Time-dependent inhibition of gamma-aminobutyric acid aminotransferase, by 3-hydroxybenzylhydrazine.
gamma-Aminobutyric acid (GABA) aminotransferase is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of GABA into succinic semialdehyde. Hydrazine analogues have long been known to act as inactivators of PLP-dependent enzymes, including GABA aminotransferase, however, no studies of the molecular mechanism of inactivation of PLP-dependent enzymes by hydrazines have been reported. 3-Hydroxybenzylhydrazine is shown to be a potent in vitro time-dependent inhibitor of pig brain GABA aminotransferase. UV-visible and 1H NMR studies, both with GABA aminotransferase and with PLP as a chemical model for the enzyme-catalyzed reaction, indicate that 3-hydroxybenzylhydrazine reacts both enzymatically and nonenzymatically to form the 3-hydroxybenzylhydrazone of PLP without tautomerization.
Lightcap
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Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA.
Hopkins
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MH
Olson
G T
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Silverman
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RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology; D018756:GABA Antagonists / Q000494:pharmacology*; D006834:Hydrazines / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011732:Pyridoxal Phosphate / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013552:Swine; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D006834:Hydrazines; D005680:gamma-Aminobutyric Acid; D011732:Pyridoxal Phosphate; C004297:3-hydroxybenzylhydrazine; D000612:4-Aminobutyrate Transaminase