Mahmoud Akhtar

Enantiospecific synthesis of 3-substituted aspartic acids via enzymic amination of substituted fumaric acids

Abstract The use of the enzyme 3-methylaspartase in the synthesis of L-aspartic acids containing 3-halogeno- or 3-alkyl- substituents, in the (S)-configuration, and also some of the corresponding C-3 deuteriated isotopomers is described.

Structural and stereochemical studies of methiomine decarboxylase from dryopteris felix-mas

Abstract Each diastereomer of N-(−)-camphanoyl-(3-methylthio)-1-aminopropane chirally deuteriated at C-1 has been synthesized and compared to deuteriated samples derived from L-methionine via enzymic decarboxylation. Here we report that decarboxylatlon occurs in a retentive mode.

Structure–activity relationship on human serum paraoxonase (PON1) using substrate analogues and inhibitors

Substrate analogues based on the parent compounds paraoxon and phenyl acetate were tested on human serum paraoxonase (PON1) to explore the active site of the enzyme. Replacement of the nitro group of paraoxon with an amine or hydrogen, as well as electronic changes to the parent compound, converted these analogues into inhibitors. Introduction of either electron-withdrawing or donating groups onto phenyl acetate resulted in reduction in their rate of hydrolysis by PON1.

Stereochemical course of the enzymic amination of chloro- and bromo- fumaric acid by 3-methylaspartate ammonia-lyase

Abstract Enzymic amination of chloro- and bromo- fumaric acid using 3-methylaspartate ammonia-lyase in the presence of ammonia leads to the formation of 3-chloro- and 3-bromo-aspartic acid respectively; the absolute configuration of each product is (R) at C-2 and (S) at C-3.

Reactions of glutamate 1-semialdehyde aminomutase with R- and S-enantiomers of a novel, mechanism-based inhibitor, 2,3-diaminopropyl sulfate.

Glutamate semialdehyde aminomutase is a recognized target for selective herbicides and antibacterial agents because it provides the aminolevulinate from which tetrapyrroles are synthesized in plants and bacteria but not in animals. The reactions of the enzyme with R- and S-enantiomers of a novel compound, diaminopropyl sulfate, designed as a mechanism-based inhibitor of the enzyme are described. The S-enantiomer undergoes transamination without significantly inactivating the enzyme. The R-enantiomer inactivates the enzyme rapidly. Inactivation is accompanied by the formation of a 520 nm-absorbing chromophore and by the elimination of sulfate. The inactivation is attenuated by simultaneous transamination of the enzyme to its pyridoxamine phosphate form but inclusion of succinic semialdehyde to reverse the transamination leads to complete inactivation. The inactivation is attributed to further reactions arising from generation of an external aldimine between the pyridoxal phosphate cofactor and the 2,3-diaminopropene that results from enzyme-catalyzed beta-elimination of sulfate.

Synthesis of [4-2H2]-, (4R)[4-2H1]- and (4s)[4-2H1]-4-(methylnitrosamino)-1-(3'-pyridyl)-1-butanone, C-4 deuteriated isotopomers of the procarcinogen NNK

The synthesis of C-4 dideuteriated and both C-4 monodeuteriated enantiomers of NNK, the metabolic precursor to a variety of potential carcinogens, starting from (2S)-glutamic acid and nicotinic acid is described. The route is suitable for the synthesis of NNK isotopomers labelled in each of the putative sites for metabolic activation.

The stereochemical course of decarboxylation, transamination and elimination reactions catalysed by Escherichia coli glutamic acid decarboxylase

Pyridoxal 5′-phosphate dependent Escherichia coli glutamic acid decarboxylase reprotonates the quinonoid intermediate derived from the coenzyme and its natural substrate, (2S)-glutamic acid on the 4′-Si-face of the coenzyme during an abortive decarboxylation–transamination reaction. The enzyme introduces the 3-pro-R hydrogen of β-alanine with retention of configuration during the decarboxylation of (2S)-aspartic acid. In the absence of pyridoxal 5′-phosphate, treatment of the inactive apoenzyme with the inhibitor N4′-(2″-phosphoethyl)pyridoxamine 5′-phosphate results in reactivation through the formation of the active pyridoxal 5′-phosphate holoenzyme complex. During this reaction hydrogen phosphate is eliminated from the phosphoethyl moiety. Using synthetic chirally deuteriated isotopomers of the inhibitor it is demonstrated that the 1-pro-R hydrogen of inhibitor is removed during the reactivation reaction. The results suggest that protonations and deprotonations at Cα of quinonoid intermediates derived from the coenzyme and the substrate occur from the 4′-Si-face of the coenzyme and that the distal binding groups of the substrates and inhibitors occupy similar positions at the active site on the 3′-phenolic group side of the coenzyme.

Synthesis of the isosteric L-valine analogues (2r,3s)- and (2r,3r)-3-bromobutyrine

Abstract Both diastereomers of the isosteric analogue of L-valine, in which one methyl group has been replaced by a bromine atom, have been prepared. The synthesis of the (2R,3R)-isomer provides a route to (2S,3S)-3-hydroxybutyrine (L- allo -threonine) starting from (2S,3S)-3-methylaspartic acid.

Solid-phase synthesis on functionalised fluoropolymer resins. Part 1: Nafion resin sulfonamide-immobilised carboxylic acid derivatives and aryl vinyl sulfones

Abstract The preparation and properties of Nafion resin sulfonamide systems derived from methyl glycinate and from 3-hydroxyethylaniline are described. Nafion derivatisation reactions were slow and maximum achievable functionalisations were 50% of the ion exchange capacity. In aqueous solution the resin derivatives were acid and base labile but in organic solvents the systems were stable to powerful nucleophiles and to heat. An aryl vinyl sulfone derivative used in the synthesis of tertiary amines afforded very pure products.

Mechanism of the enzymic elimination of ammonia from 3-substituted aspartic acids by 3-methylaspartase

Kinetic experiments with 3-methylaspartase, using aspartic, 3-methylaspartic, and 3-ethylaspartic acid and the appropriate C-3 deuteriated isotopomers as substrates, reveal that C(3)–H bond cleavage is partially rate-limiting for 3-methylaspartic acid, much less rate-limiting for 3-ethylaspartic acid, and not rate-limiting at all for aspartic acid.