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Molecules 2014, 19 20098 reaction products are still a matter of debate. Sulfonation of curcumin through human phenol sulfur transferase enzymes and the formation of reduction products through alcohol dehydrogenase is proposed. Comparing these metabolic products with the degradation products, it appears that simple hydrolytic degradation is prevented in biofluids. Since the degradation may occur through the β-diketo structure, one can presume that in these systems curcumin is not in free form but rather in conjugated form bound to some proteins or other biomolecules, and as the diketo moiety is involved in binding to the proteins [5,6], it is not available for hydrolytic degradation. It may also be implied that the specific enzymatic reactions are probably much faster and do not allow the slow hydrolytic degradation, therefore the latter process cannot compete with the former reaction. This leaves a bigger challenge for chemists to understand the differences between degradation and metabolic reactions in terms of kinetic parameters and also identify the crucial mechanism in these reactions. 5.3. Nucleophillic Addition Reactions of Curcumin The α,β-unsaturated β-diketo moiety of curcumin participates in nucleophilic addition reactions. This reaction, known as the Michael addition, occurs between the unsaturated ketone as an acceptor and anions of –OH, –SH, –SeH as donors. It is a 1,4-addition reaction and the resultant product formations are mostly irreversible, but they can be made reversible under oxidizing and basic conditions. Since the anions only act as nucleophiles, pH conditions are very important for this reaction to take place. At physiological pH both –OH and –SH are protonated but –SeH can easily undergo deprotonation, therefore it acts as a better nucleophile. This reaction has been reported to be extremely useful to explain the biological chemistry of curcumin in living cells [3,5,6,54–57]. Of special interest has been the reaction of biological thiols like glutathione having –SH groups [54,55]. Indeed curcumin-glutathione conjugates have been isolated in different systems. Formation of this addition product would lead to the depletion of the intracellular glutathione levels in cells, thereby leading to reduction in the overall antioxidant defense. Although a few reports suggest that this is a reversible reaction, it is not yet confirmed, under the conditions present in living cells, whether such reaction is reversible or not. Reversibility of the reaction can be expected under oxidizing conditions and at basic pH. A similar reaction has been observed during the inhibition of thioredoxin reductase by curcumin [5,6,56]. Thioredoxin reductase is a crucial enzyme involved in maintaining cellular redox homeostasis. The active centre in this enzyme is selenocysteine. The selenol of selenocysteine, being a stronger nucleophile at physiological pH, easily undergoes 1,4-addition with curcumin, forming covalently bonded species. This reaction is speculated to be mainly responsible for the effective inhibition of the thioredoxin reductase enzyme by curcumin. Scheme 4 shows the structure and the chemical reaction product of curcumin with protein thiols and selenols by Michael addition. Scheme 4. Michael addition products of curcumin with protein thiols and selenols where, X = S or Se. H3CO OH OCH3 HO Protein-X- H3CO OH OCH3 HO O HO Protein X OHOPDF Image | Curcumin: From Extraction to Therapeutic Agent
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