360 2. ANALOGS OF ENZYME KE ACTION COMPONENTS 



bond with enzyme-bound pyridoxal-P, and also an acyl bond with a cat- 

 ionic group at the active site, these two groups thus being connected by a 

 bridge would prevent access to the site. The L-asparagine:a-ketoglutarate 



I 

 HC = NH— 0— CHa— CH— CO 



I I 



Pyr X 



Apoenzyme 



transaminase is inhibited by L-cycloserine with respect to L-asparagine 

 {K^ = 0.0001 mM) but D-cycloserine is a much weaker inhibitor {K^ = 

 1 mM) (Braunstein et al., 1962). L-Cycloserine likewise competitively 

 inhibits the L-alanine: a-ketoglutarate transaminase {K^ = 0.008 mM). 

 This taken with previous work indicates that the cycloserines inhibit 

 specifically those enzyme attacking substrates of the same optical isomerism. 

 Another possible site of action of D-cycloserine in bacteria would be the 

 D-alanyl-D-alanine synthetase, a block of which would prevent the incor- 

 poration of D-alanine into cell wall material. Alanylalanine is often able to 

 reverse the cycloserine inhibition of bacterial growth, sometimes more ef- 

 fectively than alanine. One example of this is the inhibition of the prolif- 

 eration of agents of the psittacosis group in chick embryo yolk sac (Moulder 

 et al., 1963). Chick embryos infected with the mouse pneumonitis organism, 

 for example, are well protected by D-cycloserine at 0.004-0.008 mM, and, of 

 all the possible reversors tested, only alanylalanine is effective. The d- 

 alanyl-D-alanine synthetase of Streptococcus fecalis is inhibited competi- 

 tively with respect to D-alanine {K^ = 0.022 mM), and Neuhaus and 

 Lynck (1964) felt that this enzyme may well be the major site of inhibition 

 in certain bacteria. It is unfortunate that cycloserine and aminooxyacetate 

 have not been accurately compared in any study. 



DIAMINE OXIDASE (HISTAMINASE) 



Enzymes in this group exhibit different degrees of substrate specificity 

 depending on the source, but most oxidatively deaminate diamines of the 

 type +H3N — (CH2),i — NH3+ (with maximal rates when n is around 5) and 

 histamine, in all cases primary amines being attacked. The usual substrate 

 in most studies has been cadaverine {n = 5). 



The diamines have been written as cations because the p^^'s are usually 

 between 8.5 and 10.5. The amidines and guanidines exist almost entirely 

 as cations at physiological pH since the p^^'s for these groups are around 

 13 to 14. The structures have been written in a rather unconventional way 



