Beta-ketoacyl-ACP synthase 1 (KasA) (KasA)

Beta-ketoacyl-ACP synthase 1 (KasA) is a pivotal enzyme in the Type II Fatty Acid Synthase (FAS-II) system of Mycobacterium tuberculosis, where it works in complex with the acyl carrier protein AcpM to elongate fatty acid chains [1, 2]. This process is fundamental for the biosynthesis of mycolic acids, which are long-chain fatty acids that constitute a major and essential part of the mycobacterial cell envelope, contributing to its impermeability and virulence [2, 4]. The AcpM–KasA complex represents the functional unit where the growing acyl chain is transferred and condensed, making the protein-protein interface and the active site prime targets for drug discovery [2, 4]. KasA is a validated target for antitubercular drug development because its inhibition leads to the collapse of the cell wall and bacterial death, and it lacks a direct human homolog, minimizing potential toxicity [3, 5]. Small molecule inhibitors, such as indazoles (e.g., GSK3011724A), have demonstrated potent activity by binding to the KasA-AcpM interface or the hydrophobic tunnel, effectively blocking the elongation cycle [3, 5]. Consequently, KasA remains a high-priority target in the search for treatments against multi-drug resistant tuberculosis strains [5]. Citations: [1] UniProt (P9WNG3); [2] Schiebel et al. (2013) Nature Communications; [3] Abrahams et al. (2016) Nature Communications; [4] Capodagli et al. (2020) Communications Biology; [5] North et al. (2020) Drug Discovery Today.

Other names

3-oxoacyl-[acyl-carrier-protein] synthase 1Beta-ketoacyl-acyl carrier protein synthase 1Ketoacyl-ACP synthase AKAS I

Inhibition of the condensation reaction between malonyl-AcpM and acyl-AcpM, preventing the elongation of long-chain fatty acids required for mycolic acid production.