ANALOG INHIBITION OF THE METABOLISM OF VARIOUS AMINO ACIDS 359 



product of aminooxyacetate and pyridoxal. It may be that aminooxyacetate 

 should be classed as a carbonyl reagent which reacts with pyridoxal-P, 

 rather than strictly as an amino acid analog, but it is sometimes difficult 

 to distinguish these actions. Nevertheless, the effects of aminooxyacetate 

 on GABA levels in the tissues will undoubtedly make it a useful compound 

 for the study of the physiological role of GABA. 



Cycloserine 



D-Cycloserine (orientomycin, Oxamycin) is a tuberculostatic antibiotic 

 isolated from Streptomyces which can be considered as a cyclic form of 

 aminooxyalanine or 0-aminoserine. It is written in the zwitterion state be- 



I I 

 H nh; 



Cycloserine 



cause there is some evidence that this is the inhibitory form (Neuhaus and 

 Lynch, 1964). Its actions are similar to aminooxyacetate in many respects 

 but differ occasionally in interesting ways. D-Cycloserine inhibits the growth 

 of many bacteria and this is often well antagonized by D-alanine, and 

 competitively inhibits the incorporation of D-alanine into a uridine nucleo- 

 tide necessary for the synthesis of cell wall material. The growth of myco- 

 bacteria is 50% suppressed, for example, by D-cycloserine at 0.03-0.045 mM 

 and this is reversed by D-alanine but not by L-alanine (Zygmunt, 1963). 

 L-Cycloserine is also inhibitory to certain bacteria and this is antagonized 

 by L-alanine. It is interesting that *S. aureus can develop a 50-fold resistance 

 to D-cycloserine, no cross-resistance with other antibiotics being observed 

 (Howe et al., 1964). In animals it produces sedation, lethargy, muscular 

 relaxation, ataxia, an accentuated startle response, and, above all, epi- 

 leptic convulsions (Dann and Carter, 1964; Holtz and Palm, 1964). In these 

 respects it at least superficially acts like aminooxyacetate and, furthermore, 

 these effects are antagonized by pyridoxal. 



D-Cycloserine inhibits certain enzymes dependent on pyridoxal-P, such 

 as the transaminases and glutamate decarboxylase, and it has been postu- 

 lated that it simply reacts with pyridoxal-P to form a substituted oxime. 

 However, this is not the usual reaction in which a Schiff base is produced, 

 but involves an opening of the cycloserine ring. The inhibition of GABA: 

 or-ketoglutarate transaminase is initially competitive with respect to GABA 

 {K^ is 0.25 TCiM for the enzyme from cat brain and around 0.6 mM for the 

 enzyme from E. coli), but a secondary progressive irreversible inhibition 

 also occurs (Dann and Carter, 1964). This may be related to the hypothesis 

 of Khomutov et al. (1961) that the decyclicized cycloserine forms an oxime 



