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Biomedical subjects

A Meister

Publications and source records attributed to A Meister.

At least 217 records · Page 12Linked to original sources
PubMed1981

Formation of gamma-glutamycyst(e)ine in vivo is catalyzed by gamma-glutamyl transpeptidase.

These studies indicate that gamma-glutamylcyst(e)ine, found in the urine of a patient with gamma-glutamyl transpeptidase deficiency and also in the urine of experimental animals injected with glutathione or with inhibitors of gamma-glutamyl transpeptidase, is formed by the action of gamma-glutamyltranspeptidase. The evidence demonstrates that transpeptidation between glutathione and cystine occurs in vivo and also that this reaction constitutes a significant physiological function of the enzyme. The appearance of large amounts of gamma-glutamylcyst(e)ine in the urine seems to reflect an inhibitory effect of glutathione on the transport of gamma-glutamylcyst(e)ine into cells. The findings also indicate that conversion of glutathione to gamma-glutamylcysteine by hydrolytic cleavage of the COOH-terminal glycine moiety of glutathione (or analogous cleavage of glutathione disulfide) is not a quantitatively significant pathway. The results reported here show that gamma-glutamyl transpeptidase activity is not completely absent in a patient found to have a deficiency of this enzyme and that the activity of the enzyme is not abolished in experimental animals treated with potent gamma-glutamyl transpeptidase inhibitors.

Animals↗
PubMed1980

Interaction of L- and D-3-amino-1-chloro-2-pentanone with gamma-glutamylcysteine synthetase.

The optical isomers of 3-amino-1-chloro-2-pentanone, which are the alpha-chloroketone analogs of L- and D-alpha-aminobutyrate, were synthesized and found to be highly potent irreversible inactivators of gamma-glutamylcysteine synthetase. These chloroketones are 20 to 30 times more active than L-2-amino-4-oxo-5-chlorpentanoate. L- and D-Glutamate, in the presence of Mg2+ or Mn2+, protect the enzyme against inactivation. The enzyme is almost completely inhibited by cystamine under conditions in which 0.5 mol of this compound is bound/mol of enzyme. Treatment of the enzyme with cystamne, which produces inhibition that is reversible by dithiothreitol, prevents the interaction of the new chloroketones, L-2-amino-4-oxo-5-chloropentanoate and methionine sulfoximine with the enzyme. The findings suggest that a sulfhydryl group at the active site interacts with the chloroketones and with cystamine and that the chloroketone inhibitors and cystamine bind to the enzyme as glutamine analogs. The data also suggest that a gamma-glutamyl-S-enzyme intermediate may be formed in the reaction catalyzed by this enzyme.

Animals↗
PubMed1980

L-gamma-(Threo-beta-methyl)glutamyl-L-alpha-aminobutyrate, a selective substrate of alpha-glutamyl cyclotransferase.

L-gamma(Threo-beta-methyl)glutamyl-L-alpha-aminobutyrate was was prepared and found to be an excellent substrate of gamma-glutamyl cyclotransferase; in contrast to gamma-glutamyl-glutamine and other good substrates of cyclotransferase, the new substrate is not acted upon by gamma-glutamyl transpeptidase. gamma-Glutamyl cyclotransferase converts the new substrate to alpha-aminobutyrate and 3-methyl-5-oxoproline; the latter compound is not a substrate of 5-oxoprolinase. These properties of L-gamma-(threo-beta-methyl)glutamyl-L-alpha-aminobutyrate facilitate its use in selectively determining cyclotransferase activity in biological materials that have transpeptidase activity. Thus, the new substrate was used here for the determination of the cyclotransferase activity of homogenates of various mouse tissues. The new substrate was also used to examine gamma-glutamyl cyclotransferase activity in vivo; thus, the rate of respiratory 14CO2 formation after administration of L-gamma-(threo-beta-methyl)glutamyl-L-alpha-amino[14C]butyrate to mice provides a valid measure of cyclotransferase activity. beta-Aminoglutaryl-L-alpha-aminobutyrate is a competitive inhibitor of cyclotransferase (apparent Ki, 0.6 mM). Administration of beta-amino-glutaryl-L-alpha-aminobutyrate to mice out only decreased the level of 5-oxoproline in the kidney of control mice, but also of mice in which kidney 5-oxoproline levels were increased by administration of methionine. Administration of beta-aminoglutaryl-L-alpha-aminobutyrate to mice decreased the in vivo metabolism of L-(threo-beta-methyl)glutamyl-L-alpha-amino[14C]butyrate as indicated by a marked decrease in the rate of respiratory 14CO2 formation. The findings indicate that gamma-glutamyl cyclo-transferase is a major in vivo catalyst for the formation of 5-oxoproline.

Acyltransferases↗
PubMed1980

Dynamic state of glutathione in blood plasma.

