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Substrate Inhibitors (substrate + inhibitor)
Selected AbstractsPreferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunctionJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Imane Nafia Abstract Nigral depletion of the main brain antioxidant GSH is the earliest biochemical event involved in Parkinson's disease pathogenesis. Its causes are completely unknown but increasing number of evidence suggests that glutamate transporters [excitatory amino acid transporters (EAATs)] are the main route by which GSH precursors may enter the cell. In this study, we report that dopamine (DA) neurons, which express the excitatory amino acid carrier 1, are preferentially affected by EAAT dysfunction when compared with non-DA neurons. In rat embryonic mesencephalic cultures, l -trans-pyrrolidine-2,4-dicarboxylate, a substrate inhibitor of EAATs, is directly and preferentially toxic for DA neurons by decreasing the availability of GSH precursors and lowering their resistance threshold to glutamate excitotoxicity through NMDA-receptors. In adult rat, acute intranigral injection of l -trans-pyrrolidine-2,4-dicarboxylate induces a large regionally selective and dose-dependent loss of DA neurons and ,-synuclein aggregate formation. These data highlight for the first time the importance of excitatory amino acid carrier 1 function for the maintenance of antioxidant defense in DA neurons and suggest its dysfunction as a candidate mechanism for the selective death of DA neurons such as occurring in Parkinson's disease. [source] Benzene-1,2-, 1,3-, and 1,4-di- N -substituted carbamates as conformationally constrained inhibitors of acetylcholinesteraseJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2007Ming-Cheng Lin Abstract Benzene-1,2-, 1,3-, and 1,4-di- N -substituted carbamates (1,15) are synthesized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti -conformations of acetylcholine, respectively. All carbamates 1,15 are characterized as the pseudo substrate inhibitors of acetylcholinesterase. For a series of geometric isomers, the inhibitory potencies are as follows: benzene-1,4-di- N -substituted carbamate (para compound) > benzene-1,3-di- N -substituted carbamate (meta compound) > benzene-1,2-di- N -substituted carbamate (ortho compound). Therefore, benzene-1,4-di- N -substituted carbamates (para compounds), with the angle of 180° between two C(benzene),O bonds, mimic the preferable anti C,O/C,N conformers of acetylcholine for the choline ethylene backbone in the acetylcholinesterase catalysis. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:348,353, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20202 [source] Substrate activation of butyrylcholinesterase and substrate inhibition of acetylcholinesterase by 3,3-dimethylbutyl- N - n -butylcarbamate and 2-trimethylsilyl-ethyl- N - n -butylcarbamateJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2007Shyh-Ying Chiou Abstract Carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work is to use the substrate analogs of butyrylcholinesterase, 3,3-dimethylbutyl- N - n -butylcarbamate (1) and 2-trimethylsilyl-ethyl- N - n -butylcarbamate (2) to probe the substrate activation mechanism of butyrylcholinesterase. Compounds 1 and 2 are characterized as the pseudo substrate inhibitors of acetylcholinesterase; however, compounds 1 and 2 are characterized as the essential activators of butyrylcholinesterase. Therefore, compounds 1 and 2 mimic the substrate in the acetylcholinesterase-catalyzed reactions, but the behavior of compounds 1 and 2 mimics the substrate activation in the butyrylcholinesterase-catalyzed reactions. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:24,31, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20158 [source] QSAR for Inhibition of Pseudomonas Species Lipase by 1-Acyloxy-3- N-n -octylcarbamyl-benzenesMOLECULAR INFORMATICS, Issue 3 2009Shyh-Ying Chiou Abstract 1-Acyloxy-3- N-n -octylcarbamyl-benzenes (1,9) are synthesized to characterize the Quantitative Structure,Activity Relationship (QSAR) for the Third Acyl Group Binding Site (TACS) of Pseudomonas species lipase. Inhibitors 1,9 are characterized as pseudo or alternate substrate inhibitors of the enzyme. The inhibition constant (Ki) and carbamylation constant (k2) for the enzyme inhibitions by inhibitors 1,9 are determined. The carbamate carbons of the n -octylcarbamyl moieties of inhibitors 1,9 are nucleophilically attacked by the active site serine of the enzyme and the n -octylcarbamyl groups of inhibitors 1,9 are bound to the Acyl Group Binding Site (ACS) of the enzyme. Both pKi and log,k2 values are linearly corrected with the Hansch hydrophobicity , values of the substituents of the acyl moieties of inhibitors 1,7. The slopes for these corrections are 0.13 and 0.02, respectively. This result suggests that the enzyme inhibitions by inhibitors 1,7 have a common mechanism. Thus, all acyl moieties of inhibitors 1,7 should bind to the TACS of the enzyme since the acyl and carbamyl moieties of inhibitors 1,7 are meta to each other. This result also indicates that the major interaction between the acyl moiety of inhibitors 1,7 and the TACS of the enzyme is primarily the hydrophobic interaction. The more hydrophobic characters of inhibitors 1,7 are, the more tightly these inhibitors bind to the enzyme. In contrast, 1-triphenylacetoxy-3- N-n -octylcarbamyl-benzene (8) and 1-trimethylacetoxy-3- N-n -octylcarbamyl-benzene (9) do not bind to the TACS of the enzyme due to the fact that the inhibitions by both inhibitors are not linearly correlated with ,. It is possible that these two inhibitors are too bulky to fit into the TACS of the enzyme. [source] | ||||||||||