(R)-citramalate

Citramalic acid is a five-carbon organic acid synthesized from pyruvate and acetyl-CoA through a condensation reaction catalyzed by citramalate synthase. In microbial production systems, citramalate synthesis can be achieved through the heterologous expression of cimA from Methanococcus jannaschii, which encodes citramalate synthase. Citramalic acid is an important precursor for the production of methacrylic acid, a commodity monomer widely used in the manufacture of poly(methyl methacrylate) [235].

Efficient microbial production of citramalic acid is constrained by competition for acetyl-CoA, particularly from the native citrate synthase encoded by gltA. Although deletion of gltA can increase acetyl-CoA availability for citramalate synthesis, it also disrupts the tricarboxylic acid cycle and compromises cellular growth unless additional nutrients are supplied. An alternative metabolic engineering strategy is to modify the native citrate synthase through targeted point mutations that decrease its affinity for acetyl-CoA. This approach reduces competition for the precursor and redirects carbon flux toward citramalic acid synthesis while preserving sufficient citrate synthase activity to support the tricarboxylic acid cycle and cell growth on glucose [235].