Abstract
Despite impressive progress made over the past 20 years in our understanding of mycolylarabinogalactan-peptidoglycan (mAGP) biogenesis, the mechanisms by which the tubercle bacillus Mycobacterium tuberculosis adapts its cell wall structure and composition to various environmental conditions, especially during infection, remain poorly understood. Being the central portion of the mAGP complex, arabinogalactan (AG) is believed to be the constituent of the mycobacterial cell envelope that undergoes the least structural changes, but no reports exist supporting this assumption. Herein, using recombinantly expressed mycobacterial protein, bioinformatics analyses, and kinetic and biochemical assays, we demonstrate that the AG can be remodeled by a mycobacterial endogenous enzyme. In particular, we found that the mycobacterial GlfH1 (Rv3096) protein exhibits exo-β-d-galactofuranose hydrolase activity and is capable of hydrolyzing the galactan chain of AG by recurrent cleavage of the terminal β-(1,5) and β-(1,6)-Galf linkages. The characterization of this galactosidase represents a first step toward understanding the remodeling of mycobacterial AG.
Highlights
Despite impressive progress made over the past 20 years in our understanding of mycolylarabinogalactan-peptidoglycan biogenesis, the mechanisms by which the tubercle bacillus Mycobacterium tuberculosis adapts its cell wall structure and composition to various environmental conditions, especially during infection, remain poorly understood
The seminal observation of arabinan-degrading activity in M. smegmatis introduced the idea that mycobacteria may produce a set of specific glycosidases designed to remodel endogenous cell wall polysaccharides [8]
Significant attention has been paid to glycosidases at the therapeutic level in the past two decades: several glycosidase inhibitors have been discovered for potential use in the treatment of cancer, viral infections, neurodegenerative diseases, autoimmune diseases, and diabetes [32]
Summary
Despite impressive progress made over the past 20 years in our understanding of mycolylarabinogalactan-peptidoglycan (mAGP) biogenesis, the mechanisms by which the tubercle bacillus Mycobacterium tuberculosis adapts its cell wall structure and composition to various environmental conditions, especially during infection, remain poorly understood. We found that the mycobacterial GlfH1 (Rv3096) protein exhibits exo--D-galactofuranose hydrolase activity and is capable of hydrolyzing the galactan chain of AG by recurrent cleavage of the terminal -(1,5) and -(1,6)-Galf linkages. The characterization of this galactosidase represents a first step toward understanding the remodeling of mycobacterial AG. MAGP represents an essential and major constituent of the envelope [3] In this composite molecule, AG is the polysaccharide providing the physical link between the PG and the mycolic acids producing a viscous hydrophilic region [4]. Uncertainties regarding some structural features remain, the overall architecture of the AG is well-established, especially in the case of Mycobacterium tuberculosis [5, 6]
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