(Below N is a link to NCBI taxonomic web page and E link to ESTHER at designed phylum.) > cellular organisms: NE > Eukaryota: NE > Euglenozoa: NE > Kinetoplastida: NE > Trypanosomatidae: NE > Leishmaniinae: NE > Leishmania [genus]: NE > Leishmania [subgenus]: NE > Leishmania donovani species complex: NE > Leishmania donovani: NE
Warning: This entry is a compilation of different species or line or strain with more than 90% amino acide identity. You can retrieve all strain data
(Below N is a link to NCBI taxonomic web page and E link to ESTHER at designed phylum.) Leishmania donovani BPK282A1: N, E.
LegendThis sequence has been compared to family alignement (MSA) red => minority aminoacid blue => majority aminoacid color intensity => conservation rate title => sequence position(MSA position)aminoacid rate Catalytic site Catalytic site in the MSA MPHSSCSRIVVVAALLLLCGSARAVVLSREYSQTDARRSLQYANVTYADI DAIESWKCGGSCNANPSFKVTSIVKGDDAHSLLAYVGVDDGSAQVVVALR GSATQQEKLMRRPAEPVLYDITSGCGLECRVHTGFQRSYLAVRRTVRAAV VRDLTMHPGYNVLVTGHSVGAAVALLAAVDVQAHVNRMFFVSRPIVSLYT FGMPRVGNRAFAVWAAGMLSRGSHFRITSRHDPVPRMPSSGSAGFQHVPY EVYCAAAAGTNCRVCEDSADGDDPTCIVQASKVDMRDHFFYFGERISGGA AGDAMLYL
Leishmaniasis is a neglected tropical disease, caused by several species of Leishmania. Being an opportunistic lipid-scavenging pathogen, Leishmania relies extensively on lipid metabolism especially for host-pathogen interaction, utilizing host lipids for energy and virulence. The rational approach is to target lipid metabolism of the pathogen focusing lipid-catabolizing lipases. The LdLip3 lipase is considered as drug target as it is constitutively expressed in both promastigote and amastigote forms. Since the LdLip3 structure is not known, we modeled its three-dimensional structure to implement structure-based drug discovery approach. Similarity-based virtual screening was carried out to identify potential inhibitors utilizing NCI diversity set on ZINC database including natural products. Implementing computational and experimental approaches, four anti-leishmanial agents were discovered. The screened molecules ZINC01821375, ZINC04008765, ZINC06117316 and ZINC12653571 had anti-leishmanial activity with IC50 (% viable promastigotes vs. concentration) of 5.2+/-1.8muM, 13.1+/-2.6muM, 9.4+/-2.6muM and 17.3+/-3.1muM, respectively. The molecules showed negligible toxicity toward mouse macrophages. Based on the contact footprinting analysis, new molecules were designed with better predicted free energy of binding than discovered anti-leishmanial agents. Further validation for the therapeutic utility of discovered molecules can be carried out by the research community to combat leishmaniasis.
Lipases have been implicated to be of importance in the life cycle development, virulence, and transmission of a variety of parasitic organisms. Potential functions include the acquisition of host resources for energy metabolism and as simple building blocks for the synthesis of complex parasite lipids important for membrane remodeling and structural purposes. Using a molecular approach, we identified and characterized the structure of an LdLip3-lipase gene from the primitive trypanosomatid pathogen of humans, Leishmania donovani. The LdLip3 encodes a approximately 33 kDa protein, with a well-conserved substrate-binding and catalytic domains characteristic of members of the serine lipase-protein family. Further, we showed that LdLip3 mRNA is constitutively expressed by both the insect vector (i.e., promastigote) and mammalian (i.e., amastigote) life cycle developmental forms of this protozoan parasite. Moreover, a homologous episomal expression system was used to express an HA epitope-tagged LdLip3 chimeric construct (LdLip3::HA) in these parasites. Expression of the LdLip3 chimera was verified in these transfectants by Western blots and indirect immuno-fluorescence analyses. Results of coupled immuno-affinity purification and enzyme activity experiments demonstrated that the LdLip3::HA chimeric protein was secreted/released by transfected L. donovani parasites and that it possessed functional lipase enzyme activity. Taken together these observations suggest that this novel secretory lipase might play essential role(s) in the survival, growth, and development of this important group of human pathogens.
