Diversity, Biosynthesis, and Metabolism of Capsaicinoids

Returning to the question in the title of this section, capsaicin does not fall into any of the three classic types of nitrogen-bearing plant natural products, being neither a true alkaloid, a protoalkaloid, or a pseudoalkaloid. Capsaicin is oflimited distribution in Nature and shows pharmacological activity, but is non-basic, structurally unsophisticated, and not directly derived from an amino acidic precursor. On the other hand, the lack of attributes such as basicity, complexity, and an amino acidic pedigree can also be found in compounds commonly perceived as alkaloids. Thus, colchicine is neutral, ephedrine is structurally unsophisticated, and the nitrogen atom of the potato alkaloid solanine is not derived from an amino acid, but rather incorporated into as non-amino acidic framework by a transamination reaction. For the sake of clarity and consistency, it seems therefore convenient to adopt the modern definition of alkaloids, and consider capsaicin, as well as alkylamides such as piperine (18) and pellitorine (19), as such. 

The formation of acyl conjugates of vanillamine (capsaicinoids, 20) or vanillic alcohol (capsinoids, 21) with various Cg/Ci3 alkenoic and alkanoic acids is a unique chemical trait of plants from the genus Capsicum. Hot peppers are characterized by the presence of vanillyl conjugates of the amide type, absent or replaced by their nonpungent ester isosters (capsinoids) in bell (sweet) peppers [19]. Indeed, the difference between the sensory properties of capsaicin (la) and its naturally occurring ester analog capsiate (22) is a remarkable example of the biological relevance of isosterism. 

The combination of these elements generates the diversity of capsaicinoids reported to date. Generally, the major constituent of the capsaicinoid soup are capsaicin (la) and its dihydroderivative (lb). Commercial capsaicin potvder is an approximately 5 1 mixture of capsaicin and dihydrocapsaicin, while analytical ( 95 %) capsaicin contains mainly nonivamide as impurity. Despite its trivial name of synthetic capsaicin, nonivamide is a natural trace constituent of capsicum oleoresin, and concentration 3 % are indicative of adulteration [26]. The addition of nonivamide to capsicum oleoresin has been detected in products from both the food and the pharmaceutical markets. Some of them have been found to contain exclusively nonivamide, even though capsaicin is the only individual constituent of capsicum oleoresin to be approved by the FDA for human use [26]. 

From a biogenetic standpoint, capsaicin is an acylated degraded phenylpropanoid. Both its aromatic and its acyl moiety are the result of unique metabolic processes that, though simple in principle, are still poorly characterized in terms of enzymology and regulation. Since vanillamine (23) is abundant in placental tissues of Capsicum, the only site of biosynthesis of capsaicinoids, the limiting factor for the synthesis of 

An ortho-diphenol-O-methyltransferase responsible for the transformation of coumarate to ferulate has been cloned from pepper, and found to bear similarity with a similar enzyme from tobacco [32]. 

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