PMID: 3761305Oct 1, 1986Paper

Inactivation of gamma-aminobutyric acid aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid and effect on the enzyme of (E)-3-(1-aminocyclopropyl)-2-propenoic acid

Journal of Medicinal Chemistry
R B SilvermanJ Mathew

Abstract

(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known gamma-aminobutyric acid aminotransferase (gamma-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1). Compound 6 is a mechanism-based inactivator of gamma-Abu-T: time-dependent inactivation is saturatable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis. This compound (6) binds 50 times more tightly to gamma-Abu-T than does the saturated analogue (1). No transamination of 6 occurs prior to inactivation. However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions. Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid. It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of gamma-Abu-T by 6. The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme. This study shows the usefulness and hazards of incorporation of a trans double bond into potential gamma-Abu-T inactivators.

Citations

Feb 15, 1988·Biochemical and Biophysical Research Communications·R B Silverman, C George
Jan 1, 1988·Medicinal Research Reviews·P Krogsgaard-Larsen
Mar 1, 2008·Angewandte Chemie·Richard B Silverman
Dec 5, 2012·Beilstein Journal of Organic Chemistry·Jolanta WierzejskaHidemi Yoda
Jan 1, 1988·Journal of Enzyme Inhibition·R B Silverman
Jun 1, 2012·The Journal of Organic Chemistry·Hatice Gökcan, F Aylin Sungur Konuklar
Dec 23, 2020·The Journal of Organic Chemistry·Kosuke OhsawaTakayuki Doi
Feb 3, 2006·Journal of Medicinal Chemistry·Daniel P BeckerDai-C Yang

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