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Structure‐based inhibitor design of AccD5/AccD6, essential carboxyltransferases of Mycobacterium tuberculosis
Author(s) -
Lin TingWan,
Nguyen Tan,
Kurth Daniel,
Swamidass Joshua,
Baldi Pierre,
Gramajo Hugo,
Tsai Sheryl
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.839.4
Subject(s) - mycobacterium tuberculosis , cell envelope , virulence , biochemistry , mycobacterium , in silico , biosynthesis , lipid ii , biology , microbiology and biotechnology , cell wall , mycolic acid , tuberculosis , bacteria , chemistry , enzyme , gene , genetics , escherichia coli , medicine , pathology
Mycolic acids and multimethyl‐branched fatty acids are found uniquely in the cell envelope, which are essential for the survival, virulence and antibiotic resistance of Mycobacterium tuberculosis . Acyl‐CoA carboxylases (ACCases) commit acyl‐CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms, Mycobacterium tuberculosis contains six ACCase carboxyltransferase domains, AccD1‐6. Previous studies indicate that AccD4, AccD5 and AccD6 are important for cell envelope lipid biosynthesis and its disruption leads to pathogen death. We have determined the structures of AccD5 and AccD6, whose sequences, structures, and active site are highly conserved to each other. However, both crystals structure and kinetic assays indicate that AccD5 prefers propionyl‐CoA as its substrate and produces methylmalonyl‐CoA. Contrary to AccD5, AccD6 prefers acetyl‐CoA (versus propiony‐CoA) to generate malonyl‐CoA, the extender unit for fatty acids. We also conduct extensively in‐silico screening and identify inhibitors NCI‐65828 (Ki=13 μ M for AccD5) and NCI‐172033 (Ki=1.8 μ M for AccD6). Moreover, NCI‐172033 also inhibited growth of several pathogenic species of Mycobacterium , including MDR‐TB. Our results pave the first step towards understanding the biological roles of key ACCases, in addition to providing a new target for structure‐based development of anti‐tuberculosis therapeutics.