N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.

Stuehr, Dennis J.; Kwon, Nyoun Soo; Nathan, Carl; Griffith, Owen W.; Feldman, Paul L.; Wiseman, Jeffrey S.

doi:10.1016/s0021-9258(18)38112-2

Cited by 531 publications

(169 citation statements)

References 40 publications

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“…The subsequent conversion of L-NHA to products is proposed to involve reaction of O 2 with ferrous heme and the abstraction of H • from L-NHA. The stoichiometries for NADPH [35] are consistent with the donation of two electrons from NADPH in the first step and one electron in the second step.…”

Section: Figuresupporting

confidence: 59%

A new decoration for nitric oxide synthase – a Zn(Cys)4 site

Ludwig

Marletta

1999

Structure

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Intense interest in the action and synthesis of nitric oxide has fueled structural studies of nitric oxide synthase (NOS). The monomeric and dimeric heme domains of inducible NOS were the first NOS structures to be described. A recent independent analysis of the corresponding heme domains from endothelial NOS confirms most of the features found earlier and also reveals a novel Zn(Cys)4 center - a new feature for NOS.

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Section: Figuresupporting

confidence: 59%

A new decoration for nitric oxide synthase – a Zn(Cys)4 site

Ludwig

Marletta

1999

Structure

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“…Oxidation of Hydroxyurea to Nitrite~Nitrate. Hydroxyurea resembles the N-hydroxyguanidine group of N~~ arginine, an intermediate in NO production by macrophage NO synthase (35). This prompted us to consider that hydroxyurea might generate NO within cells.…”

Section: Dependence Of Inhibition Of Rr On Amount Of Macrophage Cytosol and On Macrophage Activation When Ilk Wasmentioning

confidence: 99%

Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide.

Kwon

Stuehr

Nathan

1991

The Journal of Experimental Medicine

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407

154

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SummaryMacrophage-derived nitric oxide (NO) is cytostatic to tumor cells and microbial pathogens. We tested whether one molecular target for the cytostatic action of NO may be ribonucleotide reductase (RR), a rate-limiting enzyme in DNA synthesis. In a concentration-dependent manner, NO gas and lysates of activated macrophages that generated comparable amounts of NO led to the same degree of inhibition of partially purified RR from L1210 mouse lymphoma cells. Lysates from nonactivated macrophages, which do not produce NO, were noninhibitory. With lysates from activated macrophages, RR was protected by omitting t-arginine or by adding the NO synthase inhibitors diphenyleneiodonium, N'~-methyl+arginine, or N'~-amino+arginine. t-Arginine, but not D-arginine, abolished the protective effect of N'~ The prototypic pharmacologic inhibitor of IkR is hydroxyurea. Its structural resemblance to N '~-hydroxy-t-arginine, a reaction intermediate of NO synthase, prompted us to test if hydroxyurea can generate NO. In the presence of H202 and CuSO4, hydroxyurea produced NO2-/NO3-, aerobic reaction products of NO. Addition of morpholine blocked NO2-/NO3-generation from hydroxyurea and led to formation of nitrosomorpholine, as detected by gas chromatography/mass spectrometry. Thus, hydroxyurea can produce an NO-like, nitrosating reactant. L1210 cell DNA synthesis was inhibited completely by activated macrophages or by hydroxyurea, and was partially restored to the same degree in both settings by providing deoxyribonucleosides to bypass the block in RR. Thus, both NO gas and NO generated by activated macrophage lysates inhibit tumor cell RR. The RR inhibitor hydroxyurea can also generate an NO-like species. Similar, partial restoration of tumor cell DNA synthesis by deoxyribonucleosides in the presence of activated macrophages or hydroxyurea suggests that cytostasis by activated macrophages and by hydroxyurea has comparable mechanisms, including, but probably not limited to, inhibition of RR.

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“…NOS II catalyzes the conversion of l -arginine into NO and citrulline in two steps. In the first one, arginine is hydroxylated to Nhydroxy-l -arginine (LOHA) and, in the second one, LOHA is further oxidized to citrulline and NO (5). Arginase hydrolyzes arginine to ornithine and urea.…”

Section: Introductionmentioning

confidence: 99%

The Inhibition of Arginase by Nω-Hydroxy-l-Arginine Controls the Growth of Leishmania Inside Macrophages

Iniesta¹,

Gómez-Nieto²,

Corraliza

2001

The Journal of Experimental Medicine

253

217

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Polyamine synthesis from l-ornithine is essential for Leishmania growth. We have investigated the dependence of Leishmania infection on arginase, which generates l-ornithine, in macrophages from BALB/c, C57BL/6, and nitric oxide synthase II (NOS II)-deficient mouse strains. We have found that N ω-hydroxy-l-arginine (LOHA), a physiological inhibitor of arginase, controls cellular infection and also specifically inhibits arginase activity from Leishmania major and Leishmania infantum parasites. The effect was proportional to the course of infection, concentration dependent up to 100 μM, and achieved without an increase in nitrite levels of culture supernatants. Moreover, when the l-arginine metabolism of macrophages is diverted towards ornithine generation by interleukin 4–induced arginase I, parasite growth is promoted. This effect can be reversed by LOHA. Inhibition of NOS II by N G-methyl-l-arginine (LNMMA) restores the killing obtained in the presence of interferon (IFN)-γ plus lipolysaccharide (LPS), whereas the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-3-oxide-1-oxyl (carboxy-PTIO) was without effect. However, exogenous l-ornithine almost completely inhibits parasite killing when added in the presence of LOHA to macrophages from NOS II–deficient mice or to BALB/c-infected cells activated with IFN-γ plus LPS. These results suggest that LOHA is an effector molecule involved in the control of Leishmania infection. In addition, macrophage arginase I induction by T helper cell type 2 cytokines could be a mechanism used by parasites to spread inside the host.

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N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.

Cited by 531 publications

References 40 publications

A new decoration for nitric oxide synthase – a Zn(Cys)4 site

A new decoration for nitric oxide synthase – a Zn(Cys)4 site

Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide.

The Inhibition of Arginase by Nω-Hydroxy-l-Arginine Controls the Growth of Leishmania Inside Macrophages

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