L-(+)-(S)-Canavanine is a non-proteinogenic amino acid found in certain leguminous plants. It is structurally related to the proteinogenic α-amino acid L-arginine, the sole difference being the replacement of a methylene bridge (-CH 2- unit) in arginine with an oxa group (i.e., an oxygen atom) in canavanine. Canavanine is accumulated primarily in the seeds of the organisms which produce it, where it serves both as a highly deleterious defensive compound against herbivores (due to cells mistaking it for arginine) and a vital source of nitrogen for the growing embryo.[citation needed] The related L-canaline is similar to ornithine.
The mechanism of canavanine's toxicity is that organisms that consume it typically mistakenly incorporate it into their own proteins in place of L-arginine, thereby producing structurally aberrant proteins that may not function properly. Cleavage by arginase also produces canaline, a potent insecticide.
The toxicity of canavanine may be enhanced under conditions of protein starvation,[1] and canavanine toxicity, resulting from consumption of Hedysarum alpinum seeds with a concentration of 1.2% canavanine weight/weight, has been implicated in the death of a malnourished Christopher McCandless.[2] (McCandless was the subject of Jon Krakauer's book (and subsequent movie) Into the Wild).
Chemical structure of canavanine compared to arginine
NZB/W F1, NZB, and DBA/2 mice fed L-canavanine develop a syndrome similar to systemic lupus erythematosus,[1] while BALB/c mice fed a steady diet of protein containing 1% canavanine showed no change in lifespan.[3]
Alfalfa seeds and sprouts contain L-canavanine. The L-canavanine in alfalfa has been linked to lupus-like symptoms in primates, including humans, and other auto-immune diseases. Often stopping consumption reverses the problem.[4][5][6]
Some specialized herbivores tolerate L-canavanine either because they metabolize it efficiently (cf. L-canaline) or avoid its incorporation into their own nascent proteins.
Herbivores may be able to metabolize canavanine efficiently. The beetle Caryedes brasiliensis is able to break canavanine down to canaline, then further detoxifies canaline by reductive deamination to form homoserine and ammonia. As a result, the beetle not only tolerates the chemical, but uses it as a source of nitrogen to synthesize its other amino acids to allow it to develop.[7]
An example of this ability can be found in the larvae of the tobacco budworm Heliothis virescens, which can tolerate large (lethal concentration 50 or LC50 300 mM) amounts of dietary canavanine.[8] These larvae fastidiously avoid incorporation of L-canavanine into their nascent proteins due to gastrointestinal expression of canavanine hydrolase, an enzyme that cleaves L-canavanine into L-homoserine and hydroxyguanidine, and L-arginine kinase, which phosphorylates L-canavanine.[9] In contrast, larvae of the tobacco hornworm Manduca sexta can only tolerate tiny amounts (1.0 microgram per kilogram of fresh body weight) of dietary canavanine because their arginine-tRNA ligase has little, if any, discriminatory capacity. No one has examined experimentally the arginine-tRNA synthetase of these organisms. But comparative studies of the incorporation of radiolabeled L-arginine and L-canavanine have shown that in Manduca sexta, the ratio of incorporation is about 3 to 1.[10]
Diocleamegacarpa seeds contain high levels of canavanine. The beetle Caryedes brasiliensis is able to tolerate this however as it has the most highly discriminatory arginine-tRNA ligase known (as of 1982). In this insect, the level of radiolabeled L-canavanine incorporated into newly synthesized proteins is barely measurable. Moreover, this beetle uses canavanine as a nitrogen source (see above).[11]
^ abAkaogi, Jun; Barker, Tolga; Kuroda, Yoshiki; Nacionales, Dina C.; Yamasaki, Yoshioki; Stevens, Bruce R.; Reeves, Westley H.; Satoh, Minoru (2006). "Role of non-protein amino acid l-canavanine in autoimmunity". Autoimmunity Reviews. 5 (6): 429–35. doi:10.1016/j.autrev.2005.12.004. PMID16890899.
^Krakauer, J., et al. (2015). "Presence of l-canavanine in Hedysarum alpinum seeds and its potential role in the death of Christopher McCandless." Wilderness & Environmental Medicine. doi:10.1016/j.wem.2014.08.014
^Rosenthal, Gerald A.; Dahlman, D. L.; Janzen, Daniel H. (3 November 1978). "L-Canaline Detoxification: A Seed Predator's Biochemical Mechanism". Science. 202 (4367): 528–529. doi:10.1126/science.202.4367.528.
^Berge MA, Rosenthal GA, Dahlman DL (1986). "Tobacco budworm, Heliothis virescens [Noctuidae] resistance to l-canavanine, a protective allelochemical". Pesticide Biochemistry and Physiology. 25 (3): 319–326. doi:10.1016/0048-3575(86)90005-2.
Rosenthal, Gerald A. (1986). "Biochemical insight into insecticidal properties ofl-Canavanine, a higher plant protective allelochemical". Journal of Chemical Ecology. 12 (5): 1145–56. doi:10.1007/BF01639001. PMID24307052. S2CID37297952.
Rosenthal, G. A.; Berge, M. A.; Bleiler, J. A.; Rudd, T. P. (1987). "Aberrant, canavanyl protein formation and the ability to tolerate or utilize L-canavanine". Experientia. 43 (5): 558–61. doi:10.1007/BF02143585. PMID3582574. S2CID24239284.
Boyar, A.; Marsh, R. E. (1982). "L-Canavanine, a paradigm for the structures of substituted guanidines". Journal of the American Chemical Society. 104 (7): 1995–1998. doi:10.1021/ja00371a033.
Ekanayake S, Skog K, Asp NG (May 2007). "Canavanine content in sword beans (Canavalia gladiata): analysis and effect of processing". Food and Chemical Toxicology. 45 (5): 797–803. doi:10.1016/j.fct.2006.10.030. PMID17187914.
