Monday, September 12, 2016

Nitrite can be a substrate of sulfite oxidase, too

Last week I came across this 2015 paper, wherein the authors report their discovery that sulfite is not the only substrate of the enzyme sulfite oxidase (that's the enzyme which according to my hypotheses is overwhelmed in situations of "morning sickness" and migraine headaches). Under hypoxic circumstances or when there is excessive sulfite, nitrite can be a substrate of sulfite oxidase. Here's the abstract:

Aims: Recent studies suggest that the molybdenum enzymes xanthine oxidase, aldehyde oxidase, and mARC exhibit nitrite reductase activity at low oxygen pressures. However, inhibition studies of xanthine oxidase in humans have failed to block nitrite-dependent changes in blood flow, leading to continued exploration for other candidate nitrite reductases. Another physiologically important molybdenum enzyme—sulfite oxidase (SO)—has not been extensively studied. Results: Using gas-phase nitric oxide (NO) detection and physiological concentrations of nitrite, SO functions as nitrite reductase in the presence of a one-electron donor, exhibiting redox coupling of substrate oxidation and nitrite reduction to form NO. With sulfite, the physiological substrate, SO only facilitates one turnover of nitrite reduction. Studies with recombinant heme and molybdenum domains of SO indicate that nitrite reduction occurs at the molybdenum center via coupled oxidation of Mo(IV) to Mo(V). Reaction rates of nitrite to NO decreased in the presence of a functional heme domain, mediated by steric and redox effects of this domain. Using knockdown of all molybdopterin enzymes and SO in fibroblasts isolated from patients with genetic deficiencies of molybdenum cofactor and SO, respectively, SO was found to significantly contribute to hypoxic nitrite signaling as demonstrated by activation of the canonical NO-sGC-cGMP pathway. Innovation: Nitrite binds to and is reduced at the molybdenum site of mammalian SO, which may be allosterically regulated by heme and molybdenum domain interactions, and contributes to the mammalian nitrate-nitrite-NO signaling pathway in human fibroblasts. Conclusion: SO is a putative mammalian nitrite reductase, catalyzing nitrite reduction at the Mo(IV) center. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523048/

What does this mean? It means that if sulfite accumulation contributes to migraine headaches and nausea and vomiting in pregnancy (NVP), one should not only avoid eating sulfites but nitrites, too, when trying to avoid migraines or alleviate NVP. That is because--if I'm correctly understanding the report's discussion of oxidation states of molybdenum--nitrite will further tie up sulfite oxidase and slow it down in its primary function of catalyzing the conversion of sulfite to sulfate. The result of sulfite oxidase's acting on nitrite is nitric oxide, and nitric oxide levels do appear to go up around the time of migraine headaches (https://www.ncbi.nlm.nih.gov/pubmed/17116218).

Considering that nitrites have been long seen as a trigger for migraines (http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/1998/398_pain.html), this isn't a revolutionary diet change to suggest to migraine sufferers. However, I've never seen nitrites mentioned as something to avoid when pregnant; deli meat, certainly, but the reason given for the counsel to avoid deli meat during pregnancy is typically listeria (http://americanpregnancy.org/is-it-safe/deli-meats/).

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