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• W2183635321 abstract "ion of a proton forming a conjugated imine, which could then react with a nucleophilic residue of the enzyme (107). However, subsequent exper­ iments have indicated that the enzyme is, in fact, inactivated by a transamina­ tion of the pyruvate prosthetic group (101 ). Such transamination occurs with the normal AdoMet substrate by incorrect protonation of the enolate interme­ diate, but the rate with AbeAdo is much greater. AbeAdo is a very effective and specific inhibitor of polyamine synthesis in protozoal parasites, in cultured tumor cells, and in vivo (21 , 22, 28, 108-1 10). Its uptake into trypanosomes occurs via the purine-nucleoside-transport system ( 109). The mechanism of uptake into mammalian cells is unclear and may not be active transport. However, some LI210 cells resistant to AbeAdo have been derived by prolonged exposure to the drug. These cells have a reduced accu­ mulation of the drug that could be due to the induction of an efflux mechanism (22). Other mechanisms of resistance are also known. Resistance to AbeAdo and to ethylglyoxal bis(guanylhydrazone) (EGBG) was obtained in mouse FM3A cells by treatment with a mutagen, which led to an increased production of AdoMetDC mRNA and protein, but the mechanism underlying the elevated mRNA level is obscure ( 1 1 1 ). Competitive Inhibitors The third approach to the production of AdoMetDC inhibitors has been taken by Regenass and colleagues ( 1 12-1 15), who have used the traditional approach of making a large number of compounds related to MGBG, a known compet­ i tive inhibitor of the enzyme (99), and then screening these compounds for those with good activity against AdoMetDC and less activi ty towards both diamine oxidase and the ability to cause mitochondrial damage, which are two additional well-known sites of MGBG action. Several compounds that are strong and apparen tly speci fic AdoMetDC inhibitors have emerged from these trials, including [2,2-bipyridine]-6,6'-dicarboximidamide (CGP-39937) ( 1 1 2," @default.
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• W2183635321 date "1995-01-01" @default.
• W2183635321 modified "2023-10-11" @default.
• W2183635321 title "Polyamines as Targets for Therapeutic Intervention" @default.
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• W2183635321 doi "https://doi.org/10.1146/annurev.pharmtox.35.1.55" @default.
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