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Several analogues of valine, leucine, and isoleucine carrying hydroxyl groups in the gamma- or delta-position have been tested in the aminoacylation of tRNA by valyl-tRNA synthetases from Saccharomyces cerevisiae and Escherichia coli. Results of the ATP/PPi exchange and of the aminoacylation reactions indicate that the amino acid analogues not only can form the aminoacyl adenylate intermediate but are also transferred to tRNA. However, the fact that the reaction consumes an excess of ATP indicates that the misactivated amino acid analogue is hydrolytically removed. Thus, valyl-tRNA synthetase from S. cerevisiae shows a high fidelity in forming valyl-tRNA. Although the much bulkier amino acid analogues allo- and iso-gamma-hydroxyvaline and allo- and iso-gamma-hydroxyisoleucine are initially charged to tRNA, the misaminoacylated tRNA(Val) is enzymatically deacylated. This cleavage reaction is mediated by the hydroxyl groups of the amino acid analogues which are converted into the corresponding lactones.

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267ChemInform Abstract The allo and iso isomers (V) and (VI) of γ-hydroxy valine are prepared by a modified Erlenmeyer synthesis; the reaction sequence involves chromatographic separation of the E-and Z-oxazolinones (III) and (IV) and subsequent conversion of the isomers into racemic allo-or iso-γ-hydroxy valine (V) or (VI) as shown for (V). The optical resolution of each isomer (V) or (VI) to give the corresponding D-or L-enantiomers is achieved enzymatically using L-or D-amino acid oxidase. The δ-hydroxy analogues (XIIa) and (XIIb) of leucine and isoleucine are synthesized via 1,4-Michael addition; the diastereomers of (XIIb) are separated by reverse phase HPLC (allo RR, SS and iso RS, SR).