Molecular modelling and comparative structural account of aspartyl beta-semialdehyde dehydrogenase of Mycobacterium tuberculosis (H37Rv).

Aspartyl beta-semialdehyde dehydrogenase (ASADH) is an important enzyme, occupying the first branch position of the biosynthetic pathway of the aspartate family of amino acids in bacteria, fungi and higher plants. It catalyses reversible dephosphorylation of L: -beta-aspartyl phosphate (betaAP) to L: -aspartate-beta-semialdehyde (ASA), a key intermediate in the biosynthesis of diaminopimelic acid (DAP)-an essential component of cross linkages in bacterial cell walls. Since the aspartate pathway is unique to plants and bacteria, and ASADH is the key enzyme in this pathway, it becomes an attractive target for antimicrobial agent development. Therefore, with the objective of deducing comparative structural models, we have described a molecular model emphasizing the uniqueness of ASADH from Mycobacterium tuberculosis (H37Rv) that should generate insights into the structural distinctiveness of this protein as compared to structurally resolved ASADH from other bacterial species. We find that mtASADH exhibits structural features common to bacterial ASADH, while other structural motifs are not present. Structural analysis of various domains in mtASADH reveals structural conservation among all bacterial ASADH proteins. The results suggest that the probable mechanism of action of the mtASADH enzyme might be same as that of other bacterial ASADH. Analysis of the structure of mtASADH will shed light on its mechanism of action and may help in designing suitable antagonists against this enzyme that could control the growth of Mycobacterium tuberculosis.