Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-L-arginine as an intermediate

Klatt, Peter; Schmidt, Kurt; Uray, Georg; Mayer, Bernd

doi:10.1016/s0021-9258(18)82401-2

Cited by 245 publications

(69 citation statements)

References 53 publications

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“…These NOS isoenzymes consist of two constitutive enzymes in neuronal and endothelial tissue, and an inducible NOS (iNOS) that releases large amounts of NO into the surrounding tissue during cytokine-triggered inflammatory processes [1][2][3][4][5][6]. All three NOS isoforms are homodimeric proteins dependent on NADPH, reduced flavins, haem-bound iron, and 6(R)-5,6,7,8-tetrahydrobiopterin as essential cofactors [7,8]. Among the different roles mediated by NO, it has become clear that NO affects the regulation of an increasing number of genes [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

Frank¹,

Kämpfer²,

Kaufmann³

et al. 2000

Biochem. J.

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Recent studies have demonstrated an induction of expression of inducible nitric oxide synthase that is associated with several inflammatory diseases of the skin. To define the mechanisms of action of nitric oxide (NO) in the skin, we attempted to identify genes that are regulated by NO in keratinocytes. Using the human keratinocyte cell line HaCaT as a model system, we identified a Cu/Zn superoxide dismutase (SOD) that was strongly induced by high concentrations (500 microM) of NO-donating agents ¿S-nitrosoglutathione, sodium nitroprusside and (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2 -diolate (DETA-NO)¿, but not by serum or by single recombinant growth factors and inflammatory cytokines or by treatment with superoxide anions. Furthermore, endogenously produced NO increased the expression of Cu/Zn SOD mRNA in keratinocytes. Moreover, treatment of HaCaT cells with NO was associated with a biphasic effect on cell proliferation, because low doses (100 microM) of different NO donors (S-nitrosoglutathione and DETA-NO) mediated a proliferative signal to the cells, whereas high concentrations (500 microM) were cytostatic. To determine a possible correlation between the close regulation of Cu/Zn SOD expression and proliferation by NO in keratinocytes, we established a cell line (psp1CZ1N) carrying a human Cu/Zn SOD cDNA under the control of a ponasterone-inducible promoter construct. Ponasterone-induced overexpression of Cu/Zn SOD caused a cytostatic effect in proliferating psp1CZ1N cells. We therefore suggest that the up-regulation of Cu/Zn SOD expression by NO establishes an inhibitory mechanism on keratinocyte proliferation.

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Section: Introductionmentioning

confidence: 99%

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

Frank¹,

Kämpfer²,

Kaufmann³

et al. 2000

Biochem. J.

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“…NOS isoforms catalyze the NADPH-dependent oxidation of arginine to NO plus citrulline arginine NOS ≤≤= NOHA NOS ≤≤= NO ϩ citrulline (1) where NOHA is the principal intermediate in the reaction (21,27,38,40). Although in vitro experiments with purified NOS indicated that NOHA might be a fleeting or transient intermediate in the catalytic conversion of arginine to NO plus citrulline (21,38,40), cell culture experiments indicated clearly that NOHA can accumulate in the cell culture medium up to 20-30% of the NO and citrulline generated (5,18). These observations indicated that NOHA may not only serve as an intermediate in the production of NO but may also play a role as a distinct biological mediator in its own right.…”

