ARG2 is a mitochondrial arginase that hydrolyzes L-arginine to L-ornithine and urea using a binuclear manganese center. The enzyme forms a homotrimer and is prominent in extrahepatic tissues. It controls arginine availability and supplies ornithine for pathways including mitochondrial OAT-dependent degradation and polyamine synthesis. Although it catalyzes the same urea-forming reaction as ARG1, its usual roles extend beyond hepatic cyclic ureagenesis. Its immunological and vascular effects depend strongly on cellular context: fetal dendritic-cell ARG2 suppresses T-cell TNF production, whereas endothelial ARG2 can promote nitric-oxide-synthase uncoupling, oxidative stress and senescence. Some vascular signaling effects persist with a catalytically inactive variant and therefore cannot all be attributed to arginine hydrolysis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000050 urea cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ARG2 executes the terminal urea-forming chemistry, with a contextual relationship to the urea cycle. Reason: Retain the pathway association as secondary: ARG2 makes urea and ornithine directly, and curated Reactome describes mitigation of ARG1-deficient urea synthesis. This does not mean its usual extrahepatic mitochondrial role is a complete hepatic urea cycle, or that each tissue expressing ARG2 has all cycle enzymes. The PAINT node is an ancestral assertion, not a pairwise transfer; no reconstruction of its placement is claimed. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Reactome:R-HSA-452036 its function appears to mitigate the effects of ARG1 deficiency on urea synthesis |
| GO:0000050 urea cycle | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: ARG2 executes the terminal urea-forming chemistry, with a contextual relationship to the urea cycle. Reason: Retain the pathway association as secondary: ARG2 makes urea and ornithine directly, and curated Reactome describes mitigation of ARG1-deficient urea synthesis. This does not mean its usual extrahepatic mitochondrial role is a complete hepatic urea cycle, or that each tissue expressing ARG2 has all cycle enzymes. The PAINT node is an ancestral assertion, not a pairwise transfer; no reconstruction of its placement is claimed. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Reactome:R-HSA-452036 its function appears to mitigate the effects of ARG1 deficiency on urea synthesis |
| GO:0001657 ureteric bud development | IEA GO_REF:0000107 | UNDECIDED | Summary: The traced mouse donor evidence is spatial expression in the developing ureteric epithelium. Reason: QuickGO traces O08691 to IEP PMID:16545622, whose abstract explicitly reports Arg2 enrichment in tip epithelium. That establishes developmental expression, but the full paper was not accessible here and a causal human ARG2 role in ureteric bud development was not verified. Retain as unresolved rather than declaring the donor experiment false or upgrading expression to direct developmental execution. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:O08691 SOURCE WEAK OR INFERRED QuickGO donor tracing returns mouse IEP PMID:16545622. The available abstract demonstrates spatial enrichment in ureteric tip epithelium, not a verified human causal developmental function; full text unavailable in this audit. ensembl:ENSMUSP00000021550 UNRESOLVED Additional seeded orthology identifier; no separate experimental source reconstructed. Supporting Evidence: PMID:16545622 We identified genes enriched in the tip epithelium, sim-1, Arg2, Tacstd1, Crlf-1 and BMP7 |
| GO:0002829 negative regulation of type 2 immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the conditional airway immune-regulatory phenotype supported by the mouse ortholog. Reason: PMID:27214549 reports greater Th2 inflammation and elevated IL-13/IL-17 in allergen-challenged Arg2-knockout mice; epithelial human-cell experiments support the metabolic/signaling mechanism. The specific cytokine knockout evidence is mouse, not a direct human ARG2 assay. This is a context-dependent regulatory effect, not the core enzymatic reaction or a universal anti-inflammatory property. Supporting Evidence: PMID:27214549 mice lacking Arg2 had greater Th2 inflammation than WT mice PMID:27214549 higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils |
| GO:0004053 arginase activity | EXP PMID:12859189 Human arginase II: crystal structure and physiological role ... | ACCEPT | Summary: Arginine hydrolysis to ornithine and urea is the defining catalytic activity of human ARG2. Reason: Direct human enzyme structure and activity (PMID:12859189), mutagenesis (PMID:16128822), and curated reaction evidence independently establish EC 3.5.3.1. The N149D substrate-switch mutant in PMID:16128822 does not establish agmatinase activity of the native enzyme. The PAINT assertion is consistent with this target evidence; target self-evidence in the descendant set is legitimate grounding. