EC Number   |
Inhibitors |
Structure |
|---|
    2.6.1.19 | (1S,3S)-(Z)-3-amino-4-(2,2,2-trifluoroethylidene)cyclopentanecarboxylic acid |
inhibition in the presence of beta-mercaptoethanol |
   |
| 2.6.1.19 | (1S,3S)-3-amino-4-(2,2,2-trifluoro-1-trifluoromethylethylidene)-cyclopentanecarboxylic acid |
weak reversible inhibition in the presence of beta-mercaptoethanol |
|
| 2.6.1.19 | (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid |
potent irreversible inhibitor |
|
| 2.6.1.19 | (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid |
i.e. CPP-115, high inhibition of GABA-AT. Potential mechanism of inactivation of GABA-AT by CPP-115, overview. CPP-115 has been designed to inactivate GABA-AT via a Michael addition mechanism that would lead to a covalent adduct with the enzyme, similar to that with vigabatrin. But it is discovered from the crystal structure of GABAT inactivated by CPP-115 that the enzyme forms a noncovalent, tightly bound complex with CPP-115 via strong electrostatic interactions between the two carboxylate groups in the resulting metabolite with Arg192 and Arg445 in the active site. Inactivation is initiated by Schiff base formation between CPP-115 and the lysine-bound PLP, followed by gamma-proton removal and tautomerization, resulting in a highly reactive Michael acceptor. Before Lys329 can attack this Michael acceptor, catalytic hydrolysis of the difluoromethylenyl group occurs, leading to the PLP-bound dicarboxylate metabolite, which elicits a conformational change in the enzyme and tightly binds to Arg192 and Arg445 via electrostatic interactions. Molecular dynamic simulations and computer modeling indicate a movement of the difluoromethylenyl group of the Michael acceptor away from Lys329 upon enzyme-catalyzed tautomerization, leaving it too far away from Lys329 for nucleophilic attack. The enzyme catalyzes its hydrolysis instead |
|
| 2.6.1.19 | (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid |
i.e. CPP-115, high inhibition of GABA-AT. Potential mechanism of inactivation of GABA-AT by CPP-115, overview. CPP-115 has been designed to inactivate GABA-AT via a Michael addition mechanism that would lead to a covalent adduct with the enzyme, similar to that with vigabatrin. But it is discovered from the crystal structure of GABAAT inactivated by CPP-115 that the enzyme forms a noncovalent, tightly bound complex with CPP-115 via strong electrostatic interactions between the two carboxylate groups in the resulting metabolite with Arg192 and Arg445 in the active site. Inactivation is initiated by Schiff base formation between CPP-115 and the lysine-bound PLP, followed by gamma-proton removal and tautomerization, resulting in a highly reactive Michael acceptor. Before Lys329 can attack this Michael acceptor, catalytic hydrolysis of the difluoromethylenyl group occurs, leading to the PLP-bound dicarboxylate metabolite, which elicits a conformational change in the enzyme and tightly binds to Arg192 and Arg445 via electrostatic interactions. Molecular dynamic simulations and computer modeling indicate a movement of the difluoromethylenyl group of the Michael acceptor away from Lys329 upon enzyme-catalyzed tautomerization, leaving it too far away from Lys329 for nucleophilic attack. The enzyme catalyzes its hydrolysis instead |
|
| 2.6.1.19 | (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid |
- |
|
| 2.6.1.19 | (1S,4R)-4-amino-2-cyclopentene-1-carboxylic acid |
analogue of 4-aminobutanoate, vigabatrin |
|
| 2.6.1.19 | (1S,4S)-2-(difluoromethylidene)-4-(1H-tetrazol-5-yl)cyclopentanamine |
time-dependent inactivation, ratio kinact/KI value at pH 8.0 is 2.48 per min and mM |
|
| 2.6.1.19 | (2E)-4-methylpentan-2-one N-(2,4-dimethylphenyl)semicarbazone |
57% inhibition at 0.125 mM |
|
| 2.6.1.19 | (2E)-butan-2-one N-(2,4-dimethylphenyl)semicarbazone |
89% inhibition at 0.0625 mM |
|
