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Inhibitory activities of various cyclic sulfonium compounds including salacinol against several glycosidases were studied and some compounds showed significant inhibition. The sulfonium ion structure was found to be essential for the inhibitory activity. Specific inhibition of salacinol toward rice alpha-glucosidase was ascribed to the tether arm.
We report here the characterization and the molecular analysis of the two high affinity permeases that mediate the transport of S-adenosylmethionine (AdoMet) and S-methylmethionine (SMM) across the plasma membrane of yeast cells. Mutant cells unable to use AdoMet as a sulfur source were first isolated and demonstrated to lack high affinity AdoMet transport capacities. Functional complementation cloning allowed us to identify the corresponding gene (SAM3), which encodes an integral membrane protein comprising 12 putative membrane spanning regions and belonging to the amino acid permease family. Among amino acid permease members, the closest relative of Sam3p is encoded by the YLL061w open reading frame. Disruption of YLL061w was shown to specifically lead to cells unable to use SMM as a sulfur source. Accordingly, transport assays demonstrated that YLL061w disruption mutation impaired the high affinity SMM permease, and YLL061w was therefore renamed MMP1. Further study of sam3Delta and mmp1Delta mutant cells showed that in addition to high affinity permeases, both sulfonium compounds are transported into yeast cells by low affinity transport systems that appear to be carrier-facilitated diffusion.
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5'-Methylthio[U-14C]adenosine was used as a culture supplement for Candida utilis. The resulting S-adenosylmethionine was hydrolyzed into its structural components. Virtually none of the label of the pentose was found in the carbohydrate part of the intracellular S-adenosylmethionine. Much of it was present in the four-carbon chain of the methionine part of the sulfonium compound. The (U-14C)-labeled adenine of 5'-methylthio[U-14C]adenosine did not contribute to the labeling of the amino acid components of the sulfonium compound.
A cyclic sulfonium compound, S-methyl homocysteine thiolactone (SMHT), is formed from methionine during in vitro tRNA aminoacylation catalyzed by Escherichia coli methionyl-tRNA synthetase. The mechanism of SMHT formation involves enzymatic deacylation of Met-tRNA (k = 0.06 s-1) and, to a lesser extent, Met-AMP (k = 0.02 s-1). Cyclization of methionine, reminiscent of cyclization of homocysteine during editing, illustrates the limited ability of methionyl-tRNA synthetase to discriminate against the cognate methionine at the editing site designed for the noncognate homocysteine. In early stages of biotic evolution, SMHT, a sulfonium compound, may have fulfilled the present day methyl donor function of S-adenosylmethionine. Existing homologies between methionyl-tRNA synthetase and S-adenosylmethionine synthetase indicate evolutionary relatedness of the two proteins.
The properties of a specific system for the transport of S-adenosylmethionine in yeast are described. The process was pH-, temperature-, and energy-dependent, and showed saturation kinetics. The K(m) for the system was 3.3 x 10(-6)m. Of the S-adenosylmethionine moieties tested, only S-adenosylhomocysteine competitively inhibited the uptake of the adenosylsulfonium compound. Adenine, adenosine, methionine, homocysteine, and the sulfonium compound S-methylmethionine were without effect. The analogue S-adenosylethionine showed competitive inhibition. Under conditions of inhibition of protein synthesis by cycloheximide or methionine starvation, permease activity was stable. The mutant sam-p3 apparently was able to transport S-adenosylmethionine only by diffusion. Uptake by diploids containing this mutation was directly proportional to the gene dose.
3-Dimethylsulfoniopropionate (DMSP) is an osmoprotectant accumulated by certain flowering plants and algae. In Wollastonia biflora (L.) DC. (Compositae) the first intermediate in DMSP biosynthesis has been shown to be S-methylmethionine (SMM) (A.D. Hanson, J. Rivoal, L. Paquet, D.A. Gage [1994] Plant Physiol 105: 103-110). Other possible intermediates were investigated by radiolabeling methods using W. biflora leaf discs. In pulse-chase experiments with [35S]SMM, 3-dimethylsulfoniopropionaldehyde (DMSP-ald) acquired label rapidly and lost it during the chase period. Conversely, 3-dimethylsulfoniopropylamine (DMSP-amine), 3-dimethylsulfoniopropionamide (DMSP-amide), and 4-dimethylsulfonio-2-hydroxybutyrate (DMSHB) labeled slowly and continuously during both pulse and chase. When unlabeled compounds were supplied along with [35S]SMM, DMSP-ald promoted [35S]DMSP-ald accumulation but DMSHB, DMSP-amide, and DMSP-amine had no such trapping effect. These data indicate that DMSP-ald is an intermediate in DMSP biosynthesis and that the other three compounds are not. Consistent with this, [35S]DMSHB was not metabolized to DMSP. Although [14C]DMSP-amine and [14C]DMSP-amide were converted slowly to DMSP, similar or higher conversion rates were found in plants that do not naturally accumulate DMSP, indicating that nonspecific reactions were responsible. These nonaccumulating species did not form [35S]DMSP-ald from [35S]SMM, implying that DMSP-ald is specific to DMSP biosynthesis. W. biflora leaf discs catabolized supplied sulfonium compounds to dimethylsulfide at differing rates, in the order DMSP-ald >> DMSP-amine > SMM > DMSP-amide > DMSHB > DMSP.
A novel gas chromatography-mass spectrometry method for analyzing sulfonium compounds as their S-demethylated silyl derivatives has clarified the origin of 5-dimethylsulfoniopentanoate. This compound, previously reported from flowers of Diplotaxis tenuifolia (L.) DC. (Cruciferae), is generated from glucoerucin during treatment with hot 6 N HCl. Glucoerucin is the characteristic glucosinolate of D. tenuifolia.
5'-Adenylylsulfate (APS) reductase was characterized in diverse marine algae. A cDNA encoding APS reductase from Enteromorpha intestinalis (EAPR) was cloned by functional complementation of an Escherichia coli cysH mutant. The deduced amino acid sequence shows high homology with APS reductase (APR) from flowering plants. Based on the probable transit peptide cleavage site the mature protein is 45.7 kD. EAPR expressed as a His-tagged recombinant protein catalyzes reduced glutathione-dependent reduction of APS to sulfite, exhibiting a specific activity of approximately 40 micromol min(-1) mg protein(-1) and Michealis-Menten kinetic constants of approximately 1.4 mM for reduced glutathione and approximately 6.5 microM for APS. APR activity and expression were studied in relation to the production of 3-dimethylsulfoniopropionate (DMSP), a sulfonium compound produced by many marine algae. A diverse group of DMSP-producing species showed extremely high enzyme activity (up to 400 times that found in flowering plants). Antibodies raised against a conserved peptide of APR strongly cross-reacted with a protein of 45 kD in several chlorophytes but insignificantly with chromophytes. In the chlorophyte Tetraselmis sp., APR activity varies significantly during the culture cycle and does not follow the changes in cellular DMSP content. However, a positive correlation was found between cell-based APR activity and specific growth rate.
The tridacnid clams maintain symbiotic associations with certain dinoflagellates (termed zooxanthellae). Tridacnids are thus candidates to have high tissue concentrations of dimethylsulfoniopropionate (DMSP), a tertiary sulfonium compound that is not synthesized by animals but is commonly produced by dinoflagellates. This study establishes that DMSP is about an order of magnitude more concentrated in the light-exposed and shaded mantle and gills of Tridacna maxima and T. squamosa than in any other known animal tissues. The DMSP concentration in the light-exposed, siphonal mantle--the location of most zooxanthellae--is an inverse function of body size, paralleling an inverse relation between apparent density of zooxanthellae (measured as pheophytin concentration) and body size. The shaded mantle and gills are high in DMSP despite having low densities of zooxanthellae, indicating that high DMSP concentrations occur in molluscan tissue, not just in algal cells. DMSP is almost an order of magnitude less concentrated in the adductor muscle than in other tissues. The high DMSP concentrations found in tridacnids, by providing abundant substrate for formation of volatile dimethylsulfide, probably explain the peculiar tendency of tridacnids to rapidly develop offensive odors and tastes after death: a serious problem for their exploitation as food. Tridacnids are the one group of animals in which DMSP concentrations are high enough in some tissues to be in the range capable of perturbing enzyme function at high physiological temperatures. Thus, tridacnids may require enzyme forms adapted to DMSP.
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The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, are described. The synthetic strategy relies on the intramolecular attack of a cyclic thioether across a terminal double bond in the presence of a suitable electrophile. We postulate that these compounds, having a permanent positive charge on the sulfur atom, will mimic the highly unstable oxacarbenium ion transition state in a glycosidase-catalyzed hydrolysis reaction. The conformational preferences of these compounds, based on analysis of 1H-1H vicinal coupling constants and 1D-NOESY data, are attributed to both steric and electrostatic interactions. These compounds will be used in the study of structure-activity relationships with glycosidase enzymes.
