ASS1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004055 argininosuccinate synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred core molecular function. This is the correct and well-supported catalytic activity for ASS1 (EC 6.3.4.5), the enzyme name itself, and is confirmed by direct enzymology of the human recombinant protein. Reason: IBA at exactly the right level of specificity for the family and directly corroborated by human experimental data. This is a defining core function. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred cytosolic localization. ASS1 is a soluble cytosolic enzyme; the substrate citrulline is exported from mitochondria and converted in the cytosol. Reason: Consistent with UniProt subcellular location (Cytoplasm, cytosol) and with direct immunofluorescence/experimental evidence. Correct compartment for a core function.
GO:0006526 L-arginine biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred role in L-arginine biosynthesis. ASS1 with ASL performs the two steps that convert citrulline to arginine, making arginine available in most tissues. Reason: Core biological process, matching UniProt PATHWAY annotation (L-arginine biosynthesis, step 2/3) and experimental patient/expression data. IBA at appropriate specificity. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0000050 urea cycle	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred participation in the urea cycle, the metabolic step condensing citrulline and aspartate to argininosuccinate. This is a core biological process for the hepatic enzyme. Reason: Well supported by human enzymology and disease genetics; ASS1 deficiency is the cause of citrullinemia type I, a urea cycle disorder. IBA correct. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0004055 argininosuccinate synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (multiple IEA methods) assignment of the core catalytic activity, backed by InterPro signatures, RHEA:10932 and EC 6.3.4.5. Fully consistent with the experimental activity. Reason: Redundant with the IBA/IMP argininosuccinate synthase activity annotations but correct; the EC/RHEA/InterPro mapping is accurate for this enzyme. Supporting Evidence: PMID:18473344 caused by deficiency of the urea cycle enzyme argininosuccinate synthetase
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO mapping of ATP binding. ASS1 uses ATP as a co-substrate (activating citrulline via a citrullyl-AMP intermediate), and UniProt documents an ATP-binding SSGGxDS motif and ATP-binding feature/keyword. Reason: Correct molecular function supported by the catalyzed reaction (ATP -> AMP + PPi) and by UniProt nucleotide-binding features; a genuine ligand-binding activity underpinning catalysis.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Subcellular-location keyword mapping to cytosol from UniProt SL-0091. Reason: Consistent with the experimentally supported cytosolic localization; redundant but correct.
GO:0006526 L-arginine biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Automated assignment of the L-arginine biosynthetic process, matching UniPathway UPA00068. Reason: Correct core process, redundant with the IBA/IMP annotations.
GO:0005515 protein binding	IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex...	REMOVE	Summary: IntAct-curated interaction with ARAF (Raf kinase) found in an exhaustive yeast two-hybrid screen. "protein binding" is uninformative and this is a high-throughput two-hybrid hit with no established biological consequence for ASS1. Reason: Per curation guidelines, bare "protein binding" (GO:0005515) is uninformative and should be avoided. The interaction is a screen-derived putative binary interaction (A-Raf/C-Raf Y2H atlas) not connected to ASS1 function; it adds no functional information to the review. Supporting Evidence: PMID:12620389 We have performed an exhaustive unbiased yeast two-hybrid analysis to identify
GO:0005515 protein binding	IPI PMID:17496144 Restructuring of the dinucleotide-binding fold in an NADP(H)...	REMOVE	Summary: IntAct-curated interaction with NMRAL1 (HSCARG, an NADP(H)-sensing redox protein). UniProt records this interaction, and NMRAL1 has been reported to regulate ASS1 activity. However the GO term captured is only the uninformative "protein binding". Reason: Bare "protein binding" is uninformative and discouraged. The underlying NMRAL1 interaction is real and biologically noted (redox regulation of ASS1), but the informative content belongs in a specific term or in the description, not in GO:0005515. The interaction itself is retained conceptually via UniProt SUBUNIT and is not lost. Supporting Evidence: PMID:17496144 may be argininosuccinate
GO:0005515 protein binding	IPI PMID:28587924 PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrup...	REMOVE	Summary: IntAct-curated interaction with PRMT7 (protein arginine methyltransferase 7), a direct interactor identified by Y2H and confirmed by pull-down; citrullinemia mutations disrupt the interaction. Captured only as uninformative "protein binding". Reason: Bare "protein binding" is discouraged. The PRMT7-ASS1 interaction is a genuine and interesting finding, but the GO term is uninformative; the biology is retained in the description and could be captured by a specific term if warranted. No functional information is lost by removing GO:0005515. Supporting Evidence: PMID:28587924 interacts with ASS1 using pull-down studies.
