ARGINASE 335 



Other Enzymes in Glutamate Metabolism 



Analog inhibition has been reported for several other enzymes involved 

 in the metabolism of glutamate but quantitative studies from which struc- 

 ture-action relationships may be derived have not been made. Some of 

 these results are summarized in Table 2-13. An interesting inhibitor is the 

 convulsant isolated from agenized flour, methionine sulfoximine, which is 

 inhibitory to the incorporation of methionine into proteins in bacteria 

 and brain. Since these actions are to a great extent antagonized by methio- 

 nine, this substance has generally been considered as a methionine antago- 

 nist, but glutamine also is antagonistic. Sellinger and Weiler (1963) have 

 shown that methionine sulfoximine inhibits brain glutamine synthetase 

 competitively with respect to glutamate, some inhibition being seen at 

 0.01 mM and around 50% inhibition at 1 mM with low glutamate concen- 

 trations {K^ = 0.05-0.064 mM). The relation between this inhibition and 

 the convulsant action is not clear but it was postulated that methionine 

 sulfoximine interferes in some vague manner with glutamine synthesis 

 in an intracellular compartment in the brain. 



ARGINASE 



The hydrolysis of arginine: 



\ / (+H2O) + / \ 



C— NH— CHoCH^CH,— CH ^ ^-^- H3N— CHoCHoCHz— CH + CO 



+ <^ \ - \ - / 



HgN COO COO H2N 



Arginine Ornithine Urea 



is catalyzed by the Mn++-activated enzyme arginase and is a step in the 

 urea cycle. Arginase is inhibited by the product ornithine, as first shown 

 by Gross (1921) and confirmed by Bach and Williamson (1942), who found 

 that the inhibition is much more marked in liver extracts than in slices 

 (50% inhibition given by 5.3 mM ornithine in extracts and by 15.9 mM 

 in slices when argmine is 3.56 mM). Edlbacher and Zeller (1936) noted that 

 several amino acids inhibit, but ornithine is the most potent with lysine 

 running a close second. 



These inhibitions were compared and subjected to quantitative treat- 

 ment by Hunter and Downs (1945) in the publication wherein the first 

 use of the single-curve plot (type F) was made (see Chapter 1-5). Orni- 

 thine and lysine inhibit competitively {K , = 4.1 mM and 4.8 mM, respec- 

 tively) but other amino acids are usually only partially competitive (since 

 the DL-forms of the inhibitors used and only the L-isomers are active, it is 

 likely that these constants should be halved). Calculations of relative 



