Article Metrics


Online attention

Mycobacterial OtsA structures unveil substrate preference mechanism and allosteric regulation by 2-oxoglutarate and 2-phosphoglycerate

DOI: 10.1128/mBio.02272-19 DOI Help

Authors: Vitor Mendes (University of Cambridge) , Marta Acebron Garcia De Eulate (University of Cambridge) , Nupur Verma (University of Cambridge) , Michael Blaszczyk (University of Cambridge) , Márcio V. B. Dias (University of São Paulo; University of Warwick) , Tom L. Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio , VOL 10

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 9007 , 9537

Open Access Open Access

Abstract: Trehalose is an essential disaccharide for mycobacteria and a key constituent of several cell wall glycolipids with fundamental roles in pathogenesis. Mycobacteria possess two pathways for trehalose biosynthesis. However, only the OtsAB pathway was found to be essential in Mycobacterium tuberculosis, with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Here, we report the first mycobacterial OtsA structures from Mycobacterium thermoresistibile in both apo and ligand-bound forms. Structural information reveals three key residues in the mechanism of substrate preference that were further confirmed by site-directed mutagenesis. Additionally, we identify 2-oxoglutarate and 2-phosphoglycerate as allosteric regulators of OtsA. The structural analysis in this work strongly contributed to define the mechanisms for feedback inhibition, show different conformational states of the enzyme, and map a new allosteric site.

Journal Keywords: Mycobacterium; OtsA; trehalose-6-phosphate synthase; trehalose

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography


Discipline Tags:

Technical Tags: