ASL

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004056 argininosuccinate lyase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred core molecular function. ASL cleaves L-argininosuccinate to L-arginine and fumarate (EC 4.3.2.1), the reaction that defines this orthology group and is directly supported for the human enzyme by biochemical assay. Reason: This is the correct, well-supported core molecular function of ASL. The IBA is concordant with multiple human experimental annotations (EXP/IDA) and with the UniProt-curated catalytic activity. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0006526 L-arginine biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in L-arginine biosynthesis. ASL performs the final (argininosuccinate-cleaving) step of de novo arginine synthesis from ornithine and carbamoyl phosphate. Reason: Correct core biological process, concordant with human IDA annotations and the UniProt-curated arginine-biosynthesis pathway (step 3/3). ASL supplies arginine both for the urea cycle in liver and for other arginine-dependent pathways in non-hepatic tissues. Supporting Evidence: PMID:11747432 a reaction involved in the biosynthesis of arginine in all species and in the production of urea in ureotelic species
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred cytosolic localization. ASL is a soluble cytosolic enzyme; its urea-cycle and arginine-biosynthesis reactions occur in the cytosol. Reason: Correct core cellular component, concordant with the human TAS cytosol/cytoplasm annotations and with the soluble, non-membrane biochemistry of the enzyme. Supporting Evidence: PMID:282632 ASL activity was visualized on gels after electrophoresis by a new method, termed bioautography
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Root-level catalytic activity assigned electronically from InterPro domain membership (fumarase/aspartase superfamily). This is the uninformative parent of the specific, correct term. Reason: ASL's molecular function is captured precisely and correctly by GO:0004056 argininosuccinate lyase activity (EC 4.3.2.1), which is annotated with strong experimental (EXP/IDA) and phylogenetic (IBA) support. GO:0003824 is the most general MF root and adds no information beyond "is an enzyme"; it should not be considered a core function statement.
GO:0004056 argininosuccinate lyase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of argininosuccinate lyase activity from InterPro signature IPR009049, RHEA:24020 and EC 4.3.2.1. This is the correct core molecular function. Reason: Correct and specific molecular function, fully concordant with the human experimental and phylogenetic annotations to the same term.
GO:0006526 L-arginine biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of L-arginine biosynthetic process from UniPathway mapping and ortholog evidence. Correct core process. Reason: Concordant with human IDA and IBA annotations to the same process; matches the UniProt-curated arginine biosynthesis pathway (step 3/3).
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Generic protein binding recorded from a proteome-scale binary interactome (Y2H) screen (interactor NTAQ1, Q96HA8). The bare protein binding term is uninformative about ASL's molecular function. Reason: Per curation guidelines, bare GO:0005515 protein binding is not an informative molecular-function statement and is not a core function. The biologically meaningful self-association of ASL is captured by GO:0042802 (identical protein binding); the physiologically important heteromeric interactions (ASS1, SLC7A1, NOS) underlie the nitric-oxide role captured by GO:0045429. The interaction evidence itself is retained as non-core.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	KEEP AS NON CORE	Summary: Generic protein binding from a high-throughput interactome study of alternative-splicing isoforms (interactor MCMBP isoform, Q9BTE3-2). Uninformative MF term. Reason: Bare protein binding is not an informative molecular function and is not core. The interaction detection is retained as non-core supporting data; the informative self-interaction is annotated separately as GO:0042802.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: Generic protein binding from a large-scale study of interaction disruption by genetic variants (interactor NTAQ1, Q96HA8). Uninformative MF term. Reason: Bare protein binding is not an informative molecular function and is not core; retained as non-core interaction evidence.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Generic protein binding from the HuRI reference binary interactome (multiple interactors, e.g. TRIM3 O75382, NTAQ1 Q96HA8, MCMBP Q9BTE3-2). Uninformative MF term. Reason: Bare protein binding is not an informative molecular function and is not core; retained as non-core interaction evidence. Physiologically relevant heteromeric partners (ASS1/SLC7A1/NOS) are not among these high-throughput hits.