GO:0042802 identical protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	ACCEPT	Summary: Self-interaction (ASS1-ASS1) consistent with the well-established homotetrameric quaternary structure of the enzyme. Reason: "identical protein binding" is informative here: ASS1 is a homotetramer composed of identical subunits, so self-association is a bona fide, functionally meaningful property (the active enzyme is the tetramer). Multiple independent interactome studies report the self-interaction. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	ACCEPT	Summary: Self-interaction detected in a human liver protein-interaction network study, consistent with the homotetrameric architecture of ASS1. Reason: Corroborates the homotetramer; "identical protein binding" is a meaningful function for this obligate oligomer. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	ACCEPT	Summary: Self-interaction from a proteome-scale human interactome map, again consistent with the homotetramer. Reason: Reinforces the biologically meaningful homo-oligomerization of ASS1. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0000050 urea cycle	IEA GO_REF:0000120	ACCEPT	Summary: Automated urea cycle assignment, matching UniPathway UPA00158. Reason: Correct core process, redundant with IBA and multiple experimental IMP annotations.
GO:0001822 kidney development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. ASS1 is expressed in fetal kidney and is part of the intestinal-renal citrulline-arginine axis, but a direct role in kidney developmental morphogenesis is not established for the human enzyme; this reads as an expression/context annotation rather than a developmental function. Reason: Ortholog-transfer IEA reflecting a tissue in which ASS1 is expressed and active rather than a core molecular role in organ development. Not a core function; retain as non-core pending direct evidence.
GO:0001889 liver development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. ASS1 is the principal hepatic urea-cycle enzyme and is developmentally regulated in fetal liver, but "liver development" (organ morphogenesis) overstates its role; its liver function is metabolic (ureagenesis). Reason: Ortholog-transfer IEA describing the tissue context (liver) of ASS1 expression rather than a causal role in liver organogenesis. Retain as non-core; the metabolic role is captured by the urea cycle / arginine biosynthesis annotations.
GO:0005739 mitochondrion	IEA GO_REF:0000107	REMOVE	Summary: Ensembl-Compara ortholog-transfer (from mouse) placing ASS1 in the mitochondrion. This contradicts the well-established cytosolic localization of ASS1; the enzyme acts in the cytosol on citrulline exported from mitochondria. Reason: ASS1 is a soluble cytosolic enzyme (UniProt: Cytoplasm, cytosol; direct IDA cytosol annotations). Mitochondrial localization is an over-propagated ortholog-transfer IEA inconsistent with the human protein and with urea-cycle compartmentalization (only the upstream steps CPS1/OTC are mitochondrial).
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000107	REMOVE	Summary: Ensembl-Compara ortholog-transfer (from rat) placing ASS1 at the mitochondrial outer membrane. Inconsistent with the established cytosolic localization of the enzyme. Reason: Over-propagated ortholog-transfer IEA. ASS1 is cytosolic; there is no reliable evidence for the human enzyme residing at the mitochondrial outer membrane.
GO:0006953 acute-phase response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. Reflects transcriptional induction of ASS1 under inflammatory/cytokine stimulation rather than a direct molecular role in the acute-phase response. Reason: Regulation-of-expression / stimulus-response context transferred from ortholog, not a core catalytic role. Retain as non-core.
