ADSL

Summary: ADSL catalyses the SAICAR-to-AICAR reaction in de novo purine synthesis.

Reason: PAINT places SAICAR-lyase activity at PTN000154581. Human ADSL biochemical characterization and the curated SAICAR reaction support inheritance of this catalytic function; the target itself is an experimental descendant used by PAINT.

Summary: ADSL cleaves adenylosuccinate to AMP and fumarate.

Reason: The PTN000154581 ancestral assertion agrees with direct kinetic measurements on recombinant human ADSL in PMID:16973378 and PMID:19405474. The conserved catalytic reaction is a core molecular function.

Summary: The functional ADSL tetramer is cytosolic.

Reason: The cytosolic PAINT assertion at PTN000154581 agrees with human immunofluorescence and the compartment of both curated Reactome reactions. Human target evidence among the descendants grounds the inherited localization.

Summary: ADSL performs the adenylosuccinate cleavage step in de novo AMP production.

Reason: The PTN000154581 process inference fits the human reaction: ADSL converts adenylosuccinate, produced from IMP by adenylosuccinate synthetase, to AMP. It therefore catalyses a step of this process.

Summary: Human substrate assays resolve two specific lyase reactions beyond the generic catalytic mapping.

Reason: The InterPro mapping is true at its broad level, but direct human assays in PMID:10888601, together with adenylosuccinate kinetics in PMID:19405474, resolve both adenylosuccinate cleavage and SAICAR cleavage. Replace the uninformative catalytic root with both established substrate-specific functions. This refinement follows the measured chemistry, rather than treating every true ancestor as a non-core activity or discarding one of the two reactions.

Proposed replacements: N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity

Summary: The electronic mapping identifies the adenylosuccinate-to-AMP lyase reaction.

Reason: The curated Rhea reaction RHEA:16853 and recombinant human enzyme kinetics support this exact activity.

Summary: ADSL catalyses reactions in purine ribonucleotide biosynthesis.

Reason: SAICAR cleavage contributes to the shared IMP pathway, and adenylosuccinate cleavage produces AMP. The broader InterPro process annotation accurately covers this catalytic participation.

Summary: The hypoxia-response transfer traces to rat renal purine nucleotide-cycle experiments.

Reason: The rat donor study PMID:8887278 assays cortical and medullary cytosol under simulated low oxygen conditions. Its cached abstract reports increased AMP deamination in both compartments and decreased IMP reamination in cortex; ADSL activity exceeds adenylosuccinate synthetase activity severalfold, and the authors identify synthetase activity and AMP supply as the main limits on cycle activity. These findings specify the measured pathway response but do not establish that the non-limiting ADSL step is unregulated. Full experiments remain unavailable to resolve the ADSL-specific response and its conservation. Human hypoxia-dependent purinosome organization (PMID:32439803) and ADSL-dependent fumarate/STING effects (PMID:40033100) occur in distinct contexts and do not establish the exact rat transfer. Retain the unresolved judgment.

Summary: ADSL directly produces AMP from adenylosuccinate.

Reason: The SAMP-to-AMP reaction establishes participation in AMP biosynthesis, irrespective of whether the IMP precursor originated through de novo synthesis or recycling.

Summary: ADSL performs the shared SAICAR-to-AICAR step that supplies IMP for GMP production.

Reason: GO:0006177 covers reactions and pathways that form GMP; it is not limited to the terminal IMPDH/GMPS branch. The mouse donor is explicitly modeled as a SAICAR-lyase activity upstream of ATIC in GMP GO-CAM 60ad85f700003015. The same reaction is established for human ADSL, supporting conserved participation in the overall pathway without assigning IMP dehydrogenase or GMP synthase activity.

Summary: ADSL converts SAICAR to AICAR within de novo IMP biosynthesis.

Reason: This is an internal reaction of the shared purine-ring synthesis pathway. The UniProt step 2/2 refers to its specified local CAIR-to-AICAR segment, not to the complete IMP biosynthetic pathway.

