The reaction of hydroxyurea with oxyhaemocyanin and methaemocyanin of the crayfish <i>Astacus leptodactylus</i> and the snail <i>Helix pomatia</i>

Hoof, D Van; Witters, Raphaël; Lontie, René

doi:10.1042/bj2540605

Cited by 4 publications

(1 citation statement)

References 14 publications

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“…Inhibition of photosystem II by this pathway appears related to the toxicity of hydroxyurea to phytoplankton [123]. Hydroxyurea also reacts with the copper center of oxyhemocyanin of Astacus leptodactylus (crayfish) to presumably form the nitroxide radical (2 ) and methemocyanin [124]. Investigation as to the involvement of NO in each of the systems described in this section may be warranted.…”

Section: Other Potential Hydroxyurea-based Nitric Oxide Generating Symentioning

confidence: 90%

The Nitric Oxide Producing Reactions of Hydroxyurea

King¹

2003

CMC

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Hydroxyurea is used to treat a variety of cancers and sickle cell disease. Despite this widespread use, a complete mechanistic understanding of the beneficial actions of this compound remains to be understood. Hydroxyurea inhibits ribonucleotide reductase and increases the levels of fetal hemoglobin, which explains a portion of the effects of this drug. Administration of hydroxyurea to patients results in a significant increase in levels of iron nitrosyl hemoglobin, nitrite and nitrate suggesting the in vivo metabolism of hydroxyurea to nitric oxide. Formation of nitric oxide from hydroxyurea may explain a portion of the observed effects of hydroxyurea treatment. At the present, the mechanism or mechanisms of nitric oxide release, the identity of the in vivo oxidant and the site of metabolism remain to be identified. Chemical oxidation of hydroxyurea produces nitric oxide and nitroxyl, the one-electron reduced form of nitric oxide. These oxidative pathways generally proceed through the nitroxide radical (2) or C-nitrosoformamide (3). Biological oxidants, including both iron and copper containing enzymes and proteins, also convert hydroxyurea to nitric oxide or its decomposition products in vitro and these reactions also occur through these intermediates. A number of other reactions of hydroxyurea including the reaction with ribonucleotide reductase and irradiation demonstrate the potential to release nitric oxide and should be further investigated. Gaining an understanding of the metabolism of hydroxyurea to nitric oxide will provide valuable information towards the treatment of these disorders and may lead to the development of better therapeutic agents.

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Section: Other Potential Hydroxyurea-based Nitric Oxide Generating Symentioning

confidence: 90%

The Nitric Oxide Producing Reactions of Hydroxyurea

King¹

2003

CMC

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The structure of molluscan haemocyanins and their homology with tyrosinases

Préaux

Gielens

Witters

et al. 1988

Bulletin des Soc Chimique

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The reaction of nitrogen monoxide with the haemocyanins of the crayfish Astacus leptodactylus and the snail Helix pomatia

Tahon

Gielens

Vinckier

et al. 1989

Biochemical Journal

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The rate of the reaction of Astacus leptodactylus methaemocyanin with NO follows the Henderson-Hasselbalch equation with a pKa of 5.85, suggesting that one imidazole ligand of Cu was exchanged for NO. The reaction is blocked by F- as a bridging ligand. The same imidazole residue might be responsible for the decomposition of nitrosylhaemocyanin, [Cu1NO+CuII], with an unlocated binding site for NO, into methaemocyanin and NO, as the rate increase with pH. NO could react preferentially with CuA of Helix pomatia methaemocyanin, CuA'IICuBII, as it possibly has only two histidine ligands instead of the three of CuA in Astacus haemocyanin. This difference might explain the higher formation rate and the much greater stability of Helix nitrosylhaemocyanin. The fast reaction is governed by a pKa of 6.80, probably of a bridging mu-aquo ligand. With F- or a mu-hydroxo bridging ligand a low reaction rate was still observed, in contrast with Astacus methaemocyanin. Helix nitrosylhaemocyanin was transformed by N3- into methaemocyanin with the liberation of N2 and N2O. This methaemocyanin could almost quantitatively be regenerated with H2O2. Helix nitrosylhaemocyanin was only partially regenerated by a direct treatment with H2O2 and almost quantitatively by HONH2 in a similar fairly fast reaction, followed by a much slower one.

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The reaction of hydroxyurea with oxyhaemocyanin and methaemocyanin of the crayfish Astacus leptodactylus and the snail Helix pomatia

Cited by 4 publications

References 14 publications

The Nitric Oxide Producing Reactions of Hydroxyurea

The Nitric Oxide Producing Reactions of Hydroxyurea

The structure of molluscan haemocyanins and their homology with tyrosinases

The reaction of nitrogen monoxide with the haemocyanins of the crayfish Astacus leptodactylus and the snail Helix pomatia

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