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0004053 arginase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Arginine hydrolysis to ornithine and urea is the defining catalytic activity of human ARG2. Reason: Direct human enzyme structure and activity (PMID:12859189), mutagenesis (PMID:16128822), and curated reaction evidence independently establish EC 3.5.3.1. The N149D substrate-switch mutant in PMID:16128822 does not establish agmatinase activity of the native enzyme. The PAINT assertion is consistent with this target evidence; target self-evidence in the descendant set is legitimate grounding. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0004053 arginase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Arginine hydrolysis to ornithine and urea is the defining catalytic activity of human ARG2. Reason: Direct human enzyme structure and activity (PMID:12859189), mutagenesis (PMID:16128822), and curated reaction evidence independently establish EC 3.5.3.1. The N149D substrate-switch mutant in PMID:16128822 does not establish agmatinase activity of the native enzyme. The PAINT assertion is consistent with this target evidence; target self-evidence in the descendant set is legitimate grounding. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0004053 arginase activity | IMP PMID:16128822 Insights into the interaction of human arginase II with subs... | ACCEPT | Summary: Arginine hydrolysis to ornithine and urea is the defining catalytic activity of human ARG2. Reason: Direct human enzyme structure and activity (PMID:12859189), mutagenesis (PMID:16128822), and curated reaction evidence independently establish EC 3.5.3.1. The N149D substrate-switch mutant in PMID:16128822 does not establish agmatinase activity of the native enzyme. The PAINT assertion is consistent with this target evidence; target self-evidence in the descendant set is legitimate grounding. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. PMID:16128822 the Asn149Asp mutant expressed almost undetectable activity on arginine, but significant activity on agmatine. |
| GO:0004053 arginase activity | TAS PMID:9144563 Chromosomal localization of the human arginase II gene and t... | ACCEPT | Summary: Arginine hydrolysis to ornithine and urea is the defining catalytic activity of human ARG2. Reason: Direct human enzyme structure and activity (PMID:12859189), mutagenesis (PMID:16128822), and curated reaction evidence independently establish EC 3.5.3.1. The N149D substrate-switch mutant in PMID:16128822 does not establish agmatinase activity of the native enzyme. The PAINT assertion is consistent with this target evidence; target self-evidence in the descendant set is legitimate grounding. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Remove the uninformative bare protein-binding annotation while preserving the reported interaction. Reason: The PMID:32814053 interactome records an ARG2βFOXD4L6 interaction, also curated in UniProt. Under the current binding policy this generic term does not describe a molecular function. No specific regulatory function is inferred solely from the binding result; removal does not dispute the interaction. Supporting Evidence: file:human/ARG2/ARG2-uniprot.txt P78540; Q3SYB3: FOXD4L6; NbExp=3; |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Refine the broad compartment to the mature mitochondrial matrix localization. Reason: Human precursor import and proteolytic processing establish mitochondrial targeting (PMID:8898077). The existing Reactome assertions place mature ARG2 in the matrix, consistent with its soluble imported enzyme role. Refine the broader cytoplasmic/mitochondrial term to that already present compartment; do not equate the original HPA or proteomics assay with a submitochondrial-resolution experiment, or exclude context-dependent relocalization. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000144386 UNRESOLVED Seeded PAINT ancestral node records the broad claim. Independent target evidence supports the more precise term; the tree, MSA and exact historical node placement were not reconstructed, and this is not a claim that the ancestor annotation is false. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Mitochondrial residence is a supported core localization. Reason: Import and proteolytic processing of the human precursor directly establish mitochondrial targeting (PMID:8898077). The organelle assignment is informative and remains supported independently of the separately annotated matrix location. Retention does not claim that every imaging or proteomics assay resolves the matrix or excludes context-dependent relocalization. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial residence is a supported core localization. Reason: Import and proteolytic processing of the human precursor directly establish mitochondrial targeting (PMID:8898077). The organelle assignment is informative and remains supported independently of the separately annotated matrix location. Retention does not claim that every imaging or proteomics assay resolves the matrix or excludes context-dependent relocalization. The inherited organelle claim agrees with independent target evidence; no ancestral-node placement defect is established or inferred from its breadth. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Mitochondrial residence is a supported core localization. Reason: Import and proteolytic processing of the human precursor directly establish mitochondrial targeting (PMID:8898077). The organelle assignment is informative and remains supported independently of the separately annotated matrix location. Retention does not claim that every imaging or proteomics assay resolves the matrix or excludes context-dependent relocalization. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial residence is a supported core localization. Reason: Import and proteolytic processing of the human precursor directly establish mitochondrial targeting (PMID:8898077). The organelle assignment is informative and remains supported independently of the separately annotated matrix location. Retention does not claim that every imaging or proteomics assay resolves the matrix or excludes context-dependent relocalization. Independent target localization supports the transferred organelle claim without treating the computational row as a new direct experiment. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005739 mitochondrion | TAS PMID:8898077 Molecular cloning of cDNA for nonhepatic mitochondrial argin... | ACCEPT | Summary: Mitochondrial residence is a supported core localization. Reason: Import and proteolytic processing of the human precursor directly establish mitochondrial targeting (PMID:8898077). The organelle assignment is informative and remains supported independently of the separately annotated matrix location. Retention does not claim that every imaging or proteomics assay resolves the matrix or excludes context-dependent relocalization. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-452036 | ACCEPT | Summary: Retain matrix ARG2 as the mature enzyme compartment. Reason: The curated Reactome annotation is consistent with human mitochondrial import and processing (PMID:8898077). The catalytic reaction record and mitochondrial proteostasis records have different purposes: ARG2 is a substrate in the latter, not a protease or an executor of its own degradation. Their summaries alone do not constitute independent ARG2 topology experiments; the source-level compartment assignment is retained conservatively. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Retain matrix ARG2 as the mature enzyme compartment. Reason: The curated Reactome annotation is consistent with human mitochondrial import and processing (PMID:8898077). The catalytic reaction record and mitochondrial proteostasis records have different purposes: ARG2 is a substrate in the latter, not a protease or an executor of its own degradation. Their summaries alone do not constitute independent ARG2 topology experiments; the source-level compartment assignment is retained conservatively. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Retain matrix ARG2 as the mature enzyme compartment. Reason: The curated Reactome annotation is consistent with human mitochondrial import and processing (PMID:8898077). The catalytic reaction record and mitochondrial proteostasis records have different purposes: ARG2 is a substrate in the latter, not a protease or an executor of its own degradation. Their summaries alone do not constitute independent ARG2 topology experiments; the source-level compartment assignment is retained conservatively. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Retain matrix ARG2 as the mature enzyme compartment. Reason: The curated Reactome annotation is consistent with human mitochondrial import and processing (PMID:8898077). The catalytic reaction record and mitochondrial proteostasis records have different purposes: ARG2 is a substrate in the latter, not a protease or an executor of its own degradation. Their summaries alone do not constitute independent ARG2 topology experiments; the source-level compartment assignment is retained conservatively. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Retain matrix ARG2 as the mature enzyme compartment. Reason: The curated Reactome annotation is consistent with human mitochondrial import and processing (PMID:8898077). The catalytic reaction record and mitochondrial proteostasis records have different purposes: ARG2 is a substrate in the latter, not a protease or an executor of its own degradation. Their summaries alone do not constitute independent ARG2 topology experiments; the source-level compartment assignment is retained conservatively. Supporting Evidence: PMID:8898077 The arginase II precursor synthesized in vitro was imported into isolated mitochondria and proteolytically processed. |