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	ACCEPT	Summary: ASL self-association (P04424-P04424) detected in a human liver protein interaction network study. This reflects the biologically real homotetramer. Reason: ASL is an obligate homotetramer whose subunits jointly form the shared active sites; self-association is intrinsic to its catalytic architecture and is directly supported by structural and biochemical work. This is an informative, correct molecular-function statement (unlike bare protein binding). Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	ACCEPT	Summary: ASL self-association (P04424-P04424) detected in a proteome-scale binary interactome, consistent with the homotetramer. Reason: Corroborates the biologically real ASL homotetramer; informative and correct. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0042802 identical protein binding	IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam...	ACCEPT	Summary: ASL self-association (P04424-P04424) detected in a massively parallel clone/variant interaction pipeline, consistent with the homotetramer. Reason: Corroborates the homotetramer; informative and correct self-interaction annotation. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	ACCEPT	Summary: ASL self-association (P04424-P04424) detected in a study of variant effects on protein interactions, consistent with the homotetramer. Reason: Corroborates the homotetramer; informative and correct self-interaction annotation. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: ASL self-association (P04424-P04424) detected in the HuRI reference binary interactome, consistent with the homotetramer. Reason: Corroborates the biologically real ASL homotetramer; informative and correct. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0045429 positive regulation of nitric oxide biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-Compara ortholog-transfer of a mouse Asl (Q91YI0) experimental annotation for the role of ASL in promoting nitric oxide biosynthesis. This transfers the same biology established experimentally for both mouse and human ASL in PMID:22081021. Reason: The underlying biology is genuine and experimentally supported in both species - ASL contributes, via a catalysis-independent structural role in the NOS multiprotein complex, to nitric oxide production. The orthology-transfer IEA is redundant with the human IMP annotation of the same term (PMID:22081021) but is not wrong. This is a secondary (moonlighting/structural) function rather than the enzyme's core catalytic function, hence non-core. Supporting Evidence: PMID:22081021 Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production.
GO:0000050 urea cycle	IEA GO_REF:0000041	ACCEPT	Summary: Electronic assignment of urea cycle from UniPathway mapping. ASL performs the step that regenerates arginine (from argininosuccinate) within the urea cycle, providing for hepatic nitrogen detoxification into urea. Reason: Correct core biological process. This is the canonical urea-cycle role of ASL and is central to the disease mechanism (hyperammonemia in argininosuccinic aciduria). Concordant with UniProt pathway curation (urea cycle, step 1/1 for this reaction). Supporting Evidence: PMID:11747432 a reaction involved in the biosynthesis of arginine in all species and in the production of urea in ureotelic species
GO:0005829 cytosol	TAS Reactome:R-HSA-9956524	ACCEPT	Summary: Reactome-asserted cytosolic localization (from the ASL variant urea-cycle reaction pathway). ASL is a soluble cytosolic enzyme. Reason: Correct core cellular component, concordant with the IBA and TAS cytosol/cytoplasm annotations.
GO:0004056 argininosuccinate lyase activity	EXP PMID:2263616 Molecular analysis of human argininosuccinate lyase: mutant ...	ACCEPT	Summary: Experimental demonstration of argininosuccinate lyase activity via characterization of human ASL and its ASA disease variants (e.g. R95C), including expression of mutant cDNA in COS cells showing loss of ASL activity. Reason: Direct experimental support for the core molecular function in the human enzyme. R95C produces little protein and less than 1% ASL activity, establishing that the assayed activity is that of the ASL gene product. Supporting Evidence: PMID:2263616 Expression in COS cells demonstrated that the R95C mutation produces normal amounts of ASAL mRNA but little protein and less than 1% ASAL activity.