Recent studies have shown that there is an interorgan cycle of glutathione metabolism in which glutathione is translocated from certain cells into the blood plasma, and that plasma glutathione is utilized by cells that have gamma-glutamyl transpeptidase. The present studies indicate that there is a significant intravascular phase of glutathione metabolism. The level of total glutathione (GSH + GSSG) in rat blood plasma was found to be 22 to 27 microM GSH equivalents, as determined by the glutathione reductase recycling method. About 85% of the total is in the form of GSH. These findings contrast with previous reports of total levels of 3 to 6 microM and 50 to 75% GSSG. We found that plasma allowed to stand at 23 degrees C for 30 to 60 min has total glutathione levels of 4 to 7 microM, most (95%) of which is GSSG; after treatment of this plasma (following deproteinization) with KBH4, levels of 21 to 24 microM were found. GSH disappears rapidly from plasma, whereas GSSG disappears very slowly. gamma-Glutamyl transpeptidase does not account for the loss of plasma GSH, nor does binding to proteins account for more than a small fraction of the GSH that disappears. Most of the GSH that disappears can be found in the deproteinized samples after treatment with KBH4. The findings are in accord with the view that glutathione is translocated to plasma in the form of GSH and that such GSH constitutes the major source of plasma thiol. The intravascular phase of GSH metabolism seems to involve reduction of disulfide bonds of plasma constituents and mobilization of compounds bound by disulfide linkage to plasma proteins to form GSSG and low molecular weight derivatives of glutathione such as disulfides.

Animals↗
PubMed1980

Excretion of cysteine and gamma-glutamylcysteine moieties in human and experimental animal gamma-glutamyl transpeptidase deficiency.

Animals treated with potent gamma-glutamyl transpeptidase inhibitors and a patient with severe gamma-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, gamma-glutamylcysteine, and cysteine in their urine; these compounds were found in disulfide forms. The findings indicate that the metabolic function of gamma-glutamyl transpeptidase is associated with the metabolism or transport (or both) of cysteine, gamma-glutamylcysteine, and glutathione, and that gamma-glutamylcysteine is a physiological substrate of the enzyme. The occurrence of gamma-glutamylcysteine in urine and other considerations suggest that this dipeptide is formed as an extracellular metabolite of glutathione in addition to its recognized role as an intrcellular precursor of glutathione. The dipeptide may be formed by a pathway involving transpeptidation or by cleavage of the Cys-Gly bond of glutathione. In the course of this work it was found that the mixed disulfide between glutathione and gamma-glutamylcysteine is a good substrate of glutathione reductase.

Animals↗
PubMed1979

Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine).

Buthionine sulfoximine (S-n-butyl homocysteine sulfoximine), the most potent of a series of analogs of methionine sulfoximine thus far studied (Griffith, O.W., Anderson, M.E., and Meister, A. (1979) J. Biol. Chem. 254, 1205-1210), inhibited gamma-glutamylcysteine synthetase about 20 times more effectively than did prothionine sulfoximine and at least 100 times more effectively than methionine sulfoximine. The findings support the conclusion that the S-alkyl moiety of the sulfoximine binds at the enzyme site that normally binds the acceptor amino acid. Thus, the affinity of the enzyme for the S-ethyl, S-n-propyl, and S-n-butyl sulfoximines increases in a manner which is parallel to those of the corresponding isosteric acceptor amino acid substrates, i.e. glycine, alanine, and alpha-aminobutyrate. Buthionine sulfoximine did not inhibit glutamine synthetase detectably, nor did it produce convulsions when injected into mice. Injection of buthionine sulfoximine into mice decreased the level of glutathione in the kidney to a greater extent (less than 20% of the control level) than found previously after giving prothionine sulfoximine. alpha-Methyl buthionine sulfoximine was also prepared and found to be almost as effective as buthionine sulfoximine; this compound would not be expected to undergo substantial degradative metabolism. Buthionine sulfoximine and alpha-methyl buthionine sulfoximine may be useful agents for inhibition of glutathione synthesis in various experimental systems.

Glutamate-Cysteine Ligase↗
PubMed1979

Resolution of the light-harvesting chlorophyll a/b-protein of vicia faba chloroplasts into two different chlorophyll-protein complexes.

Thylakoids of Vicia faba chloroplasts disaggregated by sodium dodecyl sulfate were separated by means of different electrophoretic systems. Under the conditions of a high resolving gel system the chlorophyll containing zone previously termed chlorophyll-protein complex II or light-harvesting chlorophyll a/b-protein was found to be inhomogeneous. It represents a mixture of two distinct chlorophyll-proteins characterized by different spectral properties and different apoproteins. One chlorophyll-protein exhibits a chlorophyll a/b ratio of 0.9 and is associated with polypetides of 24,000 and 23,000 daltons. The 24,000 dalton band is proved to bind chlorophyll and has a light-harvesting function. The function of the 23,000 dalton band is unknown. The second chlorophyll-protein has a chlorophyll a/b ratio of 2.1 and an additional absorption maximum in the position of 637 nm. It is associated with only one polypeptide which has an apparent molecular weight of 23,000. The two 23,000 dalton polypeptides occurring in both complexes are not identical.

Chlorophyll↗