Synthesis and evaluation of GGPP geometric isomers: divergent substrate specificities of FTase and GGTase I.
A stereocontrolled synthetic route has been used to prepare two of the geometric isomers of all-trans-GGPP. Neither of these isomers is effective substrates for mammalian GGTase I, but 3 is a potent inhibitor of this enzyme (IC(50)=100 nM). Surprisingly, both compounds are effective substrates for mammalian FTase.
Zahn
T J
TJ
Department of Pharmaceutical Sciences, College of Pharmacy and AHP, Wayne State University, Detroit, MI 48202, USA.
Whitney
J
J
Weinbaum
C
C
Gibbs
R A
RA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008322:Mammals; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013379:Substrate Specificity
D004224:Diterpenes; D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; C040155:geranylgeranic acid; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; C002963:geranylgeranyl pyrophosphate