Isolation of anthglutin, an inhibitor of γ-glutamyl transpeptidase from Penicillum oxalicum

Minato, Sadamasa

doi:10.1016/0003-9861(79)90088-2

Cited by 52 publications

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“…The present study describes two mechanisms mediating the transport of L-cystine into a human pancreatic duct cell line (PaTu 8902). Our findings demonstrate that, in contrast to L-glutamate (a poor substrate for y-GT), transport of L-cystine (acceptor for the y-glutamyl group of GSH) was significantly decreased following inhibition of duct cell y-GT activity by either acivicin or anthglutin, two structurally different inhibitors of y-GT (Minato, 1979;Allen et al 1981). This route appears to account for 40-50% of the total uptake of cystine in these cells.…”

mentioning

confidence: 67%

“…2B), strongly suggest that system xc-is expressed in this human pancreatic duct cell line. Effects of acivicin and anthglutin on y-GT activity and amino acid transport To determine whether amino acid uptake by PaTu 8902 cells was influenced by the y-glutamyl cycle, we measured transport of L-cystine and L-glutamine (substrates for y-GT) and L-glutamate (a poor substrate for y-GT, see Thompson & Meister, 1977) in cells treated for 5 min with different concentrations of either acivicin or anthglutin, structurally different inhibitors of y-GT (Minato, 1979;Allen et at. 1981).…”

Section: +3mentioning

confidence: 99%

“…and criticism (Pellefigue, Butler, Spielberg, Hollenberg, Goodman & Schulman, 1976;Minato, 1979;Sepulveda, Burton & Pearson, 1982;Hsu, Foreman, Corcoran, Ginkinger & Segal 1984;Bell, Buddington, Walton & Cowey, 1987). Most of the evidence implicating y-GT in amino acid transport is based on indirect experimental measurements (Vifia et al 1981(Vifia et al , 1990) because direct measurements of initial rates of transport for unidirectional transport of radiolabelled amino acids are lacking.…”

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confidence: 99%

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A role for gamma‐glutamyl transpeptidase and the amino acid transport system xc‐ in cystine transport by a human pancreatic duct cell line.

Sweiry

Sastre

Viña

et al. 1995

The Journal of Physiology

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1. The roles of the y-glutamyl cycle and the anionic amino acid transport system xc-in mediating L-cystine uptake were investigated in cultured human pancreatic duct PaTu 8902 cells. This cell line exhibits morphological features of normal pancreatic duct cells and expresses y-glutamyl transpeptidase (y-GT, EC 2.3.2.2), an enzyme involved in the metabolism and regulation of intracellular glutathione (GSH).2. Uptake of L-cystine (10 /M) was linear for up to 10 min, temperature dependent, Na+ independent, saturable (Michaelis-Menten constant (Km), 86 + 25 ,m; maximal velocity (Vmax), 109 + 33 nmol (mg protein)-h-') and reduced by 80-90% by a 50-fold excess concentration of L-glutamate and L-homocysteic acid, but not L-aspartate. These transport properties resemble those described for system xj-, which exchanges cystine for intracellular glutamate. 3. Acivicin, a known inhibitor of y-GT, decreased y-GT activity from 2-58 + 0-96 to 0 97 + 0.11 mU (mg protein)-' and decreased the initial rates of L-cystine and L-glutamine uptake by 41-55%. Anthglutin (1 -y-L-glutamyl-2-(2-carboxyphenylhyl)hydrazine), a structurally different inhibitor of y-GT, also caused a concentration-dependent (0 01-1 mM) decrease in y-GT activity and L-cystine uptake. 4. Neither acivicin nor anthglutin inhibited the uptake of L-glutamate, a poor substrate for y-GT. 5. In the presence of a 500-fold excess concentration of glutamate, which should abolish entry of cystine via system xj-, the remaining fraction of cystine transport was inhibited by 50% by acivicin, suggesting that transport is, in part, dependent on the activity of y-GT. 6. Cystine transport was also 60-80% inhibited by a series of y-glutamyl amino acids (5 mM) including y-glutamyl-glutamate, y-glutamyl-glutamine and y-glutamyl-glycine. a-Dipeptides inhibited cystine transport by only 6-22 %. 7. These findings demonstrate that in human pancreatic duct PaTu 8902 cells, cystine uptake is mediated by system xc-(50-60 %) and the y-glutamyl cycle. Our results provide the first evidence linking y-GT with cystine transport in human epithelial cells and are of relevance in view of the importance of cystine as a sulphur amino acid source for GSH synthesis in cells exposed to oxidative stress.A role for y-glutamyl transpeptidase (y-GT, EC 2.3.2.2), a amino acids were released. The initial hypothesis assumed cell-surface enzyme, in amino acid transport was that y-GT is involved in amino acid transport because its postulated by Meister and colleagues (Orlowski & Meister, activity

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confidence: 67%

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confidence: 99%

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confidence: 99%

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A role for gamma‐glutamyl transpeptidase and the amino acid transport system xc‐ in cystine transport by a human pancreatic duct cell line.