| GO:0006525 arginine metabolic process | IBA GO_REF:0000033 | MODIFY | Summary: Refine general arginine metabolism to the directly catalyzed catabolic step. Reason: Human ARG2 hydrolyzes arginine to ornithine and urea. The catabolic descendant GO:0006527 captures this chemistry more precisely; ornithine can subsequently enter several metabolic routes, so no unique downstream fate is implied. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000144386 UNRESOLVED Seeded PAINT ancestral node records the broad claim. Independent target evidence supports the more precise term; the tree, MSA and exact historical node placement were not reconstructed, and this is not a claim that the ancestor annotation is false. Proposed replacements: L-arginine catabolic process Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0006525 arginine metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: Refine general arginine metabolism to the directly catalyzed catabolic step. Reason: Human ARG2 hydrolyzes arginine to ornithine and urea. The catabolic descendant GO:0006527 captures this chemistry more precisely; ornithine can subsequently enter several metabolic routes, so no unique downstream fate is implied. Proposed replacements: L-arginine catabolic process Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0006809 nitric oxide biosynthetic process | TAS PMID:8898077 Molecular cloning of cDNA for nonhepatic mitochondrial argin... | MODIFY | Summary: ARG2 regulates nitric oxide formation through substrate availability rather than synthesizing nitric oxide. Reason: The original PMID:8898077 explicitly proposes down-regulation and reports mitochondrial import; its RAW264.7 coinduction result is mouse and is not an assay of human NO synthesis. Human endothelial knockdown/overexpression in PMID:22928666 supports an inhibitory effect on coupled eNOS/NO availability in that context. Replace direct NO biosynthesis with the negative regulatory process; this is not a universal direction across every cell type. Proposed replacements: negative regulation of nitric oxide biosynthetic process Supporting Evidence: PMID:8898077 Arginase II has been proposed to play a role in down-regulation of nitric oxide synthesis. PMID:22928666 Silencing Arg-II in senescent cells suppresses eNOS-uncoupling |
| GO:0016813 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines | IEA GO_REF:0000002 | MODIFY | Summary: Refine amidine-bond hydrolase activity to arginase activity. Reason: The broader hydrolase chemistry is true, but direct human substrate and product evidence supports the already asserted arginase activity. Proposed replacements: arginase activity Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. |
| GO:0030145 manganese ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Human ARG2 binds catalytic manganese ions. Reason: The directly determined human structure and curated cofactor record support a binuclear Mn center per subunit. This is a catalytic cofactor property, not nonspecific metal association. Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. file:human/ARG2/ARG2-uniprot.txt Note=Binds 2 manganese ions per subunit. |
| GO:0032651 regulation of interleukin-1 beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain context-dependent regulation of interleukin-1 beta production. Reason: In the H. pylori mouse model, Arg2 deletion increases gastric M1 markers including Il-1Ξ², with dependence on Nos2 genotype for this subset of markers. Retain the broad regulatory term as a conditional ortholog-supported effect; the study is not a direct human cytokine perturbation assay and does not establish a universal anti-inflammatory sign. Supporting Evidence: PMID:27074721 Arg2β/β mice had significantly enhanced mRNA levels of the M1 markers |
| GO:0032696 negative regulation of interleukin-13 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the conditional airway immune-regulatory phenotype supported by the mouse ortholog. Reason: PMID:27214549 reports greater Th2 inflammation and elevated IL-13/IL-17 in allergen-challenged Arg2-knockout mice; epithelial human-cell experiments support the metabolic/signaling mechanism. The specific cytokine knockout evidence is mouse, not a direct human ARG2 assay. This is a context-dependent regulatory effect, not the core enzymatic reaction or a universal anti-inflammatory property. Supporting Evidence: PMID:27214549 mice lacking Arg2 had greater Th2 inflammation than WT mice PMID:27214549 higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils |
| GO:0032700 negative regulation of interleukin-17 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the conditional airway immune-regulatory phenotype supported by the mouse ortholog. Reason: PMID:27214549 reports greater Th2 inflammation and elevated IL-13/IL-17 in allergen-challenged Arg2-knockout mice; epithelial human-cell experiments support the metabolic/signaling mechanism. The specific cytokine knockout evidence is mouse, not a direct human ARG2 assay. This is a context-dependent regulatory effect, not the core enzymatic reaction or a universal anti-inflammatory property. Supporting Evidence: PMID:27214549 mice lacking Arg2 had greater Th2 inflammation than WT mice PMID:27214549 higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils |
| GO:0032720 negative regulation of tumor necrosis factor production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Fetal human dendritic-cell ARG2 suppresses T-cell TNF production. Reason: PMID:28614294 directly tests human fetal dendritic-cell/T-cell co-cultures: arginine replenishment and arginase inhibitors restore TNF. Retain all three assertions consistently because the target claim is supported independently of propagation. This fetal immune-tolerance context does not imply that ARG2 reduces TNF or inflammation in every cell type. Supporting Evidence: PMID:28614294 the reduced TNF-Ξ± production was mediated through arginase-2 activity. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fetal human dendritic-cell ARG2 suppresses T-cell TNF production. Reason: PMID:28614294 directly tests human fetal dendritic-cell/T-cell co-cultures: arginine replenishment and arginase inhibitors restore TNF. Retain all three assertions consistently because the target claim is supported independently of propagation. This fetal immune-tolerance context does not imply that ARG2 reduces TNF or inflammation in every cell type. Supporting Evidence: PMID:28614294 the reduced TNF-Ξ± production was mediated through arginase-2 activity. |
| GO:0032720 negative regulation of tumor necrosis factor production | IMP PMID:28614294 Human fetal dendritic cells promote prenatal T-cell immune s... | KEEP AS NON CORE | Summary: Fetal human dendritic-cell ARG2 suppresses T-cell TNF production. Reason: PMID:28614294 directly tests human fetal dendritic-cell/T-cell co-cultures: arginine replenishment and arginase inhibitors restore TNF. Retain all three assertions consistently because the target claim is supported independently of propagation. This fetal immune-tolerance context does not imply that ARG2 reduces TNF or inflammation in every cell type. Supporting Evidence: PMID:28614294 the reduced TNF-Ξ± production was mediated through arginase-2 activity. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: Refine generic metal binding to catalytic manganese binding. Reason: The human structure identifies manganese rather than an unspecified metal; the precise manganese-binding term is already asserted. Proposed replacements: manganese ion binding Supporting Evidence: PMID:12859189 Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. file:human/ARG2/ARG2-uniprot.txt Note=Binds 2 manganese ions per subunit. |
| GO:0051241 negative regulation of multicellular organismal process | IEA GO_REF:0000117 | MODIFY | Summary: Refine the broad negative regulation of a multicellular process to the supported immune processes. Reason: The ARBA parent is too broad to identify the biology. Conditional airway type-2 immune restraint and extracellular arginine-dependent inhibition of CD4 T-cell proliferation are independently supported by ortholog studies; use these existing, more specific regulatory terms without assigning them as core catalysis. Proposed replacements: negative regulation of type 2 immune response negative regulation of CD4-positive, alpha-beta T cell proliferation Supporting Evidence: PMID:27214549 mice lacking Arg2 had greater Th2 inflammation than WT mice PMID:25009204 Arg2-mediated arginine depletion in the extracellular milieu impairs T cell proliferation |
| GO:0071641 negative regulation of macrophage inflammatory protein 1 alpha production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the infection-context negative regulation of the specified chemokine. Reason: PMID:27074721 measures increased CCL3, CCL4 and CCL5 protein in H. pylori-infected Arg2-deficient mouse gastric tissue, including the Nos2 double-knockout comparison. This supports the transferred regulatory direction as a conditional ortholog inference. It is neither direct human experimental evidence nor the core catalytic role. Supporting Evidence: PMID:27074721 Arg2β/β and Arg2β/β;Nos2β/β mice had significantly increased protein levels of CβC chemokine ligand (CCL) 3 (MIP-1Ξ±), CCL4 (MIP-1Ξ²), and CCL5 (RANTES) |
| GO:0071644 negative regulation of chemokine (C-C motif) ligand 4 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the infection-context negative regulation of the specified chemokine. Reason: PMID:27074721 measures increased CCL3, CCL4 and CCL5 protein in H. pylori-infected Arg2-deficient mouse gastric tissue, including the Nos2 double-knockout comparison. This supports the transferred regulatory direction as a conditional ortholog inference. It is neither direct human experimental evidence nor the core catalytic role. Supporting Evidence: PMID:27074721 Arg2β/β and Arg2β/β;Nos2β/β mice had significantly increased protein levels of CβC chemokine ligand (CCL) 3 (MIP-1Ξ±), CCL4 (MIP-1Ξ²), and CCL5 (RANTES) |
| GO:0071650 negative regulation of chemokine (C-C motif) ligand 5 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the infection-context negative regulation of the specified chemokine. Reason: PMID:27074721 measures increased CCL3, CCL4 and CCL5 protein in H. pylori-infected Arg2-deficient mouse gastric tissue, including the Nos2 double-knockout comparison. This supports the transferred regulatory direction as a conditional ortholog inference. It is neither direct human experimental evidence nor the core catalytic role. Supporting Evidence: PMID:27074721 Arg2β/β and Arg2β/β;Nos2β/β mice had significantly increased protein levels of CβC chemokine ligand (CCL) 3 (MIP-1Ξ±), CCL4 (MIP-1Ξ²), and CCL5 (RANTES) |
