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S-Allylmercaptoglutathione Is a Substrate for Glutathione Reductase (E.C

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S-Allylmercaptoglutathione Is a Substrate for Glutathione Reductase (E.C antioxidants Article S-allylmercaptoglutathione Is a Substrate for Glutathione Reductase (E.C. 1.8.1.7) from Yeast (Saccharomyces cerevisiae) Tobias Horn 1, Wolfgang Bettray 2, Alan J. Slusarenko 1 and Martin C. H. Gruhlke 1,* 1 Department of Plant Physiology, RWTH Aachen University, 52056 Aachen, Germany; [email protected] (T.H.); [email protected] (A.J.S.) 2 Institute of Organic Chemistry, RWTH Aachen University, 52056 Aachen, Germany; [email protected] * Correspondence: [email protected] Received: 19 June 2018; Accepted: 4 July 2018; Published: 6 July 2018 Abstract: Allicin (diallylthiosulfinate) is a potent thiol reagent and natural defense substance produced by garlic (Allium sativum) tissues when damaged. Allicin acts as a redox toxin and oxidizes the cellular glutathione (GSH) pool producing S-allylmercaptoglutathione (GSSA). The cellular enzyme glutathione reductase (GR) uses NADPH to reduce glutathione disulfide (GSSG) back to GSH and replenishes the GSH pool. It was not known whether GR could accept GSSA as a substrate. Here, we report that GR from yeast (Saccharomyces cerevisiae) shows Michaelis–Menten kinetics with GSSA as substrate in vitro (Km = 0.50 mM), but that GSSA is not as good a substrate as GSSG (Km = 0.07 mM). Furthermore, cells unable to synthesize GSH because the γ-glutamylcysteine synthetase (GSH1) gene is deleted, cannot grow without GSH supplementation and we show that the auxotrophic requirement for GSH in Dgsh1 mutants can be met by GSSA in the growth medium, suggesting that GSSA can be reduced to GSH in vivo. Keywords: allicin; thiosulfinate; garlic; glutathione reductase 1. Introduction Glutathione (GSH) is the major low molecular weight thiol in most eukaryotic and many prokaryotic cells and is regarded as one of the cell’s first lines of defense against several oxidative insults [1,2]. In healthy non-stressed cells, usually nearly all of the GSH in the cytosolic glutathione pool is in the reduced form, reflecting the highly reducing environment of that cell compartment. Indeed, recent estimates using reduction-potential-dependent fluorescent protein probes suggest a cytosolic EGSH of <−320 mV in yeast. Assuming a cytosolic [GSH] of 10 mM would mean a ratio of GSH:GSSG of 50,000:1 [3]. The dedicated biosynthetic pathway to GSH consists of two steps. The enzyme γ-glutamylcysteine synthetase (GSH1) catalyzes the coupling of glutamate with cysteine and the γ-glutamylcysteine product is coupled with glycine by glutathione synthetase (GSH2) to make the final product. Cells deleted for the GSH1 gene must be supplemented with GSH for survival and growth. Upon oxidative stress, caused for example by reactive oxygen species, GSH is oxidized to its dimeric form glutathione disulfide GSSG (Scheme1). The reaction with H 2O2 is rather slow and in vivo is catalysed by enzymes called peroxiredoxins [4,5]. Furthermore, under oxidative stress conditions, cysteine thiols in proteins may be reversibly glutathiolated to protect them from over-oxidation to sulfenic and sulfinic acid residues [6]. The GSH pool within the cell is restored by the reduction of GSSG to GSH by the NADPH-dependent enzyme glutathione reductase (GR, E.C. 1.8.17) (Scheme2)[ 1] whereas glutathiolated proteins are usually reduced by glutaredoxins [7]. Antioxidants 2018, 7, 86; doi:10.3390/antiox7070086 www.mdpi.com/journal/antioxidants Antioxidants 2018, 7, x FOR PEER REVIEW 2 of 8 AntioxidantsAntioxidants2018 2018,,7 7,, 86x FOR PEER REVIEW 22 of 88 Antioxidants 2018,, 7,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 88 Scheme 1. Two mol reduced glutathione (GSH) react with one mol hydrogen peroxide to yield one Schememol glutathione 1. Two mol disulfide reduced (GSSG) glutathione and (GSH)two mol react water. with one In molcells hydrogen the reaction peroxide is catalyzed to yield one by SchemeScheme 1.1. TwoTwo molmol reducedreduced glutathioneglutathione (GSH)(GSH) reactreact withwith oneone molmol hydrogenhydrogen peroxideperoxide toto yieldyield oneone molperoxiredoxin glutathione enzymes disulfide (PRX). (GSSG) and two mol water. In cells the reaction is catalyzed by mol glutathione disulfide (GSSG) and two mol water. In cells the reaction is catalyzed by molperoxiredoxin glutathione enzymes disulfide (PRX). (GSSG) and two mol water. In cells the reaction is catalyzed by peroxiredoxin enzymesperoxiredoxin (PRX). enzymes (PRX). Scheme 2. One mol glutathione disulfide (GSSG) is reduced to 2 mol GSH by one mol NADP+ + H+ Schemeunder catalysis 2. One molby glutathione glutathione reductase disulfide (GR). (GSSG) is reduced to 2 mol GSH by one mol NADP+ + H+ Scheme 2. One mol glutathione disulfide (GSSG) is