The mode of action of homocysteine on mouse brain glutamic decarboxylase and gamma-aminobutyrate aminotransferase.
In the belief that homocysteine-induced convulsions might be related to alterations in brain gamma-aminobutyric acid metabolism, we have studied the action of this amino acid on the activity of glutamic decarboxylase (GAD, EC 4.1.1.15) and gamma-aminobutyrate aminotransferase (EC 2.6.1.19) of mouse brain in vitro DL-homocysteine competitively inhibited GAD with respect to both L-glutamate and pyridoxal 5'-phosphate. The respective Ki's were 3.8 mM and 0.3 mM. The activity of GABA-T also was altered in the presence of DL-homocysteine. A competitive inhibition (Ki = 6 mM) was observed with gamma-aminobutyric acid, and an uncompetitive inhibition with respect to pyridoxal 5'-phosphate and alpha-ketoglutarate. These results are explained in terms of a dual action of homocysteine on each of the enzymes: one involving a competition for substrate binding site and the other involving the formation of an inactive inhibitor-cofactor complex. The significance of the inhibition of these enzymes of gamma-aminobutyric acid metabolism is discussed in relation to the convulsant action of homocysteine.
D000612:4-Aminobutyrate Transaminase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002262:Carboxy-Lyases / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D000637:Transaminases / Q000378:metabolism*
D005971:Glutamates; D006710:Homocysteine; D011732:Pyridoxal Phosphate; D000637:Transaminases; D000612:4-Aminobutyrate Transaminase; D002262:Carboxy-Lyases; D005968:Glutamate Decarboxylase