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Generation of Nitric Oxide by a Nitrite Reductase Activity of Xanthine Oxidase: A Potential Pathway for Nitric Oxide Formation in the Absence of Nitric Oxide Synthase Activity

https://doi.org/10.1006/bbrc.1998.9226Get rights and content

Abstract

Nitric oxide (NO) synthesis is now well-known to result from the oxidation of L-arginine by a family of NO synthases (NOS). However, under hypoxic conditions this mechanism of NO synthesis may be impaired and NO is formed by a NOS independent mechanism. This study was designed to examine the reduction of nitrite to NO by xanthine oxidase (XO) under hypoxia, because the bacterial nitrate/nitrite reductases have structural similarity to XO. We found that both purified and tissue containing XO catalyze the reduction of nitrite to NO, as demonstrated using a chemiluminescent NO meter. This redox reaction requires NADH as an electron donor, and is oxygen independent. The inhibitory profiles suggest that reduction of nitrite takes place at the molybdenum center of XO whilst NADH is oxidized at the FAD center. Heparin binding of XO caused an increase in the catalysis of nitrite reduction. The XO-catalyzed generation of NO may be important in redistribution of blood flow to ischaemic tissue as a supplement to NOS, since both nitrite and NADH have been shown to be elevated in hypoxic tissue.

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      Citation Excerpt :

      In mammalian cells, NO is generated by conversion of arginine to citrulline by nitric oxide synthase (NOS) enzymes or, alternatively, by reduction of nitrite (and in certain situations, nitrate) to NO by various heme- or molybdenum-containing proteins [1–11].

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    This work was supported in part by an Arthritis Research Campaign (UK) program grant. A preliminary report of this work was presented to the World Congress, Oxygen Club of California, in Santa Barbara, California, February 1998.

    2

    To whom correspondence should be addressed: MRC Collaborative Center, Mill Hill, London NW7 1AD, UK. Fax: 44 181 906 1359. E-mail:[email protected].

    3

    Present address: School of Postgraduate Medicine, University of Bath, Bath BA2 7AY, UK.

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