L-Cycloserine

D,L-Cycloserine 26 and its 3-methyl analog, derivatives of isoxazolinone, were prepared from D,L-Ser or o.L-Thr. The transformation involved replacement of the hydroxyl group by chlorine and subsequent treatment with hydroxylamine (57HCA1531). After being transformed into its 3-chloro derivative, l-G1u was transformed in a multistep conversion into 27, an intermediate in the synthesis of an antitumoric isoxazole-5-acetic acid (81JA7357). 

L-Cycloserine inhibits many PLP enzymes and is toxic to humans. This observation led Khomutov et al. to synthesize the following more specific "cycloglutamates," structural analogs of glutamic acid with fixed conformations J/k Nature apparently anticipated the synthetic chemist, because it has been reported that the mushroom Tricholoma muscar-... 

L-cycloserine is an inhibitor of serine palmitoyl transferase (85), the first committed step in GSL biosynthesis. However, because this inhibitor prevents the synthesis of the highly bioactive ceramide, an interpretation of GSL depletion is equivocal. 

Honke K, Hirahara Y, Dupree J, Suzuki K, Popko B, Fukushima K, Fukushima J, Nagasawa T, Yoshida N, Wada Y, Taniguchi N. Paranodal junction formation and spermatogenesis require sulfo-glycolipids. Proc. Natl. Acad. Sci. U.S.A. 2002 99 4227 232. Sundaram KS, Lev M. The long-term administration of L-cycloserine to mice specific reduction of cerebroside level. Neurochem. Res. 1989 14 245-248. 

Cycloserine can cause headache, somnolence, and tremor (2). In mice, L-cycloserine protects against auditory-invoked seizures by binding to pyridoxal phosphate in the presence of zinc ions (3). The addition of a fluoroquinolone can increase the risk of nervous system effects (4). 

Chung SH, Johnson MS, Gronenborn AM. L-cycloserine a potent anticonvulsant. Epilepsia 1984 25(3) 353-62. 

Synthetic L-cycloserine derivatives 240 [18], which show structural analogies to the penicillin family, are inactive against S. aureus and E, coli at concentrations of 1 mg/ml. 

L-Cycloserine is an inhibitor of several aminotransferases, including GABA-T. It interacts with pyridoxal phosphate and therefore inhibits GAD, although to a lesser extent than GABA-T (Dann and Carter, 1964). 

L-Cycloserine is active against E. coli but its mode of action is different from that of the natural D-isomer. 

The modulation of glycosphingolipid content can be obtained by metabolic inhibitors such as L-cycloserine, ° fumonisin PDMP, PPMP, or, more specifically by siRNAs... 

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. 

For the time being, a number of perplexing questions are still unsolved. For example - why are exclusively B-elimina-ting lyases, such as serine (threonine) dehydratase, alliin lyase etc., incapable to effect a replacement step (Michael addition) — what is the difference in dynamic topography (stereochemistry) between this enzyme subtype and the ambi-functional Q-lyases, displaying the same behaviour towards L-cycloserine or aminothiol inhibitors,etc. Further investl-ons are needed to shed light on these and other obscure aspects of the problem. 

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