Acetohydroxyacid synthase (Mycobacterium tuberculosis) (AHAS)

Acetohydroxyacid synthase (AHAS), also known as acetolactate synthase, is a critical enzyme in Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine. This enzyme functions as a complex consisting of a large catalytic subunit (IlvB1) and a small regulatory subunit (IlvN), requiring thiamine pyrophosphate (TPP), flavin adenine dinucleotide (FAD), and magnesium ions for activity. Because humans lack the BCAA biosynthetic pathway and must obtain these amino acids through diet, AHAS is considered a highly attractive target for the development of selective anti-tubercular agents with minimal host toxicity. In M. tuberculosis, AHAS is essential for survival both in vitro and during infection, as BCAA starvation leads to the cessation of protein synthesis and bacterial growth. Historically, AHAS has been the target of several classes of herbicides, such as sulfonylureas and imidazolinones, which have been repurposed in research to serve as lead compounds for new tuberculosis treatments. Inhibition typically occurs through the binding of these molecules to the substrate channel, preventing the condensation of pyruvate molecules. Current drug discovery efforts focus on optimizing these inhibitors to overcome drug-resistant strains of tuberculosis.

Other names

Acetolactate synthaseALSAcetohydroxy-acid synthase catalytic subunitIlvB1Large subunit of acetolactate synthase

Inhibition of the first common step in the branched-chain amino acid biosynthesis pathway by blocking the catalytic active site or interfering with thiamine pyrophosphate (TPP) and FAD binding, leading to amino acid starvation and bacterial death.