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Inactivation of. gamma. -aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid

Journal Article · · Biochemistry; (United States)
DOI:https://doi.org/10.1021/bi00409a024· OSTI ID:7253565
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(Z)-4-Amino-2-fluorobut-2-enoic acid (1) is shown to be a mechanism-based inactivator of pig brain ..gamma..-aminobutyric acid aminotransferase. Approximately 750 inactivator molecules are consumed prior to complete enzyme inactivation. Concurrent with enzyme inactivation is the release of 708 +/- 79 fluoride ions; transamination occurs 737 +/- 15 times per inactivation event. Inactivation of (/sup 3/H)pyridoxal 5'-phosphate ((/sup 3/H)PLP) reconstituted GABA aminotransferase by 1 followed by denaturation releases (/sup 3/H)PMP with no radioactivity remaining attached to the protein. A similar experiment carried out with 4-amino-5-fluoropent-2-enoic acid as the inactivator produces no (/sup 3/H)PMP; rather, another radioactive species is released. These results support an inactivation mechanism for 1 that involves normal catalytic isomerization followed by active site nucleophilic attack on the activated Michael acceptor. A general hypothesis for predicting the inactivation mechanism (Michael addition vs enamine addition) of GABA aminotransferase inactivators is proposed.

Research Organization:
Northwestern Univ., Evanston, IL (USA)
OSTI ID:
7253565
Journal Information:
Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 27:9; ISSN BICHA
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINATION
AMINO ACIDS
AMINOBUTYRIC ACID
AMINOTRANSFERASES
AUTONOMIC NERVOUS SYSTEM AGENTS
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
DRUGS
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
INACTIVATION
ISOMERIZATION
KINETICS
LABELLED COMPOUNDS
NEUROREGULATORS
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
REACTION KINETICS
TRANSFERASES
TRITIUM COMPOUNDS