GO:0007494 midgut development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. Likely reflects intestinal ASS1 expression (enterocytes contribute to systemic citrulline/arginine metabolism) rather than a role in gut morphogenesis. Reason: Ortholog-transfer IEA describing an expression context, not a core developmental function of the human enzyme. Retain as non-core.
GO:0007584 response to nutrient	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. ASS1 expression/activity responds to dietary protein and amino acid availability, but this is a stimulus-response context, not a core molecular function. Reason: Physiologically plausible (urea-cycle flux tracks nitrogen load) but an ortholog-transfer response annotation rather than core function. Retain as non-core.
GO:0007623 circadian rhythm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from mouse. This is corroborated by direct human/mouse evidence: CLOCK acetylates ASS1 (K165/K176) to inactivate it in a circadian manner, imposing a circadian rhythm on ureagenesis. Reason: Supported by experiment (see the IDA circadian rhythm annotation, PMID:28985504), but this is a regulated-behavior/output context rather than ASS1's core catalytic function. Retain as non-core; redundant with the experimental annotation below. Supporting Evidence: PMID:28985504 ASS1 acetylation by CLOCK exhibits circadian oscillation
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat, reflecting altered ASS1 expression on xenobiotic exposure. Stimulus-response context, not a core function. Reason: Ortholog-transfer response annotation; retain as non-core.
GO:0009636 response to toxic substance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. A broad stimulus-response term reflecting expression changes; not a core molecular function. Reason: Ortholog-transfer response annotation with no direct human evidence for a core role; retain as non-core.
GO:0010043 response to zinc ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; a specific stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0010046 response to mycotoxin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; narrow stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0014075 response to amine	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0015643 toxic substance binding	IEA GO_REF:0000107	REMOVE	Summary: Ensembl-Compara ortholog-transfer from rat asserting ASS1 "binds a toxic substance". There is no credible biochemical basis for treating ASS1 as a toxin-binding protein; ASS1 is a metabolic ligase. This is an anomalous, likely spuriously propagated molecular-function IEA. Reason: Biologically implausible for a cytosolic urea-cycle ligase; unsupported by any human evidence or by the enzyme's mechanism. The term definition ("Binding to a toxic substance, a poisonous substance that causes damage to biological systems") does not fit ASS1. Over-propagated ortholog-transfer IEA.
GO:0032355 response to estradiol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; hormone stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. ASS1 is induced with iNOS in inflammatory (LPS/cytokine) settings to supply arginine for NO production, so this context is plausible, but it is not a core function. Reason: Ortholog-transfer response annotation consistent with the citrulline-NO cycle role in immune/inflammatory cells; retain as non-core.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat placing ASS1 in the neuronal cell body. ASS1 is expressed in specific neurons (citrulline-NO cycle), and within a neuron it would be cytosolic; the specific location is an ortholog-transferred expression context. Reason: Cell-type-specific localization transferred from ortholog; plausible for the tissue context but not the canonical/core cytosolic annotation. Retain as non-core.
GO:0043200 response to amino acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; amino-acid stimulus-response context (ASS1 expression/activity responds to substrate and amino acid availability). Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0043204 perikaryon	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat placing ASS1 in the perikaryon (neuronal cell body cytoplasm). A cell-type-specific location transferred from ortholog. Reason: Ortholog-transfer localization tied to a specific tissue context; not the canonical/core cytosol annotation. Retain as non-core.
GO:0043434 response to peptide hormone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; hormone stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0048545 response to steroid hormone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; steroid-hormone stimulus-response context (ASS1 is known to be glucocorticoid-inducible). Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0051384 response to glucocorticoid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. ASS1 transcription is induced by glucocorticoids (hepatic urea-cycle regulation), so this context is plausible. Reason: Ortholog-transfer response annotation reflecting hormonal regulation of expression, not core catalytic function; retain as non-core.
