Release of nitric oxide from nitrated fatty acids: Insights from computational chemistry

Nitrated fatty acids (NO₂-FAs) exhibit a variety of important biological attributes, including a nitric oxide (˙NO) donor and a cell-signaling molecule. We investigated the mechanisms of fatty-acid nitration, and the release of ˙NO from NO₂-FAs. NO₂-FAs are formed effectively by the addition of ˙NO₂, followed by either hydrogen abstraction or addition of a second NO₂. The latter reaction results in a vicinal nitronitrite ester form of FA, which isomerizes into vicinal nitrohydroxy FA via hydronium ion catalysis. The nitrohydroxy FAs exist in equilibria with NO₂-FAs. Nitration of conjugated linoleic acid (cLA) was proved to be significantly more efficient than that of LA. In a nonaqueous environment, release of ˙NO from nitrite ester (ONO-FA) was facilitated by ˙NO₂. Furthermore, the release of ˙NO from NO₂-cLA is the most favorable in the nitrite ester mechanism. In an aqueous environment, the modified Nef reaction was shown to be feasible. In addition, the release of ˙NO from 10- and 12-NO₂-LA involves a larger reaction barrier and is more endergonic than those from 9- and 13-NO₂-LA.