Objective. Glycogen synthase kinase 3 (GSK-3) is a promising target for the treatment of various human diseases such as type 2 diabetes, Alzheimer's disease and inflammation. Successful inhibition of the homologues of this kinase in Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani makes the kinase an attractive target for the treatment of malaria, trypanosomiasis and leishmaniasis, respectively. The aim of this work was to compare the binding sites of the GSK-3 kinases of different parasites and to analyse them as possible targets for therapeutic compounds. Methods. Both a sequence alignment and homology models of the structure of 21 different GSK-3 homologues belonging to mammals, insects, pathogenic fungi, nematodes, trematodes and protozoa have been analysed, 17 of them being studied for the first time.Results. The structure of the kinases and, in particular, their binding sites, were found to be rather conserved, possessing small insertions or deletions and conserved amino acid substitutions. Nevertheless, the kinases of most species of parasite did have some amino acid differences from the human kinase, which could be exploited for the design of selective drugs. Conclusion. Comparison of the human and parasite GSK-3 ATP binding site models has shown that the development of selective drugs affecting parasite GSK-3 is possible. Known inhibitors of human GSK-3 can also be used as starting scaffolds for the search for drugs acting against parasitic diseases.
Various genetic markers such as IS-elements, DR-elements, variable number tandem repeats (VNTR), single nucleotide polymorphisms (SNPs) in housekeeping genes and other groups of genes are being used for genotyping. We propose a different approach. We suggest the type II toxin-antitoxin (TA) systems, which play a significant role in the formation of pathogenicity, tolerance and persistence phenotypes, and thus in the survival of Mycobacterium tuberculosis in the host organism at various developmental stages (colonization, infection of macrophages, etc.), as the marker genes. Most genes of TA systems function together, forming a single network: an antitoxin from one pair may interact with toxins from other pairs and even from other families. In this work a bioinformatics analysis of genes of the type II TA systems from 173 sequenced genomes of M. tuberculosis was performed. A number of genes of type II TA systems were found to carry SNPs that correlate with specific genotypes. We propose a minimally sufficient set of genes of TA systems for separation of M. tuberculosis strains at nine basic genotype and for further division into subtypes. Using this set of genes, we genotyped a collection consisting of 62 clinical isolates of M. tuberculosis. The possibility of using our set of genes for genotyping using PCR is also demonstrated.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.