细菌乙酰羟酸合成酶及作为潜在候选药物的分枝杆菌结核病乙酰羟酸合成酶特效抑制剂的机制

Title:Mechanisms of bacterial acetohydroxyacid synthase (ahas) and specific inhibitors of Mycobacterium tuberculosis ahas as potential drug candidates against tuberculosis

Volume: 16 Issue: 7

Author(s): Kunal Gokhale and Bhargav Tilak

Affiliation:

关键词: 乙酰羟酸合成酶，AHAS抑制剂，苯甲酰酯，支链氨基酸，咪唑啉酮，磺脲。

摘要: On account of the ever increasing resistance of M.tuberculosis strains to orthodox therapy regimens, the task of combating tuberculosis becomes even more challenging. Therefore, there arises a need to isolate new drug targets and subsequently design specific inhibitors for the same. In bacteria, algae, plants and fungi, the synthesis of Branched Chain Amino Acids (BCAAs) is catalyzed by Acetohydroxyacid Synthases (AHAS) group of enzymes. Bacterial AHAS (EC 2.2.1.6) catalyzes the biosynthesis of isoleucine, leucine and valine by utilizing cofactors like Thiamin Diphosphate (ThDP), Flavin Adenine Dinucleotide (FAD) and a divalent metal cation (Usually Mg²⁺). The anabolic form of the enzyme which is presently under discussion consists of two subunits out of which one is catalytic while the other is regulatory in nature. The product of this enzyme catalyzed reaction is either 2-acetolactate or 2-aceto-2-hydroxybutyrate obtained from self-condensation of pyruvate or condensation of puruvate and 2-ketobutyrate, respectively. These are further converted to the BCAAs by a series of other enzymes. The step catalyzed by AHAS is the first in the entire cascade and hence can be selectively targeted for the inhibition of this pathway. M.tuberculosis AHAS, which is encoded by the ilvB and ilvN operons is structurally related to E.coli AHAS and has a similar function. Therefore, specific drugs belonging to the classes of sulfonylureas, imidazolinones and benzoyl esters can be used as inhibitors of M.tuberculosis AHAS which would consequently deplete the BCAA supply to the bacteria. Thus, efficient bacteriostasis can be achieved.

Cite this article as:

Kunal Gokhale and Bhargav Tilak , Mechanisms of bacterial acetohydroxyacid synthase (ahas) and specific inhibitors of Mycobacterium tuberculosis ahas as potential drug candidates against tuberculosis, Current Drug Targets 2015; 16 (7) . https://dx.doi.org/10.2174/1389450116666150416115547