Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis

• DOI: 10.1073/pnas.1617655114
• Publication Date: 2017-03-07T02:00:34Z
• Authors: Susan Puckett; Carolina Trujillo; Zhe Wang; Hyungjin Eoh; Thomas R. Ioerger; Inna Krieger; James Sacchettini; Dirk Schnappinger; Kyu Y. Rhee; Sabine Ehrt
• Keywords: 0301 basic medicine; Virulence; Macrophages; Fatty Acids; Malate Synthase; Glyoxylates; Mycobacterium tuberculosis; Carbon; 3. Good health; Disease Models, Animal; Gene Knockout Techniques; Mice; 03 medical and health sciences; Inactivation, Metabolic; Mutation; Animals; Tuberculosis; Female; Metabolic Networks and Pathways

Significance

A better understanding of essential processes in Mycobacterium tuberculosis ( Mtb ) is required for the development of new chemotherapeutics. Isocitrate lyase (ICL) and malate synthase (MS) function in the glyoxylate shunt, a pathway required by Mtb to metabolize fatty acids (FAs). Here, we demonstrate that Mtb MS enables growth and survival on fatty acids through its ability to simultaneously detoxify a metabolic byproduct arising from the initial assimilation of acetyl coenzyme A (acetyl-CoA), glyoxylate, while assimilating a second molecule of acetyl-CoA. We further show that MS depletion during acute and chronic mouse infections kills Mtb . These studies expand our fundamental understanding of the glyoxylate shunt and biologically validate MS as an attractive drug target in Mtb .