GO:0004056 argininosuccinate lyase activity	IDA PMID:9045711 Intragenic complementation at the human argininosuccinate ly...	ACCEPT	Summary: Direct assay of ASL activity in COS-cell expression / intragenic complementation experiments, where the Q286R and D87G alleles each conferred loss of ASL activity and cotransfection partially restored it. Reason: Strong direct experimental support for the core catalytic function of human ASL. Supporting Evidence: PMID:9045711 each conferred loss of ASL activity in COS cell transfection assays
GO:0006525 arginine metabolic process	IDA PMID:9045711 Intragenic complementation at the human argininosuccinate ly...	KEEP AS NON CORE	Summary: Involvement in arginine metabolism inferred from direct assay of ASL activity and the resulting arginine production/loss in the complementation experiments. Reason: Correct but general. GO:0006525 arginine metabolic process is a broad parent; ASL's specific role is captured more precisely by GO:0006526 L-arginine biosynthetic process (the direction ASL contributes to). Retained as an accurate but non-core parent annotation. Supporting Evidence: PMID:9045711 each conferred loss of ASL activity in COS cell transfection assays
GO:0045429 positive regulation of nitric oxide biosynthetic process	IMP PMID:22081021 Requirement of argininosuccinate lyase for systemic nitric o...	KEEP AS NON CORE	Summary: Experimentally demonstrated requirement of ASL for nitric oxide production. Human ASA (ASL-null) subjects and cells, a hypomorphic Asl mouse, and ASL-knockdown cells all show reduced NOS-dependent NO. Crucially, catalytically dead but structurally intact human ASL mutants (R236W, R113Q) still support NOS complex formation and restore arginine-stimulated NO, showing this is a catalysis-independent structural role in assembling the NOS multiprotein complex (ASS1, SLC7A1, NOS). Reason: This is a genuine, well-supported second function of ASL (a moonlighting/structural role distinct from its catalytic activity) and explains the ammonia-independent systemic features (hypertension, hepatic/neurologic disease) of argininosuccinic aciduria. It is captured as a core function in core_functions as the NOS scaffold role, but relative to the enzyme's canonical urea-cycle/arginine-biosynthesis catalysis it is treated as non-core at the annotation level. Supporting Evidence: PMID:22081021 Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. PMID:22081021 Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production.
GO:0004056 argininosuccinate lyase activity	IDA PMID:11747433 Mechanisms for intragenic complementation at the human argin...	ACCEPT	Summary: Direct biochemical characterization of recombinant human ASL and its active-site (Q286R, D87G) and stability (M360T, A398D) mutants, confirming argininosuccinate lyase activity and its dependence on the homotetrameric shared-active-site architecture. Reason: Strong direct experimental support for the core catalytic function; the paper reconstructs the reaction in vivo and in vitro with recombinant protein. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0006526 L-arginine biosynthetic process	IDA PMID:11747432 Three-dimensional structure of the argininosuccinate lyase f...	ACCEPT	Summary: The 2.65 A structure of the human ASL Q286R allele together with catalytic characterization supports ASL's role in the arginine-producing reaction of arginine biosynthesis. Reason: Correct core biological process, supported by direct structural/biochemical study of the human enzyme. The reaction is explicitly stated to be part of arginine biosynthesis. Supporting Evidence: PMID:11747432 a reaction involved in the biosynthesis of arginine in all species and in the production of urea in ureotelic species
GO:0006526 L-arginine biosynthetic process	IDA PMID:11747433 Mechanisms for intragenic complementation at the human argin...	ACCEPT	Summary: Biochemical reconstitution of the ASL reaction (argininosuccinate to arginine + fumarate) with recombinant human protein supports involvement in arginine biosynthesis. Reason: Correct core biological process, supported by direct assay of the arginine-producing reaction. Supporting Evidence: PMID:11747433 Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate.
