Arginase-1 is a cytosolic, manganese-dependent ureohydrolase that converts L-arginine and water to L-ornithine and urea. This homotrimeric enzyme contains a binuclear manganese cluster in each subunit and catalyzes the terminal step of the hepatic urea cycle, regenerating ornithine for nitrogen disposal. In human granulocytes it is stored in granules and can be released extracellularly, where arginine depletion suppresses T-cell proliferation and cytokine production. Granulocyte ARG1 also contributes to fungicidal activity; arginine depletion within the phagolysosome has been proposed as its antimicrobial mechanism. Loss-of-function variants cause arginase deficiency with hyperargininemia and progressive neurological disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004053 arginase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO) inference of arginase activity, the defining and core molecular function of ARG1. Reason: This is the correct, specific molecular function. Arginase activity (EC 3.5.3.1, L-arginine + H2O = L-ornithine + urea) is directly demonstrated for human ARG1 by crystallographic and enzymatic studies, so the IBA inference is strongly supported. Supporting Evidence: PMID:17562323 Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to yield l-ornithine and urea. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT cytoplasmic-activity assertion is consistent with the established cytosolic catalytic pool. Reason: Human cytosolic arginase activity independently corroborates the inherited is_active_in cytoplasm assertion. The broader compartment contains the same catalytic pool and is retained as core coverage; the cited human study is independent target evidence, not a reconstruction of the PAINT ancestral placement or its topology. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0006525 arginine metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT arginine metabolism includes the direct ARG1 catabolic reaction. Reason: ARG1 itself hydrolyzes L-arginine, so it participates in arginine metabolism through its established catabolic step. This supports the inherited broad process without adding a second activity or claiming that the ancestral PAINT evidence has been reconstructed. Supporting Evidence: PMID:17562323 Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to yield l-ornithine and urea. |
| GO:0042130 negative regulation of T cell proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of an immunoregulatory role in suppressing T-cell proliferation, corroborated by direct experimental evidence in human granulocyte arginase. Reason: Well-supported secondary (myeloid/immune) function. Extracellular arginase released from human granulocytes depletes arginine and suppresses T-cell proliferation. This is a genuine role but distinct from the core hepatic urea-cycle function. Supporting Evidence: PMID:16709924 Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. |
| GO:0000050 urea cycle | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ARG1 participates in the urea cycle; this is a core biological process for the enzyme. Reason: ARG1 catalyzes the terminal step of the urea cycle, regenerating ornithine and releasing urea. This is a core biological process and the IBA inference is strongly supported by direct evidence. Supporting Evidence: PMID:3540966 Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. |
| GO:0030145 manganese ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of manganese ion binding; ARG1 requires a binuclear Mn(2+) cluster for catalysis. Reason: Directly supported by high-resolution crystal structures showing two manganese ions per subunit forming the catalytic binuclear cluster. Core molecular function cofactor requirement. Supporting Evidence: PMID:16141327 The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ARG1 acts in the cytosol; this is the established subcellular location of type I arginase. Reason: Arginase I is a cytosolic enzyme (in contrast to mitochondrial ARG2). This is the core localization where ureagenic arginine hydrolysis occurs. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0004053 arginase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multiple-method) inference of arginase activity, mapped from RHEA:20569/EC:3.5.3.1 and orthology. Reason: Correct and specific molecular function, consistent with the RHEA reaction L-arginine + H2O = L-ornithine + urea and the experimental annotations. Duplicate of the IBA/EXP arginase-activity annotations, which is acceptable. Supporting Evidence: PMID:16141327 we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt location mapping is consistent with human cytosolic ARG1. Reason: This electronic assertion maps a UniProt subcellular-location statement to cytoplasm. Independently read human arginase literature establishes the cytosolic pool, which falls within that compartment. Retain the broad core location while preserving the mapping provenance; the mapping is not described as a microscopy experiment. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0006525 arginine metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro process mapping agrees with direct L-arginine hydrolysis. Reason: The InterPro-derived arginine-metabolism assertion is consistent with the experimentally established reaction converting L-arginine to ornithine and urea. Retain this broader description of the same catabolic work; it is not an additional independent process or a newly validated rule condition. Supporting Evidence: PMID:17562323 Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to yield l-ornithine and urea. |
