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Allicin in Blood.Pdf European Journal of Medicinal Chemistry 45 (2010) 1912–1918 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Original article Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules Talia Miron a,*, Irving Listowsky b, Meir Wilchek a a Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel b Department of Biochemistry, Albert-Einstein College of Medicine, Bronx, NY, USA article info abstract Article history: Allylsulfides from garlic are chemopreventive agents. Entering cells they are expected to initially interact Received 15 October 2009 with glutathione. Accordingly, reaction mechanisms of the product, S-allylthio-glutathione, with model Received in revised form proteins and thiols were analyzed in cell free systems. With glutathionyl, cysteinyl or captopril repre- 14 January 2010 senting S-allyl aliphatic adducts, the reaction with sulfhydryl groups resulted in mixed disulfide Accepted 15 January 2010 mixtures, formed by both, S-allyl and aliphatic moieties. Available online 21 January 2010 To improve conventional prodrug treatment of blood pressure, cancer and intestinal inflammation S-allylthio prodrugs, such as S-allylthio-6-mercaptopurine and S-allylthio-captopril were synthesized. Keywords: Allicin Synergistic activities of the 2 constituents, as well as increased cell permeability allow for efficient in vivo Glutathione activity. Upon reaction of these derivatives with glutathione, S-allylthio-glutathione is formed, while S-Allylthio-mixed disulfide 6-mercaptopurine is the leaving group. Excess cellular glutathione enables several cycles of sulfhydryl- Prodrug disulfide exchange reactions to occur, extending the hybrid drug’s pharmacodynamics. Mechanism of action Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction and participates in many important biological processes, including maintenance of a reducing intracellular environment Allicin, diallyl thiosulfinate, is the major biologically active [5] and detoxification of oxidants and electrophiles [6].GSHalso compound derived from garlic. It is produced by the interaction of participates in cellular redox reactions and mixed disulfide the enzyme alliinase (alliin lyase; EC 4.4.1.4) with its substrate, formation, which leads to the production of S-glutathiolated alliin (S-allyl-L-cysteine sulfoxide) (Scheme 1) [1]. proteins [7–10]. Allicin is a short-lived compound which easily diffuses through The mechanisms by which the allylsulfides reduce the risk of cell membranes (diffusion coefficient 5 Â 10À8 cm2 sÀ1) [2] and diseases may be rationalized on the basis of their chemistry [11]. exerts its biological effects by rapidly reacting with intracellular Thus, they could affect GSH levels and cellular redox status, or free thiols, such as reduced glutathione (GSH), cysteine and sulf- react directly with key proteins involved in various physiological hydryl groups of proteins. The reaction of the allylthio group with processes. However, details of the functional course of action of those cellular components constitutes the major beneficial effects allylsulfides are obscure. Since the initial cellular products are of allicin. The first product is most likely that of the S-allylthio- likely to be GSH adducts, this study was designed to determine mixed disulfide (AS-SX) with GSH as depicted in Scheme 2 below. the outcome and reaction mechanisms of S-allylthio-glutathione Intracellular GSH is the major low molecular weight thiol that (GSSA) with model proteins and low molecular weight thiols. is present at millimolar concentrations in many cell types [3,4] The putative products, the mixed disulfide, can in turn, be involved in further exchange reactions with free thiols, potentially modulating various physiological processes in the cell Abbreviations: ASH, allylmercaptan; AS-SX, S-allylthio-mixed disulfide; CPSH, [12–14]. captopril; CPSSA, S-allylthio-captopril; DTNB, 5,50-dithio-bis (2-nitrobenzoic acid); G3PDH, glyceraldehyde 3-phosphate dehydrogenase GSSA, S-allylthio-glutathione; Several S-allylthio-mixed disulfide compounds (AS-SX) were GSH, Reduced glutathione; GSSG, Glutathione oxidized; GS-S-CP, S-glutathionyl- prepared (including drugs containing free thiol groups) and their thiocaptopril: NTB, 2-nitro-5-thiobenzoate; PTP1B, Protein tyrosine phosphatase disulfide exchange reactions with GSH and proteins containing free 1B; SA-6MP, S-allylthio-6-mercaptopurine; SA-6MPR, S-allylthio-6-mercaptopurine sulfhydryl groups were studied, in order to follow the formation of riboside. the various intermediates and final products. These substances * Corresponding author. Tel.: þ972 8 9343627; fax: þ972 8 9468256. E-mail addresses: [email protected] (T. Miron), [email protected]. could shed light on the reaction mechanisms of S-allylthio-mixed aecom.yu.edu (I. Listowsky), [email protected] (M. Wilchek). disulfide (AS-SX) with cellular thiols. 0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.01.031 T. Miron et al. / European Journal of Medicinal Chemistry 45 (2010) 1912–1918 1913 Scheme 1. Enzymatic production of allicin. 