interferon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASS induction accompanies NO metabolism during combined inflammatory treatment. Reason: PMID:12589771 reports ASS induction in rat RPE-J cells under combined interferon-gamma, TNF and LPS treatment, with arginine/citrulline-supported NO production. Retain the existing cytokine-response transfer as contextual without asserting interferon-gamma-alone sufficiency or direct human validation. The alternate donor PMID:11072090 was not independently inspected. |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASS induction accompanies NO metabolism during combined inflammatory treatment. Reason: PMID:12589771 reports ASS induction in rat RPE-J cells under combined interferon-gamma, TNF and LPS treatment, with arginine/citrulline-supported NO production. Retain the existing cytokine-response transfer as contextual without asserting TNF-alone sufficiency or direct human validation. The alternate donor PMID:11072090 was not independently inspected. |
| GO:0071377 cellular response to glucagon stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: Glucagon enhances dexamethasone-induced ASS transcription in fetal rat hepatocytes. Reason: PMID:9395312 directly measures hormonal regulation of ASS transcription in fetal rat hepatocytes, including glucagon enhancement of the dexamethasone response. The cellular observation is established. The inspected abstract does not resolve ASS participation beyond being a regulated metabolic output, and the complete functional context remains unread; an ASS knockout is not a prerequisite for a valid response annotation. |
| GO:0071400 cellular response to oleic acid | IEA GO_REF:0000107 | UNDECIDED | Summary: Oleate represses dexamethasone-induced ASS mRNA in cultured rat hepatocytes. Reason: PMID:8985169 reports conditional repression of ASS mRNA by oleate in dexamethasone-treated rat hepatocytes, with carnitine-related conditions also examined. The inspected abstract establishes that expression response. Its functional significance for cellular adaptation and conservation in human ASS1 remain unresolved without the full target-specific context. |
| GO:0071418 cellular response to amine stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An arginine-containing polymer induces endothelial ASS in a functional NO-cycle response. Reason: PMID:18457831 reports ASS protein induction after polyaspartoyl-L-arginine treatment of rat aortic endothelial cells, together with functional arginine/NO-cycle endpoints. Retain the existing cellular amine response as non-core in this specific context. The inhibitor experiments target NOS and ASL, not ASS itself; they do not isolate ASS causality, demonstrate the human response or justify generalization to every amine. This retained child also supports the broader GO:0014075 response-to-amine annotation; the separate spermine experiment is not treated as equivalent mechanistic evidence. |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Dexamethasone regulates ASS expression and enzyme activity in rat cellular models. Reason: PMID:9395312 establishes dexamethasone-induced ASS transcription in fetal rat hepatocytes using dose-response, inhibitors and nuclear run-on measurements. The independent astrocyte study PMID:8923475 explicitly reports increased ASS enzyme activity after dexamethasone treatment. Together these support the existing cellular response as non-core with a functional enzyme readout, consistently with the zinc-response criterion. Preserve the human ortholog-transfer provenance; neither direct human replication nor an isolated ASS1 perturbation is claimed. |
| GO:0000050 urea cycle | IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p... | ACCEPT | Summary: Human ASS1 deficiency supports its established catalytic and urea-cycle roles. Reason: PMID:7977368 identifies ASS1 mutations in patients with classical citrullinemia; it is not a purified-enzyme kinetic study. Independent recombinant human ASS1 studies directly establish the enzyme reaction underlying the disease phenotype. Retain the curator assertion without attributing those independent assays to the patient-genetics paper. |
| GO:0006533 L-aspartate catabolic process | IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p... | ACCEPT | Summary: ASS1 catalyzes conversion of its amino-acid substrates in the argininosuccinate pathway. Reason: ASS1 catalyzes the argininosuccinate-forming step of the ASS1–ASL pathway: aspartate carbon proceeds to fumarate through ASL, its nitrogen enters the urea-cycle route, and citrulline is converted through argininosuccinate into arginine. This established metabolic route supports retention of the existing curator-assigned catabolic process term. It is not a general inference that any substrate consumption proves catabolism. PMID:7977368 supplies human genetic evidence; direct substrate and catalytic evidence comes from independent human structural/kinetic studies. No new catabolic term or duplicate core is proposed. |
| GO:0019241 L-citrulline catabolic process | IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p... | ACCEPT | Summary: ASS1 catalyzes conversion of its amino-acid substrates in the argininosuccinate pathway. Reason: ASS1 catalyzes the argininosuccinate-forming step of the ASS1–ASL pathway: aspartate carbon proceeds to fumarate through ASL, its nitrogen enters the urea-cycle route, and citrulline is converted through argininosuccinate into arginine. This established metabolic route supports retention of the existing curator-assigned catabolic process term. It is not a general inference that any substrate consumption proves catabolism. PMID:7977368 supplies human genetic evidence; direct substrate and catalytic evidence comes from independent human structural/kinetic studies. No new catabolic term or duplicate core is proposed. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol is the principal established location of ASS1. Reason: The cytosolic urea-cycle reaction, curated UniProt location and supported human immunofluorescence localization agree. This is not an exclusivity claim: peripheral mitochondrial association and context-dependent nuclear localization are compatible. Supporting Evidence: Reactome:R-HSA-70577 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9956517 | ACCEPT | Summary: The curated variant reaction occurs in the cytosol. Reason: Reactome R-HSA-9956517 assigns the human ASS1 variant reaction to the cytosol, consistent with the normal enzyme location. Its grouping of variants is not interpreted as evidence that every variant has exactly zero residual activity. Supporting Evidence: Reactome:R-HSA-9956517 |
