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Supplement: Significance of Garlic and Its Constituents in Cancer and Cardiovascular Disease

Redox-Sensitive Proteins Are Potential Targets of Garlic-Derived Mercaptocysteine Derivatives^1–3,

John T. Pinto^*,4, Boris F. Krasnikov^*, and Arthur J. L. Cooper^*,,**

^* Burke Medical Research Institute, White Plains, New York 10605 and Departments of Neurology and Neuroscience and ^** Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

⁴ To whom correspondence should be addressed: Email: jpinto{at}burke.org.

Molecular investigations support existing clinical and epidemiological data that garlic-derived allylsulfides reduce cancer risk. Various allylsulfides can diminish progression of cancer cells at either the G₁/S or G₂/M phase. Allylsulfide derivatives modify redox-sensitive signal pathways and cause growth inhibition, mitotic arrest, and apoptosis induction. Whether allylsulfides modify intracellular redox potentials by affecting the ratio of glutathione:glutathione disulfide and/or by interacting directly with sulfhydryl domains on regulatory or catalytic-signal proteins requires further investigation. To understand the possible biochemical mechanisms contributing to the protective effects of allylsulfides, we investigated the ability of these compounds to undergo enzyme-catalyzed transformations. In addition to catalyzing -elimination reactions, -cystathionase can perform ß-elimination reactions with cysteinyl S-conjugates derived from garlic extracts when the S-alkyl group (R) is larger than ethyl. The reaction products are pyruvate, ammonium, and a sulfur-containing fragment (RSH). ß-Lyase substrates of -cystathionase thus far identified from garlic include: S-allyl-L-cysteine (R = CH₂=CHCH₂-), S-allylmercapto-L-cysteine (R = CH₂=CHCH₂S-), and S-propylmercapto-L-cysteine (R = CH₃CH₂CH₂S-). Mercapto derivatives yield persulfide products (RSSH) that are potential sources of sulfane sulfur, which may modify protein function by reacting at important cysteinyl domains. Thus, ß-elimination reactions with cysteine S-conjugates in garlic may modify cancer-cell growth by targeting redox-sensitive signal proteins at sulfhydryl sites, thereby regulating cell proliferation and/or apoptotic responses. These interactions may be useful in identifying efficacy of garlic-derived compounds and/or developing other novel organosulfur compounds that may modify intracellular redox potentials or interact with thiols associated within cysteine domains in regulatory, catalytic, signal, or structural proteins.

KEY WORDS: • garlic • ß-lyase; glutathione • cysteine S-conjugates • -cystathionase • sulfane sulfur

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