2-methylcitrate synthase (MCS)

2-methylcitrate synthase (MCS) is a key metabolic enzyme that catalyzes the condensation of propionyl-CoA and oxaloacetate to form 2-methylcitrate, representing the first dedicated step of the methylcitrate cycle [2, 13]. This pathway is essential for the detoxification and utilization of propionate, a byproduct of the degradation of odd-chain fatty acids, cholesterol, and branched-chain amino acids in various microorganisms [3, 11]. While critical for the survival and virulence of major pathogens such as Mycobacterium tuberculosis and Aspergillus fumigatus, the enzyme is absent in humans, who instead utilize the vitamin B12-dependent methylmalonyl-CoA pathway for propionate disposal [1, 15]. This evolutionary distinction makes MCS a high-priority target for the development of selective antimicrobial and antifungal therapies [4, 6]. Inhibition of MCS leads to the toxic accumulation of propionyl-CoA and 2-methylcitrate, which interferes with central carbon metabolism and prevents pathogen growth, particularly during host infection where lipid substrates are the primary carbon source [10, 14, 18]. Experimental inhibitors like V-13-009920 and ZINC08964784 have demonstrated the potential to disrupt these metabolic processes, providing a foundation for novel anti-infective strategies [9, 10].

Other names

PrpCMcsA2-MCS2-methylcitrate oxaloacetate-lyase (CoA-propanoylating)Citrate synthase 1

Direct inhibition of the 2-methylcitrate synthase enzyme, which prevents the conversion of propionyl-CoA into 2-methylcitrate and results in the toxic accumulation of metabolic intermediates.