Literature summary for 2.6.1.19 extracted from

Juncosa, J.I.; Takaya, K.; Le, H.V.; Moschitto, M.J.; Weerawarna, P.M.; Mascarenhas, R.; Liu, D.; Dewey, S.L.; Silverman, R.B.
Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of addiction (2018), J. Am. Chem. Soc., 140, 2151-2164 .

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Crystallization (Commentary)

Crystallization (Comment)	Organism
enzyme bound to inhibitor (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, X-ray diffraction structure determination and analysis at 1.95 A resolution	Sus scrofa

Inhibitors

Inhibitors	Comment	Organism	Structure
(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	Rattus norvegicus
(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	Sus scrofa
(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid	a highly potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of addiction, design, synthesis method and mechanism, overview. Enzyme-bound structure analysis shows binding between the enzyme and a stable PLP-inhibitor noncovalent complex, rather than covalent modification, tautomeric forms of the structure of inhibitor-inactivated GABA-AT (eight theoretical tautomers of inhibitor-inactivated GABA-AT)	Rattus norvegicus
(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid	a highly potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of addiction, design, synthesis method and mechanism, overview. Enzyme-bound structure analysis shows binding between the enzyme and a stable PLP-inhibitor noncovalent complex, rather than covalent modification, tautomeric forms of the structure of inhibitor-inactivated GABA-AT (eight theoretical tautomers of inhibitor-inactivated GABA-AT)	Sus scrofa
additional information	molecular dynamics simulations, design of mechanism-based inhibitors, drug design, overview	Rattus norvegicus
additional information	molecular dynamics simulations, design of mechanism-based inhibitors, drug design, overview	Sus scrofa
vigabatrin	FDA-approved drug, inactivator of GABA-AT, moderate activity	Rattus norvegicus
vigabatrin	FDA-approved drug, inactivator of GABA-AT, moderate activity	Sus scrofa

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
mitochondrion	-	Sus scrofa	5739	-
mitochondrion	-	Rattus norvegicus	5739	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
4-aminobutanoate + 2-oxoglutarate	Sus scrofa	-	succinate semialdehyde + L-glutamate	-	?
4-aminobutanoate + 2-oxoglutarate	Rattus norvegicus	-	succinate semialdehyde + L-glutamate	-	?

Organism

Organism	UniProt	Comment	Textmining
Rattus norvegicus	P50554	-	-
Sus scrofa	P80147	-	-

Reaction

Reaction	Comment	Organism	Reaction ID
4-aminobutanoate + 2-oxoglutarate = succinate semialdehyde + L-glutamate	catalytic mechanism of GABA-AT for degradation of GABA into succinic semialdehyde, overview	Sus scrofa	a
4-aminobutanoate + 2-oxoglutarate = succinate semialdehyde + L-glutamate	catalytic mechanism of GABA-AT for degradation of GABA into succinic semialdehyde, overview	Rattus norvegicus	a

Source Tissue

Source Tissue	Comment	Organism	Textmining
brain	-	Sus scrofa	-
hippocampus	-	Sus scrofa	-
liver	-	Rattus norvegicus	-
nucleus accumbens	-	Sus scrofa	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
4-aminobutanoate + 2-oxoglutarate	-	Sus scrofa	succinate semialdehyde + L-glutamate	-	?
4-aminobutanoate + 2-oxoglutarate	-	Rattus norvegicus	succinate semialdehyde + L-glutamate	-	?

Synonyms

Synonyms	Comment	Organism
ABAT	-	Sus scrofa
GABA aminotransferase	-	Sus scrofa
GABA aminotransferase	-	Rattus norvegicus
GABA-AT	-	Sus scrofa
GABA-AT	-	Rattus norvegicus

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
22	-	assay at room temperature	Rattus norvegicus

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
8.5	-	assay at	Rattus norvegicus

Cofactor

Cofactor	Comment	Organism	Structure
pyridoxal 5'-phosphate	PLP, dependent on	Sus scrofa
pyridoxal 5'-phosphate	PLP, dependent on	Rattus norvegicus

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
additional information	-	additional information	inihbition kinetics	Rattus norvegicus

General Information

General Information	Comment	Organism
malfunction	inhibition of GABA aminotransferase (GABA-AT), the enzyme that degrades GABA, is a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of the inhibition antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy	Sus scrofa
malfunction	inhibition of GABA aminotransferase (GABA-AT), the enzyme that degrades GABA, is a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of the inhibition antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy	Rattus norvegicus
physiological function	gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The enzyme GABA aminotransferase (GABA-AT) degrades GABA	Sus scrofa
physiological function	gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The enzyme GABA aminotransferase (GABA-AT) degrades GABA	Rattus norvegicus

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Release 2023.1 (January 2023)