| GO:0016813 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping (ureohydrolase Mn-binding site) to a broad hydrolase-on-C-N-linear-amidines term. Reason: This is the parent term of the specific and experimentally established arginase activity (GO:0004053). Arginase hydrolyzes the C-N bond of the linear amidine L-arginine, so the term is not wrong, but it is over-general given the precise activity is known. Replace with the specific molecular function. This MF refinement names the established catalytic specificity; the valid broader CC/BP umbrellas elsewhere describe the same location or process coverage and do not create extra core activities. Proposed replacements: arginase activity Supporting Evidence: PMID:21728378 Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: A broad electronic proliferation annotation is compatible with the established secondary T-cell regulatory role. Reason: ARG1-mediated arginine depletion experimentally suppresses human T-cell proliferation. The broad electronic population-proliferation assertion is compatible with this non-core regulatory role; broadness alone does not establish over-annotation. The exact ARBA derivation is not independently reconstructed. Supporting Evidence: PMID:16709924 Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to a generic metal ion binding term. Reason: The specific metal bound is known to be manganese (a binuclear Mn(2+) cluster, two ions per subunit), captured by GO:0030145 (manganese ion binding), which is also annotated. The generic parent should be specialized. This names a directly established cofactor specificity, without treating the broad ion-binding ancestor as a separate core activity. Proposed replacements: manganese ion binding Supporting Evidence: PMID:16141327 The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster |
| GO:0042832 defense response to protozoan | IEA GO_REF:0000107 | UNDECIDED | Summary: Mouse-derived antiprotozoal transfer retained unresolved because its precise donor experiment has not been reconstructed. Reason: The specific Ensembl-Compara antiprotozoal transfer and donor experiment have not been reconstructed. Human neutrophil fungicidal activity does not independently establish a protozoan process. Preserve the source; no target-specific loss is inferred. |
| GO:0046007 negative regulation of activated T cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara orthology transfer from mouse Arg1 of negative regulation of activated T-cell proliferation. Reason: Consistent with the well-documented human function whereby extracellular/granulocyte arginase depletes arginine and suppresses T-cell proliferation. A genuine secondary immunoregulatory role; retained as non-core. Supporting Evidence: PMID:16709924 Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. |
| GO:2000552 negative regulation of T-helper 2 cell cytokine production | IEA GO_REF:0000107 | UNDECIDED | Summary: Mouse-derived Th2 cytokine regulation retained unresolved at the source-transfer level. Reason: The exact Ensembl donor assay/transfer context is unresolved. Independent mouse macrophage literature supports suppression of Th2 cytokines, but the previous ILC2-specific account was not established and general human T-cell suppression does not close this precise transfer. |
| GO:0000050 urea cycle | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway mapping (UPA00158) to the urea cycle. Reason: Correct core biological process. ARG1 performs the terminal step of the urea cycle. Duplicate of the IBA urea-cycle annotation, which is acceptable. Supporting Evidence: PMID:3540966 Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. |
| GO:0070947 neutrophil-mediated killing of fungus | IMP PMID:15546957 Arginase I is constitutively expressed in human granulocytes... | KEEP AS NON CORE | Summary: Experimental (IMP) annotation from the study showing arginase I in azurophil granules participates in fungicidal activity of human neutrophils. Reason: The cited human granulocyte study supports the existing fungicidal role as a secondary function. Its abstract describes phagolysosomal arginine depletion as a likely mechanism, not a directly resolved compartmental reaction. The source annotation is retained without adding a new antimicrobial process. Supporting Evidence: PMID:15546957 arginase I is localized in azurophil granules of neutrophils and constitutes a novel antimicrobial effector pathway, likely through arginine depletion in the phagolysosome |