GO:0060416 response to growth hormone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; hormone stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0060539 diaphragm development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat. There is no established human evidence linking ASS1 to diaphragm morphogenesis; this reads as a weakly supported ortholog-transferred developmental annotation. Reason: Ortholog-transfer developmental annotation lacking direct human support; not a core function. Retain as non-core rather than removing, deferring to the experimental source in the orthologous species.
GO:0070542 response to fatty acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0070852 cell body fiber	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; a neuronal cell-type-specific location. Reason: Ortholog-transfer localization for a specific tissue context; not the canonical/core cytosol annotation. Retain as non-core.
GO:0071222 cellular response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; cellular stimulus-response context (inflammatory induction of ASS1 for arginine/NO supply). Reason: Ortholog-transfer response annotation consistent with the citrulline-NO cycle in immune cells; retain as non-core.
GO:0071230 cellular response to amino acid stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; amino-acid stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071242 cellular response to ammonium ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; stimulus-response context (ureagenesis responds to nitrogen/ammonia load). Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071320 cellular response to cAMP	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; second-messenger stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071346 cellular response to type II interferon	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; cytokine (IFN-gamma) stimulus-response context, consistent with immune induction of ASS1 for arginine/NO supply. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071356 cellular response to tumor necrosis factor	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; cytokine (TNF) stimulus-response context. Related human work shows ASS1/NOS3 counteract TNF-alpha-stimulated monocyte adhesion in endothelium. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071377 cellular response to glucagon stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; hormone stimulus-response context (glucagon induces hepatic urea-cycle enzymes). Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071400 cellular response to oleic acid	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; a narrow fatty-acid stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071418 cellular response to amine stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; amine stimulus-response context. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0071549 cellular response to dexamethasone stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer from rat; glucocorticoid (dexamethasone) stimulus-response context, consistent with glucocorticoid induction of ASS1. Reason: Ortholog-transfer response annotation, not core function; retain as non-core.
GO:0000050 urea cycle	IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p...	ACCEPT	Summary: Experimental (IMP) urea cycle annotation based on characterization of citrullinemia-causing ASS1 mutations in patients. Loss of ASS1 function blocks the urea cycle, causing classic citrullinemia. Reason: Directly supported by patient mutation genetics; a core biological process. Defer to the curator's full-text reading of the disease-gene relationship. Supporting Evidence: PMID:7977368 Citrullinemia is an autosomal recessive disease caused by a genetic deficiency
GO:0006533 L-aspartate catabolic process	IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p...	KEEP AS NON CORE	Summary: Experimental (IMP) annotation reflecting that ASS1 consumes L-aspartate (the second nitrogen donor) in the argininosuccinate synthase reaction. This is a curator reframing of the same catalytic step as an aspartate catabolic process. Reason: Not incorrect (ASS1 does consume aspartate as a co-substrate), but it is a redundant, substrate-centric restatement of the core argininosuccinate synthase activity / urea cycle role rather than an independent biological process. Retain as non-core; defer to the experimental curator who read the full text. Supporting Evidence: PMID:7977368 Citrullinemia is an autosomal recessive disease caused by a genetic deficiency
GO:0019241 L-citrulline catabolic process	IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p...	KEEP AS NON CORE	Summary: Experimental (IMP) annotation reflecting that ASS1 consumes L-citrulline in the argininosuccinate synthase reaction; ASS1 deficiency causes citrulline accumulation. This is a substrate-centric reframing of the same catalytic step. Reason: Not incorrect (citrulline is the substrate whose accumulation defines citrullinemia), but it is a redundant restatement of the core enzyme activity / arginine-biosynthesis and urea-cycle roles. Retain as non-core; defer to the experimental curator. Supporting Evidence: PMID:7977368 Citrullinemia is an autosomal recessive disease caused by a genetic deficiency
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (Human Protein Atlas) localization to the cytosol. Reason: Experimental confirmation of the core cytosolic localization of ASS1.
