INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Understanding Mycobacterium tuberculosis Cyclopropane methyltransferases (CMAs) structure-function relationship
DEFELIPE, LUCAS ALFREDO; MARTI, MARCELO ADRIÁN; TURJANSKI, ADRIAN GUSTAVO
Congreso; V Congreso Argentino de Bioinformática y Biología Computacional; 2014
A serious concern in Mycobacterium tuberculosis treatment is the emergence of MDR (Multi-drug resistant) and XDR (Extensively drug-resistance) stains. Choosing new relevant drug targets is prioritary to fight MDR and XDR TB. We developed TuberQ  a protein druggability datatabase to highlight relevant drug targets based on structural druggability and gene expression experiments done in different environments mimicking the stresses TB faces during infection[2,3]. Cyclopropane methyltransferases (CMAs) are shown as a potential targets. Mycobacterium tuberculosis Cyclopropane methyltransferases (CMAs) are responsible for the modification of mycolic acids by the transfer of a methyl group to the olefin, making CMAs attractive drug targets. This protein family is composed of 9 proteins (mmaA1-4, cmaA1-2, pcaA, uma A and ufaA). Mycolic acids are long chain (60-80 carbon atoms) modified fatty acids which are major components of mycobacterial cell wall and these modifications modulate properties of the cell wall (such as drug permeability) and the immune response of the host. Although CMAs are methyltrasnferases with the typical Rossman fold  they are not only able to cyclopropinate but also to introduce keto and metoxy modifications to the same olefin. In the present work we have used comparative modelling and molecular dynamics simulations to understand the different reaction mechanisms present in this protein family. We also performed a comparative druggability study of the family to develop a phamacophore model to aid in the search of drug-like compounds with the ability to bind to several members of CMAs (cmaA1, cmaA2, pcaA and umaA), an approach known as polypharmacology.