Glutamic acid stereochemistry

The glycosidases act by two different mechanisms which is revealed by the stereochemistry at the anomeiic centre of the product (McCarter and Withers, 1994). In one type of glycosidases the anomeiic centre is directly attacked by a hydroxide to give a product with inverted stereochemistry at the anomeiic centre. In the other mechanism, the anomeric centre is attacked by the carboxylate group of a glutamic acid residue to form an intermediate in which the carbohydrate moiety is covalently bound to the enzyme similar to in epoxide hydrolases (Figure 2.16) and serine hydrolases. Attack on this intermediate by a nucleophile leads to the net result which is retention of the stereochemistry at the anomeric centre. 

In a closely related asymmetric reaction, the required absolute stereochemistry at C-4 was established via a Michael addition of a cuprate reagent to a dihydropiperidinone (Scheme 12). The stereochemistry at C-3 was introduced in the form of piperidinone 61, a compound readily available from (5)-glutamic acid. Protection of both the amino and alcohol functionalities was achieved using standard reaction conditions to give 62. Introduction of the A -double bond was accomplished via phenylselenation of the lithium... 

The numbered carbons in the product correspond to the same numbered carbons in L-glutamic acid. No bonds to carbon-2 are made or broken in the synthesis. If the configuration at carbon-5 in the product is R, which of the following best represents the stereochemistry of the frog toxin ... 

One of the known mechanisms of biosynthesis is shown in the next scheme. The enzyme aminotransferase transfers the amino group from the precursor amino acid to the a-ketoacid, which is rearranged into the product amino acid. In this process, the precursor amino acid is transformed into the corresponding a-ketoacid. It must be pointed out that besides transferring the amino group, the enzyme aminotransferase also preserves the stereochemistry the L-precursor amino acid leads to the formation of the L-product aminoacid. This mechanism presented below is for the biosynthesis of L-glutamic acid. 

Johansen, T. N Janin, Y. L Nielsen, B Frydenvang, K., Brauner-Osbome, H., Stensb0l, T. B et al. (2002) 2-Amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid resolution, absolute stereochemistry and enantiopharmacology at glutamate receptors. Bioorg. Med. Chem. 10, 2259-2266. 

The reaction mechanism of a-amylases is referred to as retaining, which means that the stereochemistry at the cleaved bond of the carbohydrate is retained. Hydrolysis of the glycosidic bond is mediated by an acid hydrolysis mechanism, which is in turn mediated by Aspl97 and Glu233 in pig pancreatic amylase. These interactions have been identified from X-ray crystallography. The aspartate residue has been shown to form a covalent bond with the Cl position of the substrate in X-ray structure of a complex formed by a structurally related glucosyltransferase. " The glutamate residue is located in vicinity to the chloride ion and acts as the acidic catalyst in the reaction. The catalytic site of a-amylases is located in a V-shaped depression on the surface of the enzyme. 

As shown in Fig. 3, Lewis acids (i.e., metal ions and hydrogen bond donors) display syn or anti stereochemistry as they interact with the carboxylate anion. However, in a study of enzyme active sites. Candour (1981) first noticed that hydrogen bond donors to the carboxylates of aspartate and glutamate residues preferentially occur with syn stereochemistry. As a carboxylate-hydrogen bond donor interaction COg-H... 

Fig. 18. The carboxylaie-histidine-zinc triad represents indirect carboxylate-zinc interaction across bridging histidine. Both tautomers of histidine are observed, and the hydrogen bond stereochemistry with carboxylate (either aspartate or glutamate) is generally syn. Experimental results and theoretical calculations suggest that the carboxylate-histidine- zinc form may be in equilibrium with the carboxylic acid-histidinate- zinc form, as shown.

This reaction is crucial because it establishes the stereochemistry of the a-carbon atom (S absolute configuration) in glutamate. The enzyme binds the a-ketoglutarate substrate in such a way that hydride transferred from NAD(P)H is added to form the 1 isomer of glutamate (Figure 24,6). As we shall see, this stereochemistry is established for other amino acids by transamination reactions that rely on pyridoxal phosphate. 

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