| GO:0006527 L-arginine catabolic process | IMP PMID:22959135 Analysis of novel ARG1 mutations causing hyperargininemia an... | ACCEPT | Summary: Experimental (IMP) annotation from analysis of ARG1 mutations causing hyperargininemia, correlating loss of arginase activity with impaired L-arginine catabolism. Reason: Core biological process. ARG1 catalyzes the breakdown of L-arginine; loss-of-function mutations cause hyperargininemia (accumulation of arginine), directly demonstrating its role in L-arginine catabolism. The curator assessed erythrocyte enzyme activity across a patient mutation series. Supporting Evidence: PMID:22959135 It is caused by the deficient activity of the enzyme arginase I, encoded by the gene ARG1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9956512 | ACCEPT | Summary: Reactome traceable-author annotation (ARG1 variant reaction) placing ARG1 in the cytosol. Reason: The official Reactome graph places deficient ARG1 variants in a failed cytosolic reaction. The recovered normal cache describes the variants and distinguishes candidates from biochemically characterized members; its narrative does not independently display the compartment field. Retain the curated location with the earlier official graph and independent human cytosolic evidence, without assigning normal catalytic activity to these variants. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0004053 arginase activity | EXP PMID:16141327 Crystal structure of human arginase I at 1.29-A resolution a... | ACCEPT | Summary: Direct experimental evidence of arginase activity from the 1.29-A crystal structure and inhibition study of human arginase I. Reason: Core molecular function established by direct enzymatic assay and structural characterization of catalysis, including inhibition of arginase activity in human myeloid cells. Supporting Evidence: PMID:16141327 we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells |
| GO:0004053 arginase activity | EXP PMID:17562323 Expression, purification, assay, and crystal structure of pe... | ACCEPT | Summary: Direct experimental evidence that (perdeuterated) human arginase I catalyzes hydrolysis of L-arginine to L-ornithine and urea with wild-type activity. Reason: Core molecular function, directly assayed. The enzyme is explicitly characterized as a manganese metalloenzyme catalyzing L-arginine hydrolysis. Supporting Evidence: PMID:17562323 Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to yield l-ornithine and urea. |
| GO:0004053 arginase activity | EXP PMID:21728378 Binding of Ξ±,Ξ±-disubstituted amino acids to arginase suggest... | ACCEPT | Summary: Known human ARG1 activity retained while separating human inhibitor binding and structure from the parasite kinetic assay in this paper. Reason: The human structure and inhibitor-binding assays are distinct from the Plasmodium enzymatic inhibition assay described in the inspected Methods. Human ARG1 arginase activity is well established independently, so retain the experimental assertion without claiming the inspected source measures human reaction kinetics directly. Supporting Evidence: PMID:21728378 Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea |
| GO:0005737 cytoplasm | EXP PMID:16141327 Crystal structure of human arginase I at 1.29-A resolution a... | ACCEPT | Summary: The experimental cytoplasm assertion is retained with independent human cytosolic corroboration. Reason: The accessible abstract of PMID:16141327 establishes human arginase structural and metal-cluster work; a compartment-specific experiment from that source has not been inspected. Retain the original EXP assertion in deference to its curator because the broad location is independently established for human ARG1 by PMID:21728378. That corroborating location statement is not attributed to an inspected localization assay in the original structural paper. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0005515 protein binding | IPI PMID:28813417 CMTM6 maintains the expression of PD-L1 and regulates anti-t... | UNDECIDED | Summary: The original ARG1βCMTM6 interaction assertion is preserved pending its target-specific evidence record. Reason: The source Methods use CMTM6 immunoprecipitation with knockout controls and direct the target list to Extended Data 6c and Supplementary Table 1. The ARG1 target row has not been inspected. The user-supplied session AGENTS.md explicitly requires UNDECIDED when relevant experimental evidence cannot be accessed and reserves REMOVE for an assertion unlikely to be correct. Those criteria take precedence here over the local skill's generic-binding removal default. Genericity and a missing body-text match do not refute this original IPI assertion, and an uninspected co-IP/MS hit does not justify an invented specific replacement function. |
