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Pyridoxal-5′-phosphate-dependent enzymes involved in biotin biosynthesis: Structure, reaction mechanism and inhibition Proteins and proteomics
- Mann, Stéphane, Ploux, Olivier
- Biochimica et biophysica acta 2011 v.1814 no.11 pp. 1459-1466
- 5-aminolevulinate synthase, Mycobacterium tuberculosis, acylation, antibiotics, biosynthesis, biotin, crystal structure, decarboxylation, enzyme inactivation, herbicides, microorganisms, pyridoxal, serine C-palmitoyltransferase, transamination
- The four last steps of biotin biosynthesis, starting from pimeloyl-CoA, are conserved among all the biotin-producing microorganisms. Two enzymes of this pathway, the 8-amino-7-oxononanoate synthase (AONS) and the 7,8-diaminopelargonic acid aminotransferase (DAPA AT) are dependent on pyridoxal-5′-phosphate (PLP). This review summarizes our current understanding of the structure, reaction mechanism and inhibition on these two interesting enzymes. Mechanistic studies as well as the determination of the crystal structure of AONS have revealed a complex mechanism involving an acylation with inversion of configuration and a decarboxylation with retention of configuration. This reaction mechanism is shared by the homologous 5-aminolevulinate synthase and serine palmitoyltransferase. While the reaction catalyzed by DAPA AT is a classical PLP-dependent transamination, the inactivation of this enzyme by amiclenomycin, a natural antibiotic that is active against Mycobacterium tuberculosis, involves the irreversible formation of an adduct between PLP and amiclenomycin. Mechanistic and structural studies allowed the complete description of this unique inactivation mechanism. Several potent inhibitors of these two PLP-dependent enzymes have been prepared and might be useful as starting points for the design of herbicides or antibiotics. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology.