Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis.

ABSTRACT: BioA, a pyridoxal 5'-phosphate (PLP) dependent aminotransferase, catalyzes the second step of biotin biosynthesis, converting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-diaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolated from cultures of different Streptomyces strains is a potent mechanism-based inhibitor of BioA that operates via an aromatization mechanism, irreversibly labeling the PLP cofactor. However, ACM is plagued by inherent chemical stability. Herein we describe the synthesis of four inhibitors, inspired by ACM but containing an allylic amine as the chemical warhead, designed to both improve stability and operate via a complementary Michael addition-pathway upon enzymatic oxidation of the allylic amine substrate to an enimine. Acyclic analogue M-1 contains a terminal ol

SUBMITTER: Shi C 

PROVIDER: S-EPMC3448953 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature