Inhibition of 7,8-diaminopelargonic acid aminotransferase by amiclenomycin and analogues.
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Mann S, Marquet A, Ploux O
Inhibition of 7,8-diaminopelargonic acid aminotransferase by amiclenomycin and analogues.
Biochem Soc Trans. 2005 Aug;33(Pt 4):802-5.
- PubMed ID
- 16042602 [ View in PubMed]
- Abstract
Cis and trans stereoisomers of amiclenomycin, a natural L-amino acid antibiotic, have been prepared using unequivocal routes. By using 1H NMR spectroscopy, the configuration of the six-membered ring of natural amiclenomycin was shown to be cis and not trans as originally proposed. Amiclenomycin and some synthetic analogues with the cis configuration irreversibly inactivate DAPA AT (7,8-diaminopelargonic acid aminotransferase), an enzyme involved in biotin biosynthesis, by forming an aromatic PLP (pyridoxal-5'-phosphate)-inhibitor adduct that is tightly bound to the active site. The following kinetic parameters for the inactivation of Escherichia coli DAPA AT by amiclenomycin were derived: K(I)=2 microM and k(inact)=0.4 min(-1). The structure of the aromatic adduct formed upon inactivation was confirmed by UV-visible spectroscopy, X-ray crystal structure determination and MS. Because Mycobacterium tuberculosis DAPA AT is a potential drug target, this enzyme was cloned, overexpressed and purified to homogeneity for biochemical characterization.