Y-glutamylization

Enzymes, measured in clinical laboratories, for which kits are available include y-glutamyl transferase (GGT), alanine transferase [9000-86-6] (ALT), aldolase, a-amylase [9000-90-2] aspartate aminotransferase [9000-97-9], creatine kinase and its isoenzymes, galactose-l-phosphate uridyl transferase, Hpase, malate dehydrogenase [9001 -64-3], 5 -nucleotidase, phosphohexose isomerase, and pymvate kinase [9001-59-6]. One example is the measurement of aspartate aminotransferase, where the reaction is followed by monitoring the loss of NADH ... 

The cyclic sulfoximine 93a,b, a key intermediate in the synthesis of sulfoximine 94 designed as inhibitors of Escherichia Coli y-glutamyl synthetase, was synthesized stereoselectively (96BMC(6)1437, 98BMC(6)1935). X-ray analysis (99AX(C55)1598) of 93b was performed, elucidating the configuration. 

Antithyroid drags have several side effects. The most frequent side effects are maculopapular rashes, pruritus, urticaria, fever, arthralgia and swelling of the joints. They occur in 1-5% of patients [1, 2]. Loss of scalp hair, gastrointestinal problems, elevations of bone isoenzyme of alkaline phosphatase and abnormalities of taste and smell are less common. The incidence of all these untoward reactions is similar with MMI and PTU. Side effects of MMI are dose-related, whereas those of PTU are less clearly related to dose [1]. PTU may cause slight transient increases of serum aminotransferase and y-glutamyl transpeptidase concentrations but also severe hq atotoxicity whereas methimazole or carbimazole can be associated with cholestasis. The side... 

Activities of glutamate-pyruvate transaminase (SGPT, GPT) (EC 2.6.1.2), L-y -glutamyl-transferase (y-GT) (EC 2.3.2.2) and level of triglycerides (TG) in serum, as well as levels of glutathione (GSH) and malondialdehyde (MDA) in the liver were determined. 

In subsequent experiments (66), this locked substrate was used to obtain evidence for the hypothesis (67) that enzyme-bound y-glutamyl phosphate 14 is an intermediate in the enzyme-catalyzed reaction. All attempts to isolate this acyl phosphate 14 have failed (66), presumably because of the marked tendency of this intermediate to cyclize to pyrrolidonecarboxyUc acid, 15, and to hydrolyze to glutamic acid. 

Figure 3-3. Glutathione (y-glutamyl-cysteinyl-glycine). Note the non-a peptide bond that links Glu to Cys.

The GMT in human serum reacts most rapidly with Y-glutamyl-p-nitroanilide at pH 8.2. The same activity is found in 2-amino-2-methylpropane-l 3 diol, diethanolamine, triethanolamine and tris buffers. Magnesium ions have no effect on the activity but favor the solubilization of the substrate. Bondar and Moss (54) found that free glutamate, due to elevated serum glutamate concentrations or glutamate released by substrate breakdown, increases the apparent GMT activity. They concluded that the assay should be performed in the presence of 1.0 vM/1 glutamate in order to reduce the possibility of falsely elevated results. This was not observed by others. Rowe and co-workers have indicated that certain batches of p-nitroanilide substrate contain impurities which may reduce GMT activity and increase the values ( ). Huesby and Stromme (56) confirmed the presence of such impurities and recommended pyridine extraction for substrate purification. 

Bondar, R. J. L. and Moss, G. A. Enhancing effect of glutamate on apparent serum Y glutamyl transpeptidase activity. Clin. Chem. (1974), 20, 317-319. 

Shi, M., Gozal, E., Choy, H.A. and Forman, H.J. (1993). Extracellular glutathione and y-glutamyl transpeptidase prevent H Oj-induced injury by 2,3-dimethoxy-l,4-naphthoquinone. Free Rad. Biol. Med. 15, 57-67. 

Cholestasis (increased total bilirubin, direct bilirubin, alkaline phosphatase, and y-glutamyl transferase)... 

Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, y-glutamyl transferase, and bilirubin may be elevated in patients with hepatobiliary disease. 

Mitoxantrone (Novantrone) 12 mg/m2 up to 140 mg/m2 IV Every 3 months Nausea 76% Alopecia 61 % Menstrual disorders 61% Urinary tract infection 32% Amenorrhea 25% Leukopenia 1 9% y-Glutamyl transpeptidase increase 1 5%... 

In the second step, GSH-S catalyzes the synthesis of GSH from y-glutamyl-cysteine and glycine in the presence of ATP. A cDNA encoding human GSH-S has been cloned, and the deduced protein consists 474 amino acids with a subunit molecular weight of 52,352 (Gl). Active enzyme is considered to be a homodimer. 

The tripeptide glutathione is the major intracellular antioxidant. The tripeptide glutathione (y-glutamyl-cysteinyl-glycine) is the major intracellular antioxidant. It is synthesized via these reactions (Fig. 40-6) ... 

Glutathione + amino acid —> y-glutamyl-amino acid + cysteinylglycine... 

Routine liver assessment tests include alkaline phosphatase, bilirubin, aspartate transaminase, alanine transaminase, and y-glutamyl transpeptidase (GGT). Additional markers of hepatic synthetic activity include albumin and prothrombin time. The substances are typically elevated in chronic inflammatory liver diseases such as hepatitis C, but may be normal in others with resolved infectious processes. 

FIGURE 21-1. Interpretation of liver function tests. (ALT, alanine transaminase AST, aspartate transaminase CT, computed tomography DDX, differential diagnosis GGT, y-glutamyl transpeptidase.)... 

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