| GO:0005576 extracellular region | IDA PMID:16709924 Suppression of T-cell functions by human granulocyte arginas... | KEEP AS NON CORE | Summary: Direct experimental evidence that arginase I is liberated from human granulocytes and accumulates extracellularly during inflammation. Reason: Genuine, experimentally demonstrated secondary localization. Neutrophil arginase is released into the extracellular space, where it depletes arginine. This is real but peripheral to the core intracellular (cytosolic) hepatic function. Supporting Evidence: PMID:16709924 arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions |
| GO:0042130 negative regulation of T cell proliferation | IDA PMID:16709924 Suppression of T-cell functions by human granulocyte arginas... | KEEP AS NON CORE | Summary: Direct experimental evidence that human granulocyte arginase suppresses T-cell proliferation via arginine depletion. Reason: Well-supported secondary immunoregulatory function. Extracellular arginase depletes arginine, downregulating CD3-zeta and suppressing T-cell proliferation. Genuine but distinct from the core urea-cycle role. Supporting Evidence: PMID:16709924 This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability |
| GO:0060336 negative regulation of type II interferon-mediated signaling pathway | IMP PMID:16709924 Suppression of T-cell functions by human granulocyte arginas... | MODIFY | Summary: The same human T-cell experiment supports reduced IFN-gamma production rather than specifically testing the interferon response pathway. Reason: Original human T-cell Results/Figure 6 and cytokine ELISA/RT-PCR Methods show decreased IFN-gamma protein synthesis without decreased transcripts following arginine depletion by PMN or recombinant human ARG1. This supports negative regulation of type II interferon production; receptor-triggered interferon signaling is a distinct process. Figure 6C measures secreted IFN-gamma after 48 hours; Figure 6D tests transcript levels. The original-body locator and short figure-legend quotation are recorded in the notes. The abstract-only cache supports general cytokine suppression; the IFN-gamma-specific refinement depends on that separately identified original-body passage, not on the abstract alone. Proposed replacements: negative regulation of type II interferon production Supporting Evidence: PMID:16709924 Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. file:human/ARG1/ARG1-notes.md Human PMN arginase suppresses T-cell IFN-Ξ³ synthesis by a posttranscriptional mechanism. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798749 | KEEP AS NON CORE | Summary: Reactome annotation (exocytosis of specific granule lumen proteins) placing ARG1 in the extracellular region upon neutrophil degranulation. Reason: Consistent with the experimentally demonstrated release of neutrophil arginase into the extracellular space during degranulation. A genuine secondary localization, non-core relative to the cytosolic hepatic function. Supporting Evidence: PMID:16709924 arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome annotation (exocytosis of azurophil granule lumen proteins) placing ARG1 in the extracellular region upon neutrophil degranulation. Reason: This exocytosis event places granule-derived protein in the extracellular compartment. Human granulocyte ARG1 release is independently demonstrated by PMID:16709924; retain the secondary localization without treating the event summary as a target-specific experiment. Supporting Evidence: PMID:16709924 arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome annotation placing ARG1 in the azurophil granule lumen of neutrophils. Reason: Directly supported by experimental localization of arginase I to azurophil granules of neutrophils. A genuine myeloid-cell localization, non-core relative to the core cytosolic hepatic function. Supporting Evidence: PMID:15546957 arginase I is localized in azurophil granules of neutrophils and constitutes a novel antimicrobial effector pathway, likely through arginine depletion in the phagolysosome |
| GO:0035580 specific granule lumen | TAS Reactome:R-HSA-6798749 | KEEP AS NON CORE | Summary: Reactome annotation placing ARG1 in the specific granule lumen of neutrophils. Reason: Retain the curated specific-granule compartment as a secondary myeloid localization. The short Reactome summary describes the granule class but does not expose its ARG1-specific inventory; PMID:15546957 independently supports azurophil, not specific, granules. These distinct source scopes are not interchangeable. Supporting Evidence: Reactome:R-HSA-6798749 |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | UNDECIDED | Summary: The sperm-nucleus proteomics assertion remains unresolved because the ARG1-specific protein table has not been inspected. Reason: The abstract explicitly reports highly purified sperm nuclei and microscopy controls. No target-specific ARG1 protein table or contamination analysis was inspected; the prior carryover