Sweiry

Sastre

Viña

et al. 1995

The Journal of Physiology

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“…The activities of ASA and ASB were assayed according to the colorimetric method of and using PNCS as a substrate at 37 o C. One unit of enzyme activity is defined as one nmol of pnitrocatechol liberated per an hour under the assay condition. For ATCase, the activity was assayed, as previously described (Balbaa et al, 2001), in 12.5 mM aspartate and 3.6 mM dilithium carbamyl phosphate at pH 8.2 and 30 o C. For α-amylase, the saccharogenic enzyme activity was determined according to the method of Fischer and Stein (1961) using 3,5-dinitrosalicylic acid as a substrate at 37 o C. For GGT, the transpeptidation assay of GGT was conducted as previously described (Minato 1978;McIntyre and Curthogs 1979). The assay contained 2.5 mM γ-glutamyl-p-nitroanilide, 0.1 M HCl, 0.1 M MgCl 2 , and 0.1 M Gly-Gly in 1 M Tris-HCl buffer, pH 9.0, at 37 o C.…”

Section: Methodsmentioning

confidence: 99%

Activity of Some Hepatic Enzymes in Schistosomiasis and Concomitant Alteration of Arylsulfatase B

Balbaa

Elkersh²,

Mansour³

et al. 2004

BMB Reports

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The levels of arylsulfatases A and B, α-amylase, aspartate transcarbamylase, and γ-glutamyl transpeptidase were investigated during the infection of mice with schistosoma mansoni. This infection caused a significant (p<0.001) increase in the activity of hepatic arylsulfatase B (ASB), aspartate transcarbamylases and γ-glutamyl transpeptidase. A non-significant difference occurred for α-amylase (p<0.3) and arylsulfatase A (p>0.5) when compared to the control. The specific activity of hepatic ASB was progressively increased with the progression of the Schistosoma-infection. Moreover, the kinetic studies of hepatic ASB in Schistosomainfection showed that a slight decrease in the value of K m and about a 40% increase in V max when compared to the control. In addition, the pH optimum of hepatic ASB was altered from 6 to 7 as a result of schistosomiasis. These observations suggest that there are schistosomiasis-associated changes of the catalytic and kinetic properties of hepatic ASB.

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“…This situation mimics an inborn deficiency of y-glutamyl transferase that is accompanied by a marked glutathionemia and glutathionuria (30). Glutathionuria is also induced by administration of y-glutamyl-(o-carboxy)-phenylhydrazide (31), a competitive inhibitor of the transferase (32,33 …”

Section: Resultsmentioning

confidence: 99%

Inactivation of renal gamma-glutamyl transferase by 6-diazo-5-oxo-L-norleucylglycine, an inactive precursor of affinity-labeling reagent.

Inoue¹,

Morino²

1981

Proc. Natl. Acad. Sci. U.S.A.

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In vitro experiments showed that 6-diazo-5-oxo-L-norleucylglycine, a dipeptide analog of L-glutaminylglycine, inactivates y-glutamyl transferase bound to renal brush border membrane vesicles but does not inactivate the purified transferase. The rate of inactivation of the membrane-bound enzyme decreased markedly in the presence of dipeptides, such as L-leucylglycine and L-alanylglycine, or in the presence of o-phenanthroline, an inhibitor of renal peptidases. The presence of L-cysteinylglycine S-acetyldextran polymer (Mr 500,000), which does not permeate membranes, protected the membrane-bound transferase from inactivation by 6-diazo-5-oxo-L-norleucylglycine. This and other findings suggest that the norleucylglycine derivative was hydrolyzed by peptidase(s) bound to the outer surface ofthe brush border membranes and that the 6-diazo-5-oxo-L-norleucine thus released acts as an affinity-labeling reagent for the membranebound transferase. Similar effects were observed in vivo. Intravenous administration of 6-diazo-5-oxo-L-norleucylglycine to mice resulted in a marked decrease in renal transferase activity. Mice thus pretreated with 6-diazo-5-oxo-L-norleucylglycine, but not an untreated group, excreted significant amounts of S-carbamido['4C]methylglutathione in their urine within 30 min ofintravenous administration ofthis compound. This finding suggests that the renal transferase was involved in the hydrolysis of the glutathione S-conjugate in the glomerular filtrate in vivo and that the administered 6-diazo-5-oxo-L-norleucylglycine underwent hydrolysis peptidase(s)-catalyzed to liberate 6-diazo-5-oxo-L-norleucine that reacted with the membrane-bound y-glutamyl transferase.

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Isolation of anthglutin, an inhibitor of γ-glutamyl transpeptidase from Penicillum oxalicum

Cited by 52 publications

References 20 publications

A role for gamma‐glutamyl transpeptidase and the amino acid transport system xc‐ in cystine transport by a human pancreatic duct cell line.

A role for gamma‐glutamyl transpeptidase and the amino acid transport system xc‐ in cystine transport by a human pancreatic duct cell line.

Activity of Some Hepatic Enzymes in Schistosomiasis and Concomitant Alteration of Arylsulfatase B

Inactivation of renal gamma-glutamyl transferase by 6-diazo-5-oxo-L-norleucylglycine, an inactive precursor of affinity-labeling reagent.

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