| GO:0004055 argininosuccinate synthase activity | IMP PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | ACCEPT | Summary: ASS1 ligase activity is inhibited by CLOCK-mediated acetylation. Reason: The source reports inhibitory acetylation at K165/K176 of the argininosuccinate-synthesizing enzyme. The catalytic identity is also independently established by recombinant human enzyme experiments. |
| GO:0005515 protein binding | IPI PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | MODIFY | Summary: ASS1 binds the acetylating enzyme CLOCK. Reason: The original abstract/publisher summary reports CLOCK-mediated acetylation and rhythmic association with ASS1. Enzyme binding is a supported refinement of the generic protein-binding row. Full co-IP panels were not inspected, and ASS1 is not assigned CLOCK catalytic or transcription-factor activity. Proposed replacements: enzyme binding Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | ACCEPT | Summary: The existing cytosol localization agrees with the established ASS1 location. Reason: Retain the experimental curator assignment in the context of the source study and independent cytosolic reaction evidence. The localization-specific panel was not independently inspected; the broader biological location is well established. |
| GO:0007623 circadian rhythm | IDA PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | KEEP AS NON CORE | Summary: Circadian control modulates ASS1 activity and ureagenesis. Reason: CLOCK-dependent acetylation of ASS1 K165/K176 and rhythmic interaction were reported in human cells and mouse liver. The existing circadian annotation is retained for this metabolic context; ASS1 is not thereby established as a core oscillator or a general clock-setting protein. Supporting Evidence: |
| GO:0000050 urea cycle | IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source characterizes recombinant human wild-type and mutant ASS proteins. Purified wild-type properties match native human liver ASS, with mutation-dependent activity/kinetic changes. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0004055 argininosuccinate synthase activity | IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source characterizes recombinant human wild-type and mutant ASS proteins. Purified wild-type properties match native human liver ASS, with mutation-dependent activity/kinetic changes. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0006526 L-arginine biosynthetic process | IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source characterizes recombinant human wild-type and mutant ASS proteins. Purified wild-type properties match native human liver ASS, with mutation-dependent activity/kinetic changes. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0000050 urea cycle | IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source assays recombinant human ASS1 variants expressed in bacteria, supporting substrate-dependent activity and the consequences of mutations. Assay activity is not treated as a sufficient individual clinical prognosis. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0004055 argininosuccinate synthase activity | IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source assays recombinant human ASS1 variants expressed in bacteria, supporting substrate-dependent activity and the consequences of mutations. Assay activity is not treated as a sufficient individual clinical prognosis. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0006526 L-arginine biosynthetic process | IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source assays recombinant human ASS1 variants expressed in bacteria, supporting substrate-dependent activity and the consequences of mutations. Assay activity is not treated as a sufficient individual clinical prognosis. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0000050 urea cycle | IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source studies human ASS1 variants with activity and substrate-affinity assays, including reduced activity rescued under some in-vitro substrate conditions. That result is not asserted to establish clinical treatment efficacy. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0004055 argininosuccinate synthase activity | IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source studies human ASS1 variants with activity and substrate-affinity assays, including reduced activity rescued under some in-vitro substrate conditions. That result is not asserted to establish clinical treatment efficacy. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0006526 L-arginine biosynthetic process | IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency... | ACCEPT | Summary: Direct human enzyme characterization supports this established metabolic function. Reason: The source studies human ASS1 variants with activity and substrate-affinity assays, including reduced activity rescued under some in-vitro substrate conditions. That result is not asserted to establish clinical treatment efficacy. The retained annotation describes the enzyme reaction itself or a pathway step that ASS1 directly catalyzes. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytosolic urea-cycle enzyme. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.) |
| GO:0004055 argininosuccinate synthase activity | IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p... | ACCEPT | Summary: Human ASS1 deficiency supports its established catalytic and urea-cycle roles. Reason: PMID:7977368 identifies ASS1 mutations in patients with classical citrullinemia; it is not a purified-enzyme kinetic study. Independent recombinant human ASS1 studies directly establish the enzyme reaction underlying the disease phenotype. Retain the curator assertion without attributing those independent assays to the patient-genetics paper. |