explanation was unsupported. Nuclear localization does not require a demonstrated nuclear function. Preserve this source pending its target data. Supporting Evidence: PMID:21630459 sperm nuclei were obtained through CTAB treatment and isolated to over 99.9% purity without any tail fragments, acrosome or mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70569 | ACCEPT | Summary: Reactome annotation (arginine + H2O => ornithine + urea reaction) placing ARG1 in the cytosol. Reason: The recovered Reactome summary explicitly identifies the normal ARG1 trimer as a cytosolic catalyst that hydrolyzes arginine to ornithine and urea. This is the established core catalytic pool. Supporting Evidence: Reactome:R-HSA-70569 Cytosolic Arginase 1 (ARG1) trimer catalyzes the hydrolysis of arginine to yield ornithine and urea (DiCostanzo et al. 2005). PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9959871 | ACCEPT | Summary: Reactome annotation (ARG1 gene expression) associated with cytosolic localization. Reason: The earlier inspected official Reactome graph lists cytosolic ARG1 trimer as the protein output of this gene-expression event. The recovered normal cache describes TP53-dependent repression of ARG1 expression and does not itself expose the product compartment field. Retain the established cytosolic product location, not a transcriptional activity performed by ARG1. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0004053 arginase activity | TAS PMID:3540966 Molecular cloning and nucleotide sequence of cDNA for human ... | ACCEPT | Summary: Traceable-author statement of arginase activity from the original cloning of human liver arginase cDNA. Reason: Core molecular function. The cloned cDNA conferred arginase activity on E. coli, and the enzyme is identified as EC 3.5.3.1 catalyzing the last urea-cycle step. Duplicate of the experimental arginase-activity annotations, which is acceptable. Supporting Evidence: PMID:3540966 Arginase activity was detected in Escherichia coli cells transformed with the plasmid carrying lambda hARG6 cDNA insert. |
| GO:0005737 cytoplasm | TAS PMID:3540966 Molecular cloning and nucleotide sequence of cDNA for human ... | ACCEPT | Summary: The cDNA-era cytoplasm assertion agrees with the independently established cytosolic enzyme. Reason: PMID:3540966 reports human arginase cDNA cloning and conferred enzyme activity, not a microscopy assay in the inspected abstract. The original TAS cytoplasm assertion is consistent with the human cytosolic pool independently described in PMID:21728378. Retain that core umbrella without converting cDNA-expression evidence into a directly observed compartment experiment. Supporting Evidence: PMID:21728378 Arginase I is a cytosolic enzyme found predominantly in the liver, and arginase II is a mitochondrial enzyme found at highest concentrations in the kidney. |
| GO:0006527 L-arginine catabolic process | TAS PMID:3540966 Molecular cloning and nucleotide sequence of cDNA for human ... | ACCEPT | Summary: Traceable-author statement of ARG1's role in L-arginine catabolism (the terminal urea-cycle step) from the original cloning paper. Reason: Core biological process. ARG1 hydrolyzes L-arginine as the last step of the urea cycle. Duplicate of the IMP L-arginine catabolic process annotation, which is acceptable. Supporting Evidence: PMID:3540966 Arginase (EC 3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. |
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Download this section (compressed HTML)Q: Which human cellular contexts use ARG1-dependent arginine depletion for immune regulation, and which proposed compartment-specific mechanisms have direct experimental support?
Q: Which ARG1-specific peptides and controls support the sperm-nuclear detection in PMID:21630459, and can an independent localization assay establish that pool?
Q: Which exact mouse donor annotation and infection context underlie the antiprotozoal Ensembl transfer, and does arginine depletion limit the parasite or instead limit host nitric-oxide defense? The donor experiment is needed before assigning that mechanistic polarity.
Experiment: Structure-guided kinetic characterization of clinically observed missense variants (e.g. those affecting the Mn-binding residues or the R308 trimerization interface) to correlate residual arginase activity with argininemia phenotype severity.
Hypothesis: Argininemia severity is determined by residual arginase activity, which depends on how a given missense variant perturbs the Mn-binding active site or the R308 trimerization interface.
Experiment: Quantitative measurement of local arginine depletion and downstream T-cell CD3-zeta levels using ARG1-deficient versus wild-type human neutrophils to dissect the enzymatic basis of the immunosuppressive effect.
Hypothesis: The immunosuppressive effect of neutrophil ARG1 is entirely due to enzymatic depletion of extracellular L-arginine.
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