Differential expression of the two human arginase genes in hyperargininemia. Enzymatic, pathologic, and molecular analysis.

Grody, Wayne W.; Argyle, Craig; Kern, Rita M.; Dizikes, George J.; Spector, Elaine; Strickland, Alan D.; Klein, Deborah; Cederbaum, Stephen D.

doi:10.1172/jci113923

Cited by 51 publications

(28 citation statements)

References 29 publications

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“…1). This is c, resistent with the observations of others [22,23] who have rL'ported that arginase isoenzymes can be distinguished mainly by immunological methods.…”

Section: Effect Of Nitrite On Argandase Activitymentioning

confidence: 75%

The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase

et al. 1996

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Macrophages contain arginase and an inducible NO synthase, demonstrated by using L-arginine, the common substrate, for production of both nitric oxide and urea. Arginase was inhibited by nitrite, the stable end product of NO. This inhibition was non-competitive, and could not be explained by the reaction of nitrite with arginine, or by the irreversible covalent modification of arginase, or by the removal of Mn 2+, a cofactor of arginase.

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“…1). This is c, resistent with the observations of others [22,23] who have rL'ported that arginase isoenzymes can be distinguished mainly by immunological methods.…”

Section: Effect Of Nitrite On Argandase Activitymentioning

confidence: 75%

The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase

et al. 1996

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“…However, consistent with previously published papers demonstrating that arginase II activity may be modulated by a number of factors, including urea and arginine, we did not observe a correlation between arginase activity and absolute arginase intracellular concentration (P 5 .29) (supplemental Figure 1D). 18,19 In comparison, the arginase activity of monocytes and neutrophils from healthy donors was significantly lower (median of 0 and 0.61 mU of arginase/1 3 10 6 cells, respectively; supplemental Figure 1C), illustrating that AML blasts have significant arginase activity.…”

Section: Aml Blasts Suppress T-cell Proliferation Via Arginase II Andmentioning

confidence: 94%

Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Mussai

Santo

Abu-Dayyeh

et al. 2013

Blood

275

277

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Key Points• AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells.• AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic-severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34 1 progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through smallmolecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis. (Blood. 2013;122(5):749-758)

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“…Arginase is unique among the urea-cycle enzymes in that two distinct isoenzymes exist. Thus inherited defects in the hepatic (type I) arginase are partially compensated for by elevated expression of type II arginase in kidney [209,210], resulting in a less severe clinical disorder [130]. As Mn# + can allosterically activate hepatic arginase in a pHsensitive fashion, it has been suggested that pH-dependent regulation of arginase activity may contribute to the pHdependence of hepatic urea production [211].…”

Section: Arginase and Ureagenesismentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,446

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Differential expression of the two human arginase genes in hyperargininemia. Enzymatic, pathologic, and molecular analysis.

Abstract: Previous studies in our laboratory and others have demonstrated in humans and other mammals two isozymes of arginase

Cited by 51 publications

References 29 publications

The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase

The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase

Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Arginine metabolism: nitric oxide and beyond

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