The specificity of a transport system for S-adenosylmethionine was determined through the use of structurally related derivatives. Of the compounds tested, the analogues S-adenosylethionine and S-inosylmethionine and the naturally occurring compounds S-adenosyl-(5')-3-methylthiopropylamine and S-adenosylhomocysteine competitively inhibited uptake of the sulfonium compound. Ki values for these compounds indicate that the order of affinity for the transport protein is S-adenosylmethionine congruent to S-adenosyl-(5')-3-methyl-thiopropylamine greater than S-adenosylethionine greater than S-inosylmethionine greater than S-adenosylhomocysteins. S-adenosyl-(2-hydroxy-4-methylthio)butyric acid exerted inhibition of a mixed type. S-insoyl-(2-hydroxy-4-methylthio)butyric acid, S-inosylhomocysteine, and S-ribosylhomocysteine were without effect. On the basis of the inhibition data, the methionine-amino, adenine-amino, and methyl groups were identified as group important in the binding of S-adenosylmethionine to the transport protein. Comparison is made with the specificities of various transmethylating enzymes utilizing S-adenosylmethionine. In addition, a number of conventional and temperature-sensitive S-adenosylmethionine transport mutants were isolated and analyzed in an attempt to identify the structural character of the specific transport protein(s). The data obtained suggest that only a single gene (a single polypeptide) is involved in specific S-adenosylmethionine transport. Apparent interallelic complementation supports the assumption that the functional form of the protein is composed of two or more copies of a monomer.
Peptides such as glycyl-L-methionyl-glycine, glycyl-L-lysine, L-lysyl-glycine and glycine-L-tryptophyl-glycine are used to study side-chain reactivity of three essential amino acids during food processing. The treatment of glycyl-L-methionyl-glycine with sodium hypochlorite resulted in the two following types of reaction: 1. Methionyl residues are oxidised to the corresponding sulfoxide at sodium hypochlorite concentrations up to 0,1 p. 100 w/v; 2. Oxidation of methionine residues to methionine sulfone and deamination reactions also occur for sodium hypochlorite concentrations over 0,2 p. 100 w/v. Sodium hypochlorite treatment of glycyl-L-lysine and L-lysine-glycine causes, probably by deamination of the epsilon-NH2 groups, a loss of lysine of 20 and 30 p. 100, for sodium hypochlorite concentrations of 0,1 and 0,2 p. 100 w/v, respectively. Treatment of glycyl-L-tryptophyl-glycine with hydrogen peroxide (0,05 M) modifies tryptophan residues in such a way that it cannot be retrieved after hydrolysis of the tripeptide with methane sulfonic acid and subsequent chromatographic analysis; six new unidentified components appear on the chromatogram. Glycyl-L-methionyl-glycine was incubated with food constituents or additives such as reducing oses, acrolein, p-benzoquinone, methyl iodide, or dichloro I, I ethylene. Thin layer chromatography and RMN show that carbonyl compounds or quinones do not react with the thioether group. Alkylating agents sometimes used in food processing only gave traces of sulfonium compounds. Thus, it appears that the only reaction liable to render methionine residues unavailable in foods would be its oxidation to methionine sulfone.
A pharmacokinetic study based on the distribution of radioactivity from the double labelled S-adenosyl-L-methionine (SAM) has been carried out by oral administration of the liposoluble stable salt [methyl-(14)C, 8-(3)H]SAM N-ole-1-oyltaurate to rats. The SAM sulfate p-toluensulfonate salt, the only SAM salt at present commercialized as drug, was chosen as reference compound to have a comparative pharmacokinetic analysis. The metabolism of the SAM is characterised by a differential use of the two labelled moieties by the various organs, liver being the most active in metabolizing the sulfonium compound with a preferential uptake of the methyl-(14)C fragment. The radioactivity detected after the administration of [methyl-(14)C, 8-(3)H]SAM N-ole-1-oyltaurate is, in all the organs examined, two times higher than the [methyl-(14)C, 8-(3)H]SAM sulfate p-toluensulfonate compound, attesting that the liposoluble [methyl-(14)C, 8-(3)H]SAM N-ole-1-oyltaurate is provided with better bioavailability.