GO:0004056 argininosuccinate lyase activity	IDA PMID:11747432 Three-dimensional structure of the argininosuccinate lyase f...	ACCEPT	Summary: Catalytic characterization and high-resolution structure of human ASL (Q286R allele) directly demonstrate argininosuccinate lyase activity and its kinetics (KM 0.12 mM for argininosuccinate). Reason: Strong direct experimental support for the core molecular function in the human enzyme. Supporting Evidence: PMID:11747432 Argininosuccinate lyase (ASL) catalyzes the reversible breakdown of argininosuccinate to arginine and fumarate
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: ASL peptides detected in urinary exosomes by large-scale proteomics/phosphoproteomics. This is a mass-spectrometry catalog location, not a site where ASL performs its known function. Reason: High-throughput proteomic detection in exosomes is common for abundant cytosolic enzymes and does not reflect a functional extracellular localization. ASL is a soluble cytosolic urea-cycle enzyme; the exosome finding is retained as non-core observational data. Cytosol (GO:0005829) is the functionally relevant compartment.
GO:0005829 cytosol	TAS Reactome:R-HSA-70573	ACCEPT	Summary: Reactome-asserted cytosolic localization (from the argininosuccinate to fumarate + arginine urea-cycle reaction). Correct. Reason: Correct core cellular component, concordant with the IBA and other TAS cytosol/cytoplasm annotations.
GO:0004056 argininosuccinate lyase activity	TAS PMID:282632 Argininosuccinic aciduria: assignment of the argininosuccina...	ACCEPT	Summary: Traceable assertion of ASL enzymatic activity (EC 4.3.2.1) from an early study that assayed human ASL by bioautography and mapped the ASL gene to chromosome 7. Reason: Correct core molecular function; the enzyme activity (EC 4.3.2.1) was directly detected and used to map the human gene. Supporting Evidence: PMID:282632 associated with a deficiency of argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1)
GO:0005737 cytoplasm	TAS PMID:282632 Argininosuccinic aciduria: assignment of the argininosuccina...	ACCEPT	Summary: Traceable assertion of cytoplasmic localization for ASL. The more specific and functionally accurate term is cytosol (GO:0005829). Reason: Correct but general. Cytoplasm is accurate; the more specific cytosol term (annotated separately by IBA/TAS) is preferred as the core localization. Retained as an accurate broader-term annotation.
GO:0140378 protein complex scaffold activity	IMP PMID:22081021 Requirement of argininosuccinate lyase for systemic nitric o...	NEW	Summary: Proposed molecular-function statement for ASL's catalysis-independent structural role: it scaffolds a tissue-specific nitric oxide synthase multiprotein complex (with ASS1, SLC7A1 and NOS1/NOS2/NOS3). Catalytically dead but structurally intact human ASL (R236W, R113Q) still supports NOS complex formation, while loss of ASL disrupts the complex, defining a scaffold rather than catalytic function. Reason: GOA captures the downstream process (GO:0045429 positive regulation of nitric oxide biosynthetic process, IMP) but not the underlying molecular function. GO:0140378 protein complex scaffold activity best represents ASL's demonstrated role in holding the NOS complex together independently of its lyase catalysis, and grounds the corresponding core function. Supporting Evidence: PMID:22081021 Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. file:human/ASL/ASL-deep-research-falcon.md forming a metabolon that channels arginine directly to NOS for nitric oxide (NO) production

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the reversible cleavage of L-argininosuccinate to L-arginine and fumarate (EC 4.3.2.1), a step of the cytosolic urea cycle, as an obligate homotetramer with shared active sites.

Regenerates L-arginine from argininosuccinate as the final step of de novo arginine biosynthesis, supplying arginine for downstream pathways in hepatic and non-hepatic tissues.

Provides a catalysis-independent scaffold function that holds together a tissue-specific nitric oxide synthase multiprotein complex (with ASS1, SLC7A1 and NOS1/NOS2/NOS3), channelling arginine to nitric oxide production and thereby positively regulating nitric oxide biosynthesis.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

📄 View Raw YAML