Summary: The nutrient-response transfer derives from dietary comparisons of rat hepatic ADSL.

Reason: The rat donor annotation cites PMID:7128902, which compares purified hepatic enzyme from chow-fed and low-riboflavin basal-diet rats. Its abstract reports biochemical differences and relates them cautiously to starvation/refeeding. Full experimental details remain unavailable, so the precise nutrient-response inference and its human transfer remain unresolved. The independent rat starvation/refeeding study PMID:690130 supports nutritional regulation but does not resolve every feature of this source.

Summary: Purine-cycle support of respiratory substrates does not establish that ADSL executes aerobic respiration.

Reason: The traced rat donor study PMID:3777158 reports impaired muscle energetics after AICAriboside and interprets the purine nucleotide cycle as an anaplerotic supplier of citric-acid-cycle intermediates. That metabolic connection is credible. GO:0009060, however, denotes energy release coupled to oxygen as terminal electron acceptor, under cellular respiration and energy derivation by oxidation. ADSL cleaves adenylosuccinate to AMP and fumarate in purine metabolism; the supplied fumarate is subsequently used by respiratory enzymes. The source does not place the ADSL purine-cycle reaction within the oxygen-coupled respiratory pathway, rather than supplying intermediates to it. A bona fide pathway participant need not itself catalyze a redox reaction; the distinction here is pathway role, not reaction chemistry alone. Mark the transferred involved_in assertion as over-annotated, without denying the rat energetic phenotype or claiming that the pharmacological study is false. Full source controls remain unavailable, and no replacement regulation term is manufactured.

Summary: Rat muscle-stimulation experiments provide the source context for this response annotation.

Reason: The donor record carries experimental muscle-response evidence. The cached abstract of PMID:3777158 estimates cycle-enzyme activities from muscle metabolite content and reports increased synthetase/lyase activities during moderate stimulation in controls, prevented by AICAriboside. This supports a physiological connection, while the full assay details and precise ADSL-specific response inference remain unavailable. The contextual transfer remains unresolved; the observed stimulation-dependent change is not denied.

Summary: ADSL activity is nutritionally regulated in rat liver and spleen during starvation and refeeding.

Reason: The cached abstract of PMID:690130 reports loss of hepatic and splenic adenylosuccinase activity during prolonged rat starvation and restoration of liver activity after refeeding; kidney, brain and skeletal muscle show no starvation-associated activity change. Retain the existing mammalian response annotation as a tissue-dependent context for purine metabolism, separate from the constitutive catalytic core. The opposite hepatic response reported in chicken constrains species extrapolation.

Summary: ADSL self-association forms the functional homotetramer.

Reason: Human ADSL forms a functional homotetramer in PMID:16973378. PMID:19405474 explains that each catalytic site uses residues from three subunits and links destabilization to loss of activity. Self-association therefore contributes the assembly required for the two core reactions; it is integrated into those enzyme functions rather than split into another core. The broad protein-complex location and this specific self-association function describe compatible aspects of the same active assembly. The rat native/subunit mass measurements in PMID:3689310 corroborate the ortholog transfer.

Summary: ADSL catalyses the final adenylosuccinate cleavage step of AMP synthesis from IMP.

Reason: The UniPathway mapping fits the human SAMP-to-AMP reaction and its place after adenylosuccinate synthetase. This is direct pathway chemistry.

Summary: ADSL converts salvaged IMP-derived adenylosuccinate into AMP.

Reason: The mouse donor GO-CAMs 60897d8500000531 and 60ff660000001341 explicitly route salvaged purines through HPRT and adenylosuccinate synthetase to the ADSL reaction. ADSL performs the final cleavage in that salvage route; AMP salvage is not restricted to APRT or adenosine kinase. Human ADSL recycling activity is described in PMID:10888601, and human/mouse erythrocyte primary evidence in PMID:29079593 identifies the relevant enzymes and distinguishes salvage from altered deamination.

Summary: The electronic mapping identifies the SAICAR-to-AICAR lyase reaction.

Reason: RHEA:23920 describes the established second substrate reaction of human ADSL. Its precise chemistry agrees with the human biochemical literature and the SAICAR reaction in Reactome.

Summary: ADSL contributes the shared SAICAR-to-AICAR reaction to de novo XMP synthesis.

Reason: GO:0097294 encompasses XMP formation from simpler precursors, including the pathway that constructs IMP before IMPDH forms XMP. Mouse GO-CAM 60d5209a00001406 places Adsl in that shared sequence before ATIC and IMPDH. Human ADSL executes the same SAICAR cleavage, supporting the existing process annotation without assigning the terminal IMPDH reaction.

Summary: Human immunofluorescence localizes ADSL to the cytosol.

Reason: The current HPA ADSL page reports enhanced cytosolic localization with antibody HPA000525 in A-431, U-251MG and U2OS cells, with siRNA validation. This directly supports the source compartment and agrees with the cytosolic reactions in Reactome.

Summary: Purified recombinant human ADSL converts SAMP to AMP and fumarate.

Reason: PMID:19405474 Methods measures the loss of SAMP absorbance at 282 nm, and Results/Figure 3/Table 1 quantify wild-type and mutant kinetics in the AMP-forming direction. These are direct assays of the annotated reaction.

Summary: The human SAICAR-lyase activity is represented by the original experimental annotation.

Reason: PMID:27590927 combines recombinant-enzyme substrate preparation with CRISPR-edited HeLa cells and metabolite measurements. The local cache is abstract-only, so it does not expose the exact assay assigned IDA. Accept the established ADSL reaction and defer to the experimental curator; substrate accumulation alone is not described as a purified-enzyme activity assay. Human dual-substrate characterization and the curated reaction independently corroborate the activity.

Summary: Human ADSL is part of a homotetrameric protein complex.

Reason: Analytical ultracentrifugation in PMID:16973378 identifies the approximately 220-kDa tetramer. PMID:19405474 couples oligomeric-state measurements to catalytic activity and shows the severe destabilization/activity defect of K246E. This is the functional enzyme assembly; retain the original broad complex term at the source resolution.

Summary: Human ADSL subunits self-associate into the active tetramer.

Reason: Human ADSL forms a functional homotetramer in PMID:16973378. PMID:19405474 explains that each catalytic site uses residues from three subunits and links destabilization to loss of activity. Self-association therefore contributes the assembly required for the two core reactions; it is integrated into those enzyme functions rather than split into another core. The broad protein-complex location and this specific self-association function describe compatible aspects of the same active assembly.

Summary: The SAICAR-cleaving ADSL tetramer acts in the cytosol.

Reason: The cited Reactome event explicitly places the active tetramer in the cytosol and identifies ADSL as catalyst of SAICAR conversion to AICAR and fumarate.

Summary: The adenylosuccinate-cleaving ADSL tetramer acts in the cytosol.

Reason: The cited Reactome event assigns this compartment to the catalyst of AMP and fumarate production from adenylosuccinate.

Summary: ADSL catalyses purine nucleotide biosynthetic reactions.

Reason: The source characterizes human ADSL isoforms and mutant proteins and explicitly describes de novo purine synthesis and recycling. Production of AICAR and AMP supplies the catalytic basis for the curator-inferred broader process.

Summary: ADSL activity in blood cells contributes to AMP production.

Reason: PMID:11428554 measures ADSL enzyme activity in blood cells and discusses regulation of cellular AMP levels. The independent human enzyme assay in PMID:19405474 directly measures conversion of adenylosuccinate to AMP and fumarate. Together these support the annotated AMP-producing process while preserving the abstract-only access limitation for the original blood-cell source.

Summary: Purified human ADSL directly exhibits adenylosuccinate lyase activity.

Reason: PMID:16973378 expresses the full-length human enzyme in E. coli, purifies tagged and tag-cleaved forms and reports comparable S-AMP kinetic parameters. The expression host does not change the identity of the assayed human enzyme.