Cycloserine, inactivation

A family of m-cyclopent[r-]isoxazolidine alkaloids named pyrinodemins was isolated from the marine sponge Amphimedon sp. <1999TL4819>. These compounds, which show potent cytotoxicity, were synthesized in racemic form by different groups in order to clarify their structures. The asymmetric total synthesis of (—)-pyrinodemin A was also accomplished <20030L2611>. Both the enantiomers of cycloserine (4-amino-3-isoxazolidinone) act as alanine racemase inhibitors and the mechanism of inactivation has been studied <1998JA2256, 1998JA2268, 2005B5317>. 

The proposed mechanism of inactivation is depicted in Figure 13. It is reminiscent of that proposed for the inactivation of 7 aminobutyric acid transaminase by gabaculine or cycloserine. ... 

Interactions with enantiomeric cycloserines. The antibiotic D-cycloserlne (if-aminoisoxazolidone-3) irreversibly inhibits,in bacteria certain enzymes metabolizing D-amino acids. In eucarlotes, the L-enantiomer (and DL-cycloserine) are the potent inactivators of transaminases and some other PLP-enzymes acting on structurally analogous L-amino acids. As demonstrated earlier by our colleagues H.Karpeisky, R.Khomutov, E. Severin et al.,27-29 the following steps appear to be in-... 

L-cSer K. values of the order of 10 —10 M (for the D-iso-mer affinities are 20-100 fold lower). L-cycloserine is not bound covalently by the lyase proteins (as opposed to the transaminases) from the adducts gel-filtration will release native (labile) apoenzymes and coenzyine-inhibitor imines, yielding mainly PMP and PM on acidification (Fig.4 ). If our cri-terium based on the occurrence of abortive half-transamination from cSer to PLP is valid, the fairly high sensitivity of lyases 6 and h. to inhibition by L-cSer (though atypical in comparison with transaminase inactivation) indicates the probable involvement of PMP-ketimines ( or tautomeric quinonold Schiff bases, see Fig.1)in enzymic Of B-elimination reactions. 

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