reduced to 2 mol GSH by one mol NADP+ ++ ++ HH+++ Schemeunder catalysis 2. One molby glutathione glutathione reductase disulfide (GR). (GSSG) is reduced to 2 mol GSH by one mol NADP + H under catalysis by glutathione reductase (GR). underA GR/NADPH-dependent catalysis by glutathione reductasecycling (GR).assay was developed to determine [GSH] and [GSSG], A GR/NADPH-dependent cycling assay was developed to determine [GSH] and [GSSG], wherebyA GR/NADPH-dependent GSH is oxidized to GSSG cycling by 5,5′-dithiobis-2-nitrobenzoate assay was developed to (DTNB)determine in the[GSH] presence and of[GSSG], excess wherebyA GR/NADPH-dependent GSH is oxidized to GSSG cycling by 5,5′-dithiobis-2-nitrobenzoate assay was developed to determine (DTNB) [GSH] in the and presence [GSSG], wherebyof excess wherebyenzyme GSH(Scheme is oxidized 3) [8]. to GSSG The by 2-nitro-5-thiobenzoate 5,5′-dithiobis-2-nitrobenzoate (TNB) (DTNB) formed in thecan presence be measured of excess GSHenzyme is oxidized (Scheme to GSSG3) [8]. by 5,5The0-dithiobis-2-nitrobenzoate 2-nitro-5-thiobenzoate (DTNB) (TNB) in theformed presence can of excessbe measured enzyme enzymespectrophotometrically (Scheme 3) (λ[8].max =The 412 nm)2-nitro-5-thiobenzoate and its rate of production (TNB) dependsformed uponcan thebe ratemeasured of GSH (Schemespectrophotometricallyformation3)[ due8]. Theto GR 2-nitro-5-thiobenzoate activity (λmax = with412 nm) GSSG and (TNB)as its substrate. rate formed of production In can contrast, be measured depends under spectrophotometrically conditionsupon the rateof substrate of GSH spectrophotometrically (λmax == 412412 nm)nm) andand itsits raterate ofof productionproduction dependsdepends uponupon thethe raterate ofof GSHGSH (formationλmax = 412 due nm) to and GR its activity rate of production with GSSG depends as substrate. uponthe In ratecontrast, of GSH under formation conditions due to of GR substrate activity formationexcess, the duerate ofto TNBGR activity production with is GSSG limited as by substrate. the amount In contrast,of GR activity under present conditions and the of assaysubstrate can withexcess, GSSG the asrate substrate. of TNB production In contrast, is under limited conditions by the amount of substrate of GR excess, activity the present rate of and TNB the production assay can excess,be used the to measurerate of TNB GR productionactivity. is limited by the amount of GR activity present and the assay can isbe limited used to by measure the amount GR activity. of GR activity present and the assay can be used to measure GR activity. be used to measure GR activity. Scheme 3. Basis of the GR enzyme assay [8]. GSH is oxidized to GSSG by DTNB and reduced back to SchemeSchemeGSH by 3.GR.3. BasisBasis The ofof rate thethe of GRGR TNB enzymeenzyme production assayassay [is[8].8 ].proportional GSH is oxidized to the to concentration GSSG by DTNB of GSH and and reducedreduced can followed backback toto Scheme 3. Basis of the GR enzyme assay [8]. GSH is oxidized to GSSG by DTNB and reduced back to GSHGSHspectrophotometrically. byby GR.GR. TheThe raterate of TNB DTNB: production (5,5′-dithiobis-(2-nitrobenzoic isis proportional toto thethe concentration acid). ofof GSHGSH andand cancan followedfollowed GSH by GR. The rate of TNB production0 is proportional to the concentration of GSH and can followed spectrophotometrically.spectrophotometrically. DTNB:DTNB: (5,5(5,5′-dithiobis-(2-nitrobenzoic-dithiobis-(2-nitrobenzoic acid).acid). spectrophotometrically. DTNB: (5,5′-dithiobis-(2-nitrobenzoic acid). Allicin (diallylthiosulfinate) is produced in garlic when cells are damaged and the enzyme AllicinAllicin (diallylthiosulfinate)(diallylthiosulfinate) is producedis produced in garlicin garlic when when cells arecells damaged are damaged and the and enzyme the alliinaseenzyme alliinaseAllicin mixes (diallylthiosulfinate) with its substrate isalliin produced which isin separately garlic when compartmentalized cells are damaged in theand cell. the Aenzyme single mixesalliinase with mixes its substrate with its alliin substrate which alliin is separately which is compartmentalized separately compartmentalized in the cell. A singlein the clovecell. A of single garlic alliinaseclove of mixesgarlic withcan produce its substrate up to alliin 5 mg which of allicin is separately [9], which compartmentalized is the first and major in the volatile cell. A singlesulfur canclove produce of garlic up can to 5 mgproduce of allicin up to [9], 5 whichmg of is allicin the first [9], and which major is volatile the first sulfur and compoundmajor volatile produced sulfur clovecompound of garlic produced can produce and gives up freshto 5 garlicmg of its allicin characteristic [9], which odor. is the Allicin first was and identified major volatile as the sulfurmajor compound produced and gives fresh garlic its characteristic odor. Allicin
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