GO:0005829 cytosol	TAS Reactome:R-HSA-9956517	ACCEPT	Summary: Reactome traceable-author-statement placing ASS1 (in the context of disease variants failing to synthesize argininosuccinate) in the cytosol. Reason: Consistent with the established cytosolic localization; redundant but correct.
GO:0004055 argininosuccinate synthase activity	IMP PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes...	ACCEPT	Summary: Experimental (IMP) support for ASS1 catalytic activity from the CLOCK-acetylation study, which manipulated ASS1 and measured its activity (acetylation of K165/K176 inactivates the enzyme). Reason: Core molecular function directly assayed in the study; ASS1 "catalyzes the rate-limiting step of arginine biosynthesis". Supporting Evidence: PMID:28985504 synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of
GO:0005515 protein binding	IPI PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes...	REMOVE	Summary: IntAct/UniProt interaction with CLOCK (O15516) demonstrated in the circadian-ureagenesis study. Captured only as uninformative "protein binding". Reason: Bare "protein binding" is discouraged. The ASS1-CLOCK interaction is genuine and functionally important (CLOCK acetylates ASS1), but this content is retained in the description and in the circadian-rhythm annotation; the uninformative GO:0005515 term itself adds nothing. Supporting Evidence: PMID:28985504 CLOCK directly acetylates K165 and K176 of argininosuccinate
GO:0005829 cytosol	IDA PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes...	ACCEPT	Summary: Direct experimental (IDA) cytosolic localization from the CLOCK-acetylation study; UniProt cites this paper for the Cytoplasm, cytosol subcellular location. Reason: Experimental confirmation of the core cytosolic localization.
GO:0007623 circadian rhythm	IDA PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes...	KEEP AS NON CORE	Summary: Direct experimental (IDA) evidence that ASS1 activity is under circadian control: CLOCK acetylates ASS1 in a circadian manner, producing an oscillation in ASS1 activity and ureagenesis in human cells and mouse liver. Reason: Well supported experimentally, but this describes a regulated output/behavior in which ASS1 participates rather than ASS1's intrinsic core function. Retain as non-core. Supporting Evidence: PMID:28985504 ASS1 acetylation by CLOCK exhibits circadian oscillation
GO:0000050 urea cycle	IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci...	ACCEPT	Summary: Experimental (IMP) urea cycle annotation from characterization of wild-type and mutant human ASS proteins; the paper explicitly frames ASS as a urea cycle enzyme and links mutations to citrullinemia. Reason: Core biological process, directly supported by recombinant enzymology of the human protein. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0004055 argininosuccinate synthase activity	IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci...	ACCEPT	Summary: Experimental (IMP) measurement of ASS catalytic activity: purified recombinant wild-type human ASS matched native liver enzyme, and mutants showed reduced/abolished activity and abnormal kinetics (elevated Km for citrulline). Reason: Direct biochemical characterization of the core molecular function of the human enzyme. Supporting Evidence: PMID:8792870 G280R mutant was extracted with an amount of ASS protein similar to wild-type
GO:0006526 L-arginine biosynthetic process	IMP PMID:8792870 Characterization of human wild-type and mutant argininosucci...	ACCEPT	Summary: Experimental (IMP) support for ASS1's role in arginine biosynthesis via the biochemical characterization of the enzyme that carries out the committed step. Reason: Core biological process supported by the human enzymology; defer to the experimental curator. Supporting Evidence: PMID:8792870 Argininosuccinate synthetase (ASS) is a urea cycle enzyme with a tetrameric
GO:0000050 urea cycle	IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e...	ACCEPT	Summary: Experimental (IMP) urea cycle annotation from in vitro expression/enzymology of CTLN1 variants; the paper describes ASS as "the urea cycle enzyme argininosuccinate synthetase". Reason: Core biological process supported by disease-variant enzymology. Supporting Evidence: PMID:18473344 caused by deficiency of the urea cycle enzyme argininosuccinate synthetase