mentioning

confidence: 99%

N^G-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms

Buga

Liu

Bauer

et al. 1998

American Journal of Physiology-Regulatory, Integrative and Comp

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The objective of this study was to elucidate the role and mechanism of nitric oxide (NO) synthase (NOS) in modulating the growth of the Caco-2 human colon carcinoma cell line. The two novel observations reported here are, first, that N G-hydroxy-l-arginine (NOHA) inhibits Caco-2 tumor cell proliferation, likely by inhibiting arginase activity, and, second, that NO causes cytostasis by mechanisms that might involve inhibition of ornithine decarboxylase (ODC) activity. Both arginase and ODC are enzymes involved in the conversion of arginine to polyamines required for cell proliferation. Cell growth was monitored by cell count, cell protein analysis, and DNA synthesis. NOHA (1–30 μM) and NO in the form of DETA/NO (1–30 μM) inhibited cell proliferation by 30–85%. The cytostatic effect of NOHA was prevented by addition of excess ornithine, putrescine, spermidine, or spermine to cell cultures, whereas the cytostatic effect of NO (DETA/NO) and α-difluoromethylornithine (ODC inhibitor) was unaffected by ornithine but was prevented by putrescine, spermidine, or spermine. The cytostatic effect of NOHA appeared to be independent of its conversion to NO, and the effect of NO appeared to be independent of cGMP. NOHA inhibited urea production by Caco-2 cells and inhibited arginase catalytic activity (85% at 3 μM), whereas NO (DEA/NO and SNAP) inhibited ODC activity (≥60% at 30 μM) without affecting arginase activity. Coculture of Caco-2 cells with lipopolysaccharide/cytokine-activated rat aortic endothelial cells markedly slowed Caco-2 cell proliferation, and this was blocked by NOS inhibitors. These observations that NOHA and NO may inhibit sequential steps in the arginine-polyamine pathway suggest a novel biological role for NOS in the inhibition of cell proliferation of certain tumor cells and possibly other cell types.

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“…J Invest Dermatol 111: [1058][1059][1060][1061][1062][1063][1064]1998 be induced in a broad variety of cells by stimulation with cytokines, leading to release of NO into the surrounding tissue (Knowles and Moncada, 1994;Nathan and Xie, 1994;Kro ¨ncke et al, 1995). All three NOS isoforms are homodimeric proteins that depend on NADPH, reduced flavins, heme-bound iron, and (6R) 5,6,7,8-tetrahydrobiopterin (6-BH 4 ) as essential cofactors (Baek et al, 1993;Klatt et al, 1993). The enzymatic activity of the constitutively expressed NOS isoforms is strongly dependent on Ca 2ϩ and calmodulin, whereas iNOS is Ca 2ϩ independent and regulated at the transcriptional level.…”

mentioning

confidence: 99%

Induction of Inducible Nitric Oxide Synthase and its Corresponding Tetrahydrobiopterin-Cofactor-Synthesizing Enzyme GTP-Cyclohydrolase I During Cutaneous Wound Repair

Frank

Madlener

Pfeilschifter

et al. 1998

Journal of Investigative Dermatology

108

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Recent work has suggested a possible role of nitric oxide, a free radical gas, during the wound healing process. In this study we investigated the regulation of inducible nitric oxide synthase (iNOS) and GTP-cyclohydrolase I (GTP-CH I), the rate-limiting enzyme in the biosynthesis of the iNOS cofactor (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4), during the repair process. We found a similar time course of induction of iNOS and GTP-CH I expression, whereas absolute expression levels were different for both genes. Immunohistochemical analysis revealed colocalization of iNOS and GTP-CH I proteins in the wound. Systemic treatment with glucocorticoids significantly altered the expression levels of iNOS and GTP-CH I. Expression of iNOS and GTP-CH I was suppressed by glucocorticoids in normal, and to a much greater extent in wounded skin. Furthermore, a role of nitric oxide as a novel mediator of gene regulation during healing is suggested by the demonstration of nitric oxide-mediated induction of vascular endothelial growth factor expression in keratinocytes. These findings may provide an explanation for the beneficial effects of orally supplemented L-arginine on wound healing, and suggest that a disturbed induction of iNOS and GTP-CH I expression may at least partially underlie the wound healing defect seen in glucocorticoid-treated animals.

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Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-L-arginine as an intermediate

Cited by 245 publications

References 53 publications

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

N^G-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms

Induction of Inducible Nitric Oxide Synthase and its Corresponding Tetrahydrobiopterin-Cofactor-Synthesizing Enzyme GTP-Cyclohydrolase I During Cutaneous Wound Repair

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Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-L-arginine as an intermediate

Cited by 245 publications

References 53 publications

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation

NG-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms

Induction of Inducible Nitric Oxide Synthase and its Corresponding Tetrahydrobiopterin-Cofactor-Synthesizing Enzyme GTP-Cyclohydrolase I During Cutaneous Wound Repair

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N^G-hydroxy-l-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms