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:
Keywords:
Acetohydroxyacid synthases, AHAS inhibitors, benzoyl esters, branched chain amino acids, imidazolinones,
sulfonylureas.
Abstract: 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.