GO:0004055 argininosuccinate synthase activity	IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e...	ACCEPT	Summary: Experimental (IMP) enzymatic analysis of purified wild-type and mutant ASS proteins, with measured kinetic parameters (KM 112 uM citrulline, 68 uM aspartate) and reduced activity for pathogenic variants. Reason: Direct measurement of the core catalytic activity; underpins the UniProt EC 6.3.4.5 and kinetic parameters. Supporting Evidence: PMID:18473344 enzymatic analysis of purified wild-type and the mutant ASS proteins
GO:0006526 L-arginine biosynthetic process	IMP PMID:18473344 Investigation of citrullinemia type I variants by in vitro e...	ACCEPT	Summary: Experimental (IMP) support for the arginine-biosynthesis role via enzymology of the ASS reaction, which produces argininosuccinate en route to arginine. Reason: Core biological process supported by the human enzyme characterization. Supporting Evidence: PMID:18473344 caused by deficiency of the urea cycle enzyme argininosuccinate synthetase
GO:0000050 urea cycle	IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency...	ACCEPT	Summary: Experimental (IMP) urea cycle annotation from characterization of 21 kinetic CTLN1 mutations; the paper frames citrullinemia type 1 as "an autosomal-recessive urea cycle disorder". Reason: Core biological process supported by disease-mutation enzymology. Supporting Evidence: PMID:27287393 BACKGROUND: Citrullinemia type 1 is an autosomal-recessive urea cycle disorder
GO:0004055 argininosuccinate synthase activity	IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency...	ACCEPT	Summary: Experimental (IMP) measurement of ASS catalytic activity and kinetics for 21 mutants by tandem mass spectrometry; 13 were inactive and 8 had decreased substrate affinity, rescuable by aspartate supplementation. Reason: Direct quantitative measurement of the core molecular function of the human enzyme. Supporting Evidence: PMID:27287393 activity and kinetic parameters were measured using tandem mass spectrometry and
GO:0006526 L-arginine biosynthetic process	IMP PMID:27287393 Kinetic mutations in argininosuccinate synthetase deficiency...	ACCEPT	Summary: Experimental (IMP) support for the arginine-biosynthesis role via kinetic characterization of the ASS reaction (citrulline + aspartate + ATP -> argininosuccinate). Reason: Core biological process supported by the human enzyme kinetics. Supporting Evidence: PMID:27287393 map near the substrate (aspartate or citrulline)
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: High-throughput detection of ASS1 peptides in urinary/prostatic exosome proteomes. This is a mass-spectrometry proteomic inventory, not evidence of a functional extracellular-vesicle localization for a cytosolic metabolic enzyme. Reason: Abundant cytosolic enzymes are common background hits in exosome/secretome proteomics; the finding is real as a detection event but does not reflect a core functional localization. Retain as non-core rather than removing, since the peptide detection is genuine. Supporting Evidence: PMID:23533145 expressed prostatic secretions in urine (EPS-urine), exosome preparations were
GO:0004055 argininosuccinate synthase activity	IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p...	ACCEPT	Summary: Experimental (IMP) support for the catalytic activity via mutation analysis in citrullinemia patients; the deficiency of ASS activity underlies the disease. Reason: Core molecular function supported by patient genetics; defer to the experimental curator. Supporting Evidence: PMID:7977368 Citrullinemia is an autosomal recessive disease caused by a genetic deficiency
GO:0016597 amino acid binding	IMP PMID:7977368 Mutations in argininosuccinate synthetase mRNA of Japanese p...	ACCEPT	Summary: Experimental (IMP) annotation of amino acid binding, reflecting that ASS1 binds its amino acid substrates L-citrulline and L-aspartate; several CTLN1 mutations map to the substrate (aspartate/citrulline) binding site and impair substrate affinity. Reason: Informative molecular function distinct from the catalytic term: ASS1 has bona fide amino acid (citrulline/aspartate) binding sites (documented in UniProt BINDING features), and kinetic mutants show altered Km. Supported by the experimental mutation studies. Supporting Evidence: PMID:27287393 map near the substrate (aspartate or citrulline)