| GO:1900425 negative regulation of defense response to bacterium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ARG2 can restrain antibacterial defense in the H. pylori infection context. Reason: The mouse deletion/complementary Nos2-genotype study supports enhanced host inflammation and reduced bacterial persistence on Arg2 loss. Retain the ortholog-supported negative regulatory process as contextual. Do not generalize to every bacterium, immune lineage or human infection. Supporting Evidence: PMID:27074721 Arg2β/β;Nos2β/β mice did not lose the reduced colonization of Arg2β/β mice |
| GO:1903426 regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ARG2 modulates cellular ROS production in vascular contexts. Reason: Human endothelial knockdown/overexpression links ARG2 to eNOS uncoupling, and human vascular smooth-muscle experiments support mitochondrial oxidative effects. These are context-dependent secondary signaling effects; PMID:23832324 also finds effects of inactive H160F, so all ROS phenotypes cannot be reduced to arginine hydrolysis. Supporting Evidence: PMID:22928666 Silencing Arg-II in senescent cells suppresses eNOS-uncoupling PMID:23832324 overexpressing wild-type Arg-II or an l-arginine ureahydrolase inactive Arg-II mutant (H160F) caused similar effects on mitochondrial dysfunction, cell apoptosis, and senescence |
| GO:1905403 negative regulation of activated CD8-positive, alpha-beta T cell apoptotic process | IEA GO_REF:0000107 | MODIFY | Summary: Correct the regulatory sign inherited from the mouse annotation. Reason: QuickGO traces the mouse O08691 donor to IMP PMID:27745970. Full-text Fig. 5B/C shows activated Arg2-knockout CD4 and CD8 cells surviving longer after IL-2 withdrawal (Annexin V viability assay), and Fig. 5D shows enhanced persistence of antigen-specific knockout CD8 cells in vivo. Thus ARG2 decreases survival rather than inhibiting the apoptotic process; the transferred negative sign reverses the measured effect. Propose the positive sibling as a contextual mouse-to-human inference, corroborated by the conserved T-cell effects in PMID:31751318; do not present it as a direct human CD8 apoptosis assay. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION Sources checked: UniProtKB:O08691 SOURCE BAD Mouse IMP GO:1905403 traces to PMID:27745970 in QuickGO. Full-text Fig5 shows improved survival after Arg2 deletion, opposite to the annotated inhibitory sign. The source protein identity is correct; the phenotype direction is not. ensembl:ENSMUSP00000021550 UNRESOLVED Additional seeded donor identifier retained; no separate experimental source was reconstructed for this identifier. Proposed replacements: positive regulation of activated CD8-positive, alpha-beta T cell apoptotic process Supporting Evidence: PMID:27745970 they survived significantly longer than wild-type TΒ cells after IL-2 withdrawal PMID:27745970 Cell viability was measured two days after IL-2 withdrawal by Annexin V staining. |
| GO:2000562 negative regulation of CD4-positive, alpha-beta T cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Extrinsic ARG2-mediated arginine depletion can inhibit T-cell proliferation. Reason: PMID:25009204 tests deregulated Arg2 in mouse dendritic cells and links extracellular arginine depletion to impaired antigen-specific T-cell proliferation. Retain the mouse-to-human regulatory inference with this cellular context. It must not be conflated with T-cell-intrinsic ARG2: PMID:27745970 reports that inhibition/deletion in T cells did not alter proliferation under its conditions. Supporting Evidence: PMID:25009204 Arg2-mediated arginine depletion in the extracellular milieu impairs T cell proliferation PMID:27745970 inhibition of arginases in human TΒ cells or deletion of ARG2 in mouse TΒ cells did not affect cell proliferation |
| GO:2000774 positive regulation of cellular senescence | IDA PMID:22928666 Positive crosstalk between arginase-II and S6K1 in vascular ... | KEEP AS NON CORE | Summary: Human endothelial ARG2 promotes cellular senescence under the tested conditions. Reason: The original human endothelial study uses silencing and overexpression to connect ARG2 to senescence markers and eNOS uncoupling. This is a supported vascular phenotype but is secondary to the conserved metabolic activity and context dependent; catalytic and noncatalytic effects should be distinguished. Supporting Evidence: PMID:22928666 overexpressing Arg-II in nonsenescent cells promotes eNOS-uncoupling, endothelial senescence |
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Download this section (compressed HTML)Q: Which human tissues show quantitatively important ARG2-to-OAT-to-ALDH4A1 flux, and how does this compete with ornithine export and polyamine synthesis?
Q: Does human ARG2 have a causal ureteric bud developmental function beyond the spatial expression reported for mouse Arg2?
Q: Which ARG2 immune and vascular phenotypes require arginine hydrolysis, and which persist through separable protein-dependent signaling mechanisms?
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