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

Nitrated fatty acids (NO 2 ‐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 NO 2 ‐FAs. NO 2 ‐FAs are formed effectively by the addition of ˙NO 2 , followed by either hydrogen abstraction or addition of a second NO 2 . 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 NO 2 ‐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 ˙NO 2 . Furthermore, the release of ˙NO from NO 2 ‐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‐NO 2 ‐LA involves a larger reaction barrier and is more endergonic than those from 9‐ and 13‐NO 2 ‐LA.