Gleiciane Leal Moraes1, Guelber Cardoso Gomes2, Paulo Robson Monteiro de Sousa1, Cláudio Nahum Alves1, Thavendran Govender3, Hendrik G Kruger3, Glenn E M Maguire3, Gyanu Lamichhane4, Jerônimo Lameira5. 1. Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil. 2. Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil; Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil. 3. Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, South Africa. 4. Johns Hopkins University School of Medicine, Taskforce to Study Resistance Emergence & Antimicrobial Development Technology, 1503 E. Jefferson St, Baltimore, MD 21231, USA. 5. Laboratório de Planejamento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil; Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-110 Belém, PA, Brazil. Electronic address: lameira@ufpa.br.
Abstract
Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.
Tuberculosis (TB) is the second leading cause of n class="Species">human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.
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