TUBERCULOSIS: Targeting the Cell Wall of Mycobacterium tuberculosis: Structure and Mechanism of L,D-Transpeptidase 2

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Structure, 25 October 2012
Copyright © 2012 Elsevier Ltd All rights reserved.
10.1016/j.str.2012.09.016

Authors

Sabri B. Erdemli,Radhika Gupta,William R. Bishai,Gyanu Lamichhane,L. Mario Amzel,Mario A. BianchetSee Affiliations

• Highlights
• The structure of Mtb Ldt_Mt2 shows the binding of a peptidoglycan fragment
• The structure of the complex maps the interaction between acyl donor and enzyme
• Ldts show a conserved C-terminal ykuD domain with a divergent N-terminal domain
• Based on the structure of this complex, a reaction mechanism is proposed

Summary

With multidrug-resistant cases of tuberculosis increasing globally, better antibiotic drugs and novel drug targets are becoming an urgent need. Traditional β-lactam antibiotics that inhibit D,D-transpeptidases are not effective against mycobacteria, in part because mycobacteria rely mostly on L,D-transpeptidases for biosynthesis and maintenance of their peptidoglycan layer. This reliance plays a major role in drug resistance and persistence of Mycobacterium tuberculosis (Mtb) infections. The crystal structure at 1.7 Å resolution of the Mtb L,D-transpeptidase Ldt_Mt2 containing a bound peptidoglycan fragment, reported here, provides information about catalytic site organization as well as substrate recognition by the enzyme. Based on our structural, kinetic, and calorimetric data, we propose a catalytic mechanism for Ldt_Mt2 in which both acyl-acceptor and acyl-donor substrates reach the catalytic site from the same, rather than different, entrances. Together, this information provides vital insights to facilitate development of drugs targeting this validated yet unexploited enzyme.