2. Chemistry activity. The maximum extent of S-glutathionylation of the non- denatured enzyme under these conditions is 2-per tetramer. PTP1B All of the S-allylthio-derivatives were synthesized by coupling has 6 cysteine residues including a very reactive sulfhydryl at the allicin to the indicated sulfhydryl-derivatives at pH 6.5, using the active site. Two major reaction products were obtained in the ratio of allicin: SH-derivatives 1:1.8 (Scheme 3). reaction of PTP1B and GSSA. These included a 37 453 Da component indicating the addition of 2 allylmercapto moieties, and a 37 758 Da 3. Results component indicative of the addition of 2 allylmercapto moieties as well as a single S-glutathionylated group linked to the protein. 3.1. Reactions of S-allylthio-glutathione (GSSA) with sulfhydryl groups of proteins 3.2. Reaction between allicin and GSH Papain was incubated with GSSA to identify mixed disulfide All of the S-allylthio-derivatives were prepared using an excess derivatives formed during the reaction. Previously we showed that of allicin. The reaction was carried out at room temperature, pH 6.5. modification of papain with GSSA abolishes its enzymatic activity Under these conditions the product is stable and can be readily in a concentration dependent manner [15]. GSSA modification of isolated. When allicin (5 mM) reacted with excess of GSH (50 mM), papain in this study caused a decrease in catalytic activity in the first product formed rapidly was GSSA, which ultimately was a biphasic manner, reaching a total loss of activity after 18 h. These converted back to GSH, while releasing allylmercaptan (ASH). Only results are consistent with the formation of a papain-S-SX deriva- traces of ASH were detected by HPLC (due to its high volatility). tive. Using the tritiated allyl moiety ([3H]GSSA) enabled tracking the formation of modified papain products. Gel permeation chro- 3.3. Reaction between S-allylthio-captopril (CPSSA) and GSH matography of the reaction mixture using a PD-10 column, sug- gested that a major product is [3H] allyl-S-S papain since the CPSSA [18] and GSH were reacted at a molar ratio of 1:1. The radioactivity and protein peaks overlap (Fig. 1). In the 4th–5th ml data in Table 2A show molecular masses of the various reactants, peak, the ratio is 0.7–0.9 mCi labeled allyl group per mmole protein, intermediates and products, as established by ESI-MS and HPLC implying that at least 70% of the protein is S-allylthio-papain. retention times (Rt). However, to determine whether other derivatives, such as The time course of product formation in the reaction mixture of glutathionyl-S-S-papain were also formed papain was modified S-allylthio-captopril (CPSSA) and GSH at room temperature, pH 6.5 with unlabeled GSSA, and protein mixed disulfide formation was is shown in Table 2B. analyzed by ESI-MS. Unmodified papain showed the presence of ESI-MS analysis of the reaction mixture HPLC peaks indicated two major species [16] with molecular masses of 23 428 Da (a) and that it contained S-glutathionyl-captopril (GS-S-CP: mw 522, Rt: 23 458 Da (b). Modified papain revealed the formation of 2 distinct 4.6 min), S-allylthio-glutathione (GSSA: mw 379, Rt: 5.2 min) free products derived from each respective form. Since papain has only captopril: (CPSH: mw 217, Rt:13.0 min) as well as the starting one free sulfhydryl group, the modification results in the formation materials (Table 2B). The products that appear initially are GSSA of either S-allylthio-papain (additional mass of 73 Da, with or and CPSH. At a later stage GS-S-CP, GSSG and allylmercaptan (ASH) without Naþ) or S-glutathionyl papain (additional mass of 306 Da, are formed. In this reaction, reduced glutathione reacted with both with or without Naþ)(Table 1). moieties of S-allylthio-captopril to yield at first, S-allylthio-gluta- Papain was also reacted with S-allylthio-captopril (CPSSA). Mass thione (GSSA) and captopril (CPSH). Only at later stages do these spectra of the products indicated that two distinct modifications intermediates react with one another to yield the final product, had occurred; S-captropril-papain (23 643 kDa, additional mass of S-glutathionyl-captopril (GS-S-CP). 215 Da) and S-allylthio-papain (23 506, 23 531 kDa, additional mass The reaction is pH dependent and at pH 8.4 the maximal yield of of 73 Da). GS-S-CP, GSSA and CPSH were observed after 25 min at room Glyceraldehyde 3-phosphate dehydrogenase (G3PDH) is temperature. To obtain more precise values of reaction rates and a protein containing a reactive sulfhydryl group and known to intermediate analyses, the reaction was performed at pH 6.5. The undergo S-glutathionylation under conditions of oxidative stress overall reaction is shown in Scheme 4. [17]. After incubation of the enzyme with a ten-fold molar excess of The second step of the above reaction was deduced from the GSSA at pH 7.4, the products were analyzed by HPLC and ESI-MS.
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