کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1952544 | 1057214 | 2009 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Inhibition of 7,8-diaminopelargonic acid aminotransferase from Mycobacterium tuberculosis by chiral and achiral anologs of its substrate: Biological implications Inhibition of 7,8-diaminopelargonic acid aminotransferase from Mycobacterium tuberculosis by chiral and achiral anologs of its substrate: Biological implications](/preview/png/1952544.png)
7,8-Diaminopelargonic acid aminotransferase (DAPA AT), a potential drug target in Mycobacterium tuberculosis, transforms 8-amino-7-oxononanoic acid (KAPA) into DAPA. We have designed an analytical method to measure the enantiomeric excess of KAPA, based on the derivatization of its amine function, by ortho-phtalaldehyde and N-acetyl-l-cysteine, followed by high pressure liquid chromatography separation. Using this methodology and enantiopure samples of KAPA it appeared that racemization of KAPA occurs rapidly (half-lives from 1 to 8 h) not only in 4 M HCl but more importantly in the usual pH range, from 7 to 9. Furthermore, we showed that racemic KAPA, and not enantiopure KAPA, was used in all previous studies. The only valid enantioselective synthesis of KAPA is that reported by Lucet et al. (1996) Tetrahedron: Asymmetry 7, 985–988. KAPA is produced as a pure (S)-enantiomer by KAPA synthase and by microbial production and DAPA AT only uses (S)-KAPA as substrate. However, (R)-KAPA is an inhibitor of this enzyme. It binds to the pyridoxal 5′-phosphate form (Ki1 = 5.9 ± 0.2 μM) and to the pyridoxamine 5′-phosphate form (Ki2 = 1.7 ± 0.2 μM) of M. tuberculosis DAPA AT. Molecular modeling showed that (R)-KAPA forms specific hydrogen bonds with T309 and the phosphate group of the cofactor of DAPA AT. Desmethyl-KAPA (8-amino-7-oxooctanoic acid), an achiral analog of KAPA, is also a potent inhibitor of M. tuberculosis DAPA AT. This molecule binds to the enzyme in a similar way than (R)-KAPA with the following constants: Ki1 = 4.2 ± 0.2 μM, and Ki2 = 0.9 ± 0.2 μM. These findings pave the way to the design of new antimycobacterial drugs.
Journal: Biochimie - Volume 91, Issue 7, July 2009, Pages 826–834