Glutamyl hydrolase: properties and pharmacologic impact.
Glutamyl hydrolase cleaves the poly-gamma-glutamate chain folate and antifolate poly-gamma-glutamates. Its cellular location is lysosomal with large amounts of the enzyme constitutively secreted. The highest levels of glutamyl hydrolase mRNA in humans is found in the liver and kidney. Baculovirus-expressed human enzyme has been used to evaluate the method of hydrolysis of methotrexate-gamma-glu4 and MTA-gamma-glu4. In both cases, the substrates are hydrolyzed by removal of the outer two gamma-glutamate linkages, yielding glu and gamma-glu2 as the glutamate products. Cell lines resistant to 5,10-dideazatetrahydrofolate (lometrexol) have sevenfold higher activities of glutamyl hydrolase. These cultures have a 60% to 90% reduced amount of antifolate polygamma-glutamates and 30% reduced folyl poly-gamma-glutamates. These results suggest the possibility of using glutamyl hydrolase to favorably modulate the activity of antifolate therapy.
Galivan
J
J
Division of Molecular Medicine, Wadsworth Center, New York Department of Health, Albany 12201-0509, USA.
Ryan
T
T
Rhee
M
M
Yao
R
R
Chave
K
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002384:Catalysis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D000068437:Pemetrexed; D012333:RNA, Messenger; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D012333:RNA, Messenger; D000068437:Pemetrexed; D006147:Guanine; D011623:gamma-Glutamyl Hydrolase