71830-06-3Relevant articles and documents
Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1 S,3 S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115)
Lee, Hyunbeom,Doud, Emma H.,Wu, Rui,Sanishvili, Ruslan,Juncosa, Jose I.,Liu, Dali,Kelleher, Neil L.,Silverman, Richard B.
, p. 2628 - 2640 (2015)
γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5′-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.
Nitrilase activity screening on structurally diverse substrates: Providing biocatalytic tools for organic synthesis
Vergne-Vaxelaire, Carine,Bordier, Franck,Fossey, Aurelie,Besnard-Gonnet, Marielle,Debard, Adrien,Mariage, Aline,Pellouin, Virginie,Perret, Alain,Petit, Jean-Louis,Stam, Mark,Salanoubat, Marcel,Weissenbach, Jean,De Berardinis, Veronique,Zaparucha, Anne
, p. 1763 - 1779 (2013/07/19)
A high-throughput screening of candidate nitrilases against 25 structurally diverse substrates allowed us to create a wide collection of 125 experimentally validated nitrilases. The enzymes were selected by genomic approach from 700 diverse prokaryotic species and one metagenome as representative of the nitrilase family diversity. The enzymatic screening of this collection expands the biocatalytic toolbox for chemical synthesis by providing a large number of tested nitrilases with their assigned substrates. Three examples illustrate the synthetic potential of our enzyme collection. The syntheses of carboxylic acid building blocks, a β-substituted phenylpropanoic acid, a cyclic γ-keto carboxylic acid and a mononitrile monocarboxylic acid, were achieved from the corresponding nitrile substrates, using three new nitrilases (two from Sphingomonas wittichii and one from Syntrophobacter fumaroxidans). Improvements of nitrilase activities through the optimization of reaction parameters and the preparative biocatalytic synthesis are presented for these three examples. Copyright
Asymmetric synthesis and structure-activity relationship of the four stereoisomers of the antibiotic amidinomycin part 1: The synthesis
Sung, Sun-Young,Frahm, August Wilhelm
, p. 291 - 300 (2007/10/03)
The natural amidinomycin ((1R, 3S)-14) and its three stereoisomers are synthesized from homochiral 3-oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis-N-(1-phenylethyl)-3-aminocyclo-pentanecarboxylates (3b) via optically active methyl N-(1-phenylethyl)-3-iminocyclopentane- carboxylates (2b) for the cis-isomers of 14. Optically pure trans-3- aminocyclopentane-carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3- hydroxyiminocyclopentanecarboxylic acids (5a) and lead to the trans-isomers of 14.
CHEMOENZYMATIC SYNTHESIS OF CONFORMATIONALLY RIGID GLUTAMIC ACID ANALOGUES
Trigalo, F.,Buisson, D.,Azerad, R.
, p. 6109 - 6112 (2007/10/02)
All stereomers of cyclohexane cyclopentane-derived analogues of glutamic acid have been synthesized from the corresponding 3-keto-cycloalkyl carboxylic acid esters by a combination of microbial steps and standard chemical methods.
