Stereochemistry of Reactions Catalysed by Mammalian‐Brain <scp>L</scp>‐Glutamate 1‐Carboxy‐lyase and 4‐Aminobutyrate: 2‐Oxoglutarate Aminotransferase

Bouclier, Martine; Jung, Michael J.; Lippert, Bruce

doi:10.1111/j.1432-1033.1979.tb13195.x

Cited by 49 publications

(20 citation statements)

References 18 publications

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“…These are a concerted E2, or a non-concerted E1cb type elimination. Lys329 is the candidate base for the elimination, and modelling suggests that it abstracts the (S)-γ proton from (R)-2 or (S)-2, as is known from labeling studies (50). A concerted E2 mechanism requires an antiperiplanar relationship between the eliminating H and F atoms.…”

Section: Discussionmentioning

confidence: 99%

Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding

Clift

Ji²,

Deniau

et al. 2007

Biochemistry

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Abstractγ-Aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of α-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)-and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH 3

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Section: Discussionmentioning

confidence: 99%

Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding

Clift

Ji²,

Deniau

et al. 2007

Biochemistry

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“…In both cases the signal from protons at C4 was halved, indicating that the 4-aminobutyrate produced by each form of the enzyme was monodeuterated at C4 (equivalent to C␣ of glutamate). When the products were treated in D 2 O with 4-aminobutyrate aminotransferase, which labilizes the pro-S proton at C4 of 4-aminobutyrate exclusively (24), the signal from C4 protons was lost in each case. This indicated incorporation of a second deuterium at C4 .…”

Section: Fig 1 Sequence Alignment Of Lactobacillus 30a Ornithine Dementioning

confidence: 99%

The Roles of His-167 and His-275 in the Reaction Catalyzed by Glutamate Decarboxylase from Escherichia coli

Tramonti¹,

Biase²,

Giartosio³

et al. 1998

Journal of Biological Chemistry

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Two histidine residues in glutamate decarboxylase from Escherichia coli, potential participants in catalysis because they are conserved among amino acid decarboxylases and because they are at the active site in the homologous enzyme ornithine decarboxylase, were mutated. His-275 is shown to bind the cofactor pyridoxal 5-phosphate but not to contribute directly to catalysis. The H275N enzyme was unable to bind the cofactor whereas the H275Q mutant contained 50% of the normal complement of cofactor and its specific activity (expressed per mole of cofactor) was 70% of that of the wild-type enzyme. The H167N mutant bound the cofactor tightly, its specific activity was approximately half that of the wild-type enzyme and experiments in D 2 O showed that it catalyzed replacement of the carboxyl group with retention of configuration as does the wildtype enzyme. Comparison of reaction profiles by observing changes in the absorbance of the cofactor after stopped-flow mixing, revealed that a slow reaction, in which approximately one-third of the wild-type enzyme is converted to an unreactive complex during catalysis, does not occur with the H167N mutant enzyme. This reaction is attributed to a substrate-induced conformational change, a proposal that is supported by differential scanning calorimetry.

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“…Bacterial and mammalian -transaminases also remove exclusively the pro-S hydrogen from the prochiral -carbon atom of amino donors [17,89].…”

Section: Amination Bioprocessesmentioning

confidence: 99%

High-Yield Biocatalytic Amination Reactions in Organic Synthesis

Ward¹,

Wohlgemuth²

2010

COC

140

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The amino functionality gives important biological activity in pharmaceutical compounds. The formation of chiral amines and amino acids can be accomplished by several chemical routes but enzymatic formation of amines offers many advantages in preparing chiral amino compounds or amination of fragile compounds compared to stoichiometric or catalytic chemical transformations. Biocatalytic routes to amines primarily use enzymes of the transaminase class (also known as aminotransferases) which transfer the amino function from a donor organic compound to a ketone or aldehyde acceptor. Although known since 1937, the transamination reaction experiences renewed interest due to the advances in biochemistry and molecular biology and the excellent selectivity of biocatalysts. Other enzymes that have been used to synthesize chiral amines are from the phenylalanine ammonia lyase class that use ammonia as the amino source. The use of recombinant enzymes for the biocatalytic preparation of amines is expanding at a great rate and the range of enzymes revealed in DNA sequence databases is of the order of tens of thousands. Since a large number of substrates like ketones, hydroxyketones and ketoacids can be made by chemical synthesis, the growing toolbox of -, -, -, -, -and -transaminases enable the synthesis of various new chemical entities by biocatalytic amination reactions. In order to simplify the isolation and purification of the product, it is useful to drive the amination reaction to completion. The biocatalytic processes that have been developed show different strategies of overcoming the kinetic limitations of the transaminase reactions and show how some enzymes have been used in processes to make large quantities of chiral compounds with amino functionalities.

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Stereochemistry of Reactions Catalysed by Mammalian‐Brain L‐Glutamate 1‐Carboxy‐lyase and 4‐Aminobutyrate: 2‐Oxoglutarate Aminotransferase

Cited by 49 publications

References 18 publications

Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding

Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for γ-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding

The Roles of His-167 and His-275 in the Reaction Catalyzed by Glutamate Decarboxylase from Escherichia coli

High-Yield Biocatalytic Amination Reactions in Organic Synthesis

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