Irreversible inhibition of rat S-adenosylmethionine decarboxylase by 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine.
5'-([(Z)-4-Amino-2-butenyl]methylamino)-5'-deoxyadenosine [Z)-AbeAdo) was tested in vitro and in vivo as a potential inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC), a pyruvoyl-containing enzyme, purified from rat liver. In vitro (Z)-AbeAdo produces a time- and dose-dependent irreversible inhibition of the enzyme. Saturation kinetics are observed when the enzyme is preincubated with (Z)-AbeAdo in the presence of 50 microM putrescine, a known activator of AdoMetDC. Under these conditions kinetic constants were measured (Ki = 0.56 +/- 0.04 microM; tau 1/2 = 0.51 +/- 0.03 min). The inhibition is not relieved by prolonged dialysis of the inactivated enzyme. The turnover number for (Z)-AbeAdo, i.e. the number of inactivator molecules required to inactivate one enzyme molecule, is approximately 1.5. The selectivity of (Z)-AbeAdo was explored: the compound is not a substrate of adenosine deaminase, mitochondrial monoamine oxidase and diamine oxidase, but is slowly oxidized by benzylamine oxidase from rat aorta. The (E)-isomer of AbeAdo, is at least 100-fold less active than (Z)-AbeAdo as a time-dependent inhibitor of rat liver AdoMetDC. In rats, intraperitoneal administration of (Z)-AbeAdo produces a rapid, long-lasting and dose-dependent decrease of AdoMetDC activity in ventral prostate, testis and brain.
Danzin
C
C
Merrell Dow Research Institute, Strasbourg Research Centre, France.
Marchal
P
P
Casara
P
P
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D001595:Benzylamine Oxidase / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D011467:Prostate / Q000201:enzymology; D011700:Putrescine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013737:Testis / Q000201:enzymology; D013997:Time Factors
D003839:Deoxyadenosines; C065859:MDL 73811; D001595:Benzylamine Oxidase; D012437:Adenosylmethionine Decarboxylase; D011700:Putrescine