Assembling of the Mycobacterium tuberculosis Cell Wall Core

• Published in: The Journal of biological chemistry Vol. 291; no. 36; pp. 18867 - 18879
• Main Authors: Grzegorzewicz, Anna E., de Sousa-d'Auria, Célia, McNeil, Michael R., Huc-Claustre, Emilie, Jones, Victoria, Petit, Cécile, Angala, Shiva kumar, Zemanová, Júlia, Wang, Qinglan, Belardinelli, Juan Manuel, Gao, Qian, Ishizaki, Yoshimasa, Mikušová, Katarína, Brennan, Patrick J., Ronning, Donald R., Chami, Mohamed, Houssin, Christine, Jackson, Mary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2016; American Society for Biochemistry and Molecular Biology
• Subjects: arabinogalactan; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; cell wall; Cell Wall - genetics; Cell Wall - metabolism; Corynebacterium glutamicum - genetics; Corynebacterium glutamicum - metabolism; cryo-electron microscopy; Galactans - genetics; Galactans - metabolism; Glycobiology and Extracellular Matrices; Life Sciences; ligase; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - metabolism; outer membrane; peptidoglycan; Peptidoglycan - genetics; Peptidoglycan - metabolism; polysaccharide; Teichoic Acids - genetics; Teichoic Acids - metabolism; outer membrane; peptidoglycan; Mycobacterium tuberculosis; polysaccharide; arabinogalactan; ligase; cell wall; cryo-electron microscopy
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.739227

The unique cell wall of mycobacteria is essential to their viability and the target of many clinically used anti-tuberculosis drugs and inhibitors under development. Despite intensive efforts to identify the ligase(s) responsible for the covalent attachment of the two major heteropolysaccharides of the mycobacterial cell wall, arabinogalactan (AG) and peptidoglycan (PG), the enzyme or enzymes responsible have remained elusive. We here report on the identification of the two enzymes of Mycobacterium tuberculosis, CpsA1 (Rv3267) and CpsA2 (Rv3484), responsible for this function. CpsA1 and CpsA2 belong to the widespread LytR-Cps2A-Psr (LCP) family of enzymes that has been shown to catalyze a variety of glycopolymer transfer reactions in Gram-positive bacteria, including the attachment of wall teichoic acids to PG. Although individual cpsA1 and cpsA2 knock-outs of M. tuberculosis were readily obtained, the combined inactivation of both genes appears to be lethal. In the closely related microorganism Corynebacterium glutamicum, the ortholog of cpsA1 is the only gene involved in this function, and its conditional knockdown leads to dramatic changes in the cell wall composition and morphology of the bacteria due to extensive shedding of cell wall material in the culture medium as a result of defective attachment of AG to PG. This work marks an important step in our understanding of the biogenesis of the unique cell envelope of mycobacteria and opens new opportunities for drug development.