Glutathione substrate specificity

Yu SJ (2002) Substrate specificity of glutathione S-transferases from the fall armyworm. Pestic Biochem Physiol 74 41-51... 

Henderson, G. B., Murgolo, N.J., Kuriyan, J., Osapay, K., Kominos, D., Berry, A., Scrutton, N. S., Hinchlifife, N. W., Perham, R. N. Cerami, A. (1991). Engineering the substrate specificity of glutathione reductase toward that of trypanothione reduction. Proceedings of the National Academy of Sciences USA, 88, 8769-73. 

Perham, R. N., Scrutton, N.S. Berry, A. (1991)- New enzymes for old redesigning the coenzyme and substrate specificities of glutathione reductase. Bioessays, 13, 515-25. 

Jedhtschky G, Leier I, Buchholz U et al. (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 54 4833—4836 Keppler D, Jedlitschky G, Leier I (1998) Transport function and substrate specificity of multidrug resistance protein. Methods Enzymol 292 607-616... 

LeBlanc, G.A. and B.J. Cochrane. 1985. Modulation of substrate-specific glutathione s-transferase activity in Daphnia magna with concomitant effects on toxicity tolerance. Comp. Biochem. Physiol. 82C 37. 

Stenersen, J. and N. Oien. 1981. Glutathione s-transferases in earthworms (Lubricidae) substrate-specificity, tissue and species distribution, and molecular weight. Comp. Biochem. Physiol. 69 243-252. 

PG endoperoxlde E isomerase has been partially purified by solubilization of microsomes from bovine vesicular gland.A sulphydryl-con-talning compound (e.g. glutathione, dithlothreltol, 2-mercapto ethanol) is required to stabilize the enzyme and glutathione acts specifically as a co-factor for the isomerization of PGH to PGE. The pathway PGG- -15-hydroperoxy PGE- -PGE originally suggested53>54 seems unlikely since a) PGH rather than PGG is the preferred substrate, b) the isomerase does not contain peroxidase activity and converts PGG only to 15-hydroperoxy PGE and c) 15-hydroperoxy - PGE is not a substrate for purified PG endoperoxlde synthetase and might well inactivate this enzyme as do other hydroperoxides. 7,51... 

There are, as seems to be the rule with enzymes involved in the metabolism of xenobiotics, multiple isoenzymes with glutathione transferase activity. This fact combined with their low substrate specificity is considered to account for the variety of OP metabolites produced as shown in Figure 5 (39). There are at least three different isoenzymes in the house fly (40). One of the house fly glutathione transferases is identical to the enzyme responsible for DDT dehydrochlorination (41). This form is rather substrate specific, and is not known to confer metabolic cross resistance between DDT and any OP. 

Other ways of indicating the relationships and similarities of glutathione transferases have been used earlier. The first method, to classify them according to their activity, i.e., what they do, would have been much more useful for the toxicologist, but their substrate specificity is overlapping and there is a myriad of known and unknown possible substrates. A structural basis for classification is therefore more rational than a functional basis, such as the earlier terms aryl transferases, methyl transferases, epoxide transferases, DDT dehydrochlorinases, etc. 

The mechanism of L-1210 resistance to cisplatin and other platinum antitumour agents remains to be clearly defined. Both Waud [77] and others [78] suggest that reduced cisplatin uptake may be responsible in part for the resistance of the cell line. It has also been found that glutathione levels are high in human ovarian carcinoma cells made resistant to cisplatin in vitro [79]. However, reduction in the level did not alter the resistance to the drug [80]. Decreases in amino-acid transport and changes in amino-acid substrate specificities have also been suggested as the basis for the resistance [81], but definitive evidence has been difficult to obtain. 

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