GO:0045429 positive regulation of nitric oxide biosynthetic process	IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ...	KEEP AS NON CORE	Summary: Experimental (IMP) evidence in endothelial cells that ASS1, by regenerating arginine (the NOS3 substrate) from citrulline, increases NO production; overexpression of ASS1 raised NO and ASS1/NOS3 siRNAs attenuated shear-stress-induced NO. This is the citrulline-NO cycle role. Reason: Genuine, physiologically important extrahepatic function of ASS1 (supplying arginine for NO synthesis) but it is a downstream regulatory consequence of the core arginine-biosynthesis activity in a specific cell type, not the enzyme's intrinsic core function. Retain as non-core. Supporting Evidence: PMID:21106532 increased NO production and decreased monocyte adhesion stimulated by tumor
GO:0071499 cellular response to laminar fluid shear stress	IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ...	KEEP AS NON CORE	Summary: Experimental (IMP) evidence that laminar shear stress induces ASS1 in endothelial cells and that ASS1 (with NOS3) is required for the shear-stress-stimulated increase in NO production. Reason: A cell-type-specific stimulus-response/physiological role, downstream of ASS1's core arginine supply function; not the enzyme's intrinsic core function. Retain as non-core. Supporting Evidence: PMID:21106532 SiRNAs of NOS3 and ASS1 attenuated
GO:1903038 negative regulation of leukocyte cell-cell adhesion	IMP PMID:21106532 Endothelial argininosuccinate synthetase 1 regulates nitric ...	KEEP AS NON CORE	Summary: Experimental (IMP) evidence that ASS1 (via NO production) reduces TNF-alpha-stimulated monocyte adhesion to endothelial cells, an anti-inflammatory endothelial effect downstream of arginine/NO supply. Reason: A downstream physiological consequence of the endothelial citrulline-NO cycle role, mediated by NO rather than a direct ASS1 activity on adhesion; not a core function. Retain as non-core. Supporting Evidence: PMID:21106532 increased NO production and decreased monocyte adhesion stimulated by tumor
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: High-throughput "interactome capture" detection of ASS1 among mRNA-binding proteins in proliferating HeLa cells (mRNA interactome atlas). Many metabolic enzymes were unexpectedly captured; no dedicated RNA-binding function has been demonstrated for ASS1. Reason: This derives from a single high-throughput RNA-interactome screen that recovered numerous "moonlighting" metabolic enzymes. There is no orthogonal validation of a functional RNA-binding role for ASS1, so it is very likely an over-annotation rather than a core or established secondary function. Flag as over-annotated rather than accepting. Supporting Evidence: PMID:22658674 RNA-binding enzymes of intermediary
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput detection of ASS1 in a large-scale urinary-exosome proteome. As above, an MS inventory hit for a cytosolic enzyme rather than evidence of a functional extracellular localization. Reason: Genuine peptide detection in an exosome proteomics dataset, but not a core functional localization for this cytosolic urea-cycle enzyme. Retain as non-core. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes
GO:0005829 cytosol	TAS Reactome:R-HSA-70577	ACCEPT	Summary: Reactome traceable-author-statement localizing the ASS1 tetramer (in complex with NMRAL1 dimer and NADPH) to the cytosol, in the argininosuccinate-forming reaction. Reason: Consistent with the established cytosolic localization of ASS1; correct.
GO:0005737 cytoplasm	TAS PMID:6194510 Sequence for human argininosuccinate synthetase cDNA.	MODIFY	Summary: Traceable author statement (from the human ASS cDNA sequencing paper) localizing ASS1 to the cytoplasm. This is the general parent of the more specific cytosol annotations. Reason: Correct but less specific than warranted: ASS1 is specifically cytosolic (GO:0005829), which is directly supported by immunofluorescence (IDA) and multiple sources. Replace the general "cytoplasm" with the more informative "cytosol". Proposed replacements: cytosol

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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