| GO:0016597 amino acid binding | IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p... | ACCEPT | Summary: ASS1 binds its amino-acid substrates as part of catalysis. Reason: Human substrate-bound structures and variant kinetic studies directly establish binding of citrulline and aspartate. PMID:7977368 is a patient-genetics source; the independent structure/enzymology is cited explicitly rather than attributed to that paper. This is part of the ligase core, not an additional binding core. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ... | KEEP AS NON CORE | Summary: Endothelial ASS1 supports nitric-oxide production and limits monocyte adhesion under the studied conditions. Reason: The human endothelial-cell study manipulates ASS1 expression and examines nitric-oxide metabolites, laminar-shear responses and TNF-stimulated monocyte adhesion with controls. ASS1 supplies arginine upstream of NOS rather than catalyzing NO synthesis itself. Retain these existing perturbation-supported annotations as contextual functions; they do not establish ASS1 as a shear sensor or justify additional broad response terms. The NOS3 overexpression comparator used a bovine construct, distinct from the human ASS1 manipulations. Supporting Evidence: |
| GO:0071499 cellular response to laminar fluid shear stress | IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ... | KEEP AS NON CORE | Summary: Endothelial ASS1 supports nitric-oxide production and limits monocyte adhesion under the studied conditions. Reason: The human endothelial-cell study manipulates ASS1 expression and examines nitric-oxide metabolites, laminar-shear responses and TNF-stimulated monocyte adhesion with controls. ASS1 supplies arginine upstream of NOS rather than catalyzing NO synthesis itself. Retain these existing perturbation-supported annotations as contextual functions; they do not establish ASS1 as a shear sensor or justify additional broad response terms. The NOS3 overexpression comparator used a bovine construct, distinct from the human ASS1 manipulations. Supporting Evidence: |
| GO:1903038 negative regulation of leukocyte cell-cell adhesion | IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ... | KEEP AS NON CORE | Summary: Endothelial ASS1 supports nitric-oxide production and limits monocyte adhesion under the studied conditions. Reason: The human endothelial-cell study manipulates ASS1 expression and examines nitric-oxide metabolites, laminar-shear responses and TNF-stimulated monocyte adhesion with controls. ASS1 supplies arginine upstream of NOS rather than catalyzing NO synthesis itself. Retain these existing perturbation-supported annotations as contextual functions; they do not establish ASS1 as a shear sensor or justify additional broad response terms. The NOS3 overexpression comparator used a bovine construct, distinct from the human ASS1 manipulations. Supporting Evidence: |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: ASS1 occurs in the experimentally defined HeLa mRNA interactome. Reason: PMID:22658674 Table 1 explicitly lists ASS1 in the mRNA interactome rather than the candidate-RBP group. The study combines in-cell UV crosslinking, stringent oligo(dT) capture, RNase release and quantitative enrichment over controls. Retain the existing human HDA RNA-binding observation as non-core. The inspected evidence does not establish an ASS1-specific RNA target, regulatory function or isolated binding affinity; no second core function follows. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: ASS1 was detected in the human urinary-exosome proteomic dataset. Reason: The study laboratory's NIH/NHLBI urinary-exosome database explicitly lists ASS1, argininosuccinate synthetase 1, RefSeq NP_000041, and assigns the entry to references 1 and 2; reference 2 is the original PMID:19056867 study. The database header specifies healthy human urinary exosomes and provides the instrument/reference mapping. This closes target-level detection for this source. It does not establish an intravesicular catalytic role, membrane topology or a classical secretory function. The displayed peptide count 20 is an aggregate database field and is not independently assigned to this one study. Source: https://esbl.nhlbi.nih.gov/UrinaryExosomes/ . Supporting Evidence: |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70577 | ACCEPT | Summary: The normal human ASS1 reaction is assigned to the cytosol. Reason: The original Reactome reaction places the ASS1 tetramer/NMRAL1 complex and amino-acid ligation in the cytosol. Association with an inhibitory regulator does not change the core enzyme identity. Supporting Evidence: Reactome:R-HSA-70577 |
| GO:0005737 cytoplasm | TAS PMID:6194510 Sequence for human argininosuccinate synthetase cDNA. | MODIFY | Summary: Cytosol is more precise than the broad cytoplasm label. Reason: The original cDNA paper does not independently establish a modern subcellular localization assay. The existing broad TAS assignment can be refined using independent curated cytosolic reaction and human localization evidence; those observations are not attributed to the cDNA sequencing experiment. Proposed replacements: cytosol Supporting Evidence: Reactome:R-HSA-70577 |
| GO:0005634 nucleus | IDA PMID:38858597 ASS1 metabolically contributes to the nuclear and cytosolic ... | NEW | Summary: ASS1 localizes to the nucleus in the examined human cells. Reason: The 2024 primary study shows ASS1 nuclear signal by immunofluorescence and fractionation in human HCT116 cells, including increased nuclear signal after doxorubicin. Targeted original Results, Fig. 2 legends and localization/fractionation Methods were independently inspected. Retain this as context-dependent localization, not a new nuclear catalytic core or a claim of nuclear exclusivity. The correction changes author order only. No DNA-repair, transcription, or cell-cycle process term is proposed; the fumarate isotope-tracing caveat does not negate the separate localization evidence. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which original ASS1-specific assay records support the unresolved interaction, RNA-binding and ortholog-transferred regulatory annotations?
Q: How broadly does nuclear ASS1 localization occur across primary human cell types, and how is its distribution regulated?
Q: Does independently measured vesicular ASS1 have enzymatic activity, and which side of the vesicle membrane contains it?
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