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Inhibition of Diamino Pelargonic Acid Aminotransferase, an Enzyme of the Biotin Biosynthetic Pathway, by Amiclenomycin: A Mechanistic Study
Author(s) -
Mann Stéphane,
Florentin Dominique,
Lesage Denis,
Drujon Thierry,
Ploux Olivier,
Marquet Andrée
Publication year - 2003
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200390322
Subject(s) - chemistry , adduct , moiety , stereochemistry , enzyme , pharmacophore , covalent bond , active site , pyridoxal , biochemistry , organic chemistry
The mechanism of action of amiclenomycin ( 1a ), a naturally occuring inhibitor of diaminopelargonic acid aminotransferase, has been established. The enzyme catalyzes the formation of an aromatic adduct between the inhibitor and pyridoxal‐5′‐phosphate. The structure of the adduct, determined by mass spectrometry, is in agreement with the reported X‐ray crystal structure. Kinetic parameters, characteristic of k cat inhibitors, have been observed, with a K I value of 2 μ M and a k inact value of 0.4 min −1 . The irreversibility of the inactivation observed, in spite of the absence of covalent bond between the inhibitor and the protein, reveals the high affinity of the adduct for the active site. Two other cis ‐1‐amino‐4‐substituted‐cyclohexa‐2,5‐dienes, 3a and 4a , were also found to efficiently inhibit the enzyme. The trans ‐isomers were either much less potent ( 1b ) or inactive ( 3b and 4b ). The aminocyclohexadiene moiety, which is, apparently, responsible for the inhibition, could constitute an original pharmacophore for the design of new herbicides.