Molecular modeling and molecular dynamics simulations of GPI 14 in Leishmania major: Insight into the catalytic site for active site directed drug design

Shinde, Sonali; Mol, Milsee; Jamdar, Virashree; Singh, Shailza

doi:10.1016/j.jtbi.2014.02.017

Cited by 19 publications

(11 citation statements)

References 34 publications

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“…GPI-14 is a rational target for leishmaniasis chemotherapy since it is a key enzyme in the biosynthesis of LPG and GIPLs, which are important molecules in the parasite’s interaction with vertebrate and invertebrate hosts and has a structural variation in the side chain and lipid moiety compared to humans [14]. Ruhela et al [29] described the synthesis and evaluation of new iminosugars as inhibitors of GPI-14 using microsomal membranes from L. donovani .…”

Section: Discussionmentioning

confidence: 99%

“…GPI-14 is functionally different from that of the mammalian pathway. Structural variations in the side chain and lipid moiety between Leishmania and humans make GPI-14 a rational drug target [14]. In addition, this enzyme can be a good target for antiparasitic chemotherapy due to its role in the biosynthesis of LPG and GIPLs, which are important molecules involved in the parasite’s infection cycle.…”

Section: Introductionmentioning

confidence: 99%

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Mannosyltransferase (GPI-14) overexpression protects promastigote and amastigote forms of Leishmania braziliensis against trivalent antimony

et al. 2019

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BackgroundGlycosylphosphatidylinositol is a surface molecule important for host-parasite interactions. Mannosyltransferase (GPI-14) is an essential enzyme for adding mannose on the glycosylphosphatidyl group. This study attempted to overexpress the GPI-14 gene in Leishmania braziliensis to investigate its role in the antimony-resistance phenotype of this parasite.ResultsGPI-14 mRNA levels determined by quantitative real-time PCR (qRT-PCR) showed an increased expression in clones transfected with GPI-14 compared to its respective wild-type line. In order to investigate the expression profile of the surface carbohydrates of these clones, the intensity of the fluorescence emitted by the parasites after concanavalin-A (a lectin that binds to the terminal regions of α-D-mannosyl and α-D-glucosyl residues) treatment was analyzed. The results showed that the clones transfected with GPI-14 express 2.8-fold more mannose and glucose residues than those of the wild-type parental line, indicating effective GPI-14 overexpression. Antimony susceptibility tests using promastigotes showed that clones overexpressing the GPI-14 enzyme are 2.4- and 10.5-fold more resistant to potassium antimonyl tartrate (SbIII) than the parental non-transfected line. Infection analysis using THP-1 macrophages showed that amastigotes from both GPI-14 overexpressing clones were 3-fold more resistant to SbIII than the wild-type line.ConclusionsOur results suggest the involvement of the GPI-14 enzyme in the SbIII-resistance phenotype of L. braziliensis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mannosyltransferase (GPI-14) overexpression protects promastigote and amastigote forms of Leishmania braziliensis against trivalent antimony

et al. 2019

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“…In addition, the inability of CaGpi14‐deficient cells to undergo yeast to hyphal transitions should drastically limit the invasiveness and virulence of the organism (Sudbery, ). Some attempts have been made in recent times to model the Gpi14 enzyme from Leishmania major as a drug target and to identify probable candidate molecules that would specifically inhibit the protozoan enzyme (Shinde et al ., ). CaGpi14 could provide a similar target in C .…”

Section: Resultsmentioning

confidence: 97%

The catalytic subunit of the first mannosyltransferase in the GPI biosynthetic pathway affects growth, cell wall integrity and hyphal morphogenesis in Candida albicans

Singh

Chandra

Sah³

et al. 2016

Yeast

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CaGpi14 is the catalytic subunit of the first mannosyltransferase that is involved in the glycosylphosphatidylinositol (GPI) biosynthetic pathway in Candida albicans. We show that CaGPI14 is able to rescue a conditionally lethal gpi14 mutant of Saccharomyces cerevisiae, unlike its mammalian homologue. The depletion of this enzyme in C. albicans leads to severe growth defects, besides causing deficiencies in GPI anchor levels. In addition, CaGpi14 depletion results in cell wall defects and upregulation of the cell wall integrity response pathway. This in turn appears to trigger the osmoticstress dependent activation of the HOG1 pathway and an upregulation of HOG1 as well as its downstream target, SKO1, a known suppressor of expression of hyphae-specific genes. Consistent with this, mutants of CaGPI14 are unable to undergo hyphal transformations in different hyphae-inducing media, under conditions that produce abundant hyphae in the wild-type cells. Hyphal defects in the CaGPI14 mutants could not be attributed either to reduced protein kinase C activation or to defective Ras signalling in these cells but appeared to be driven by perturbations in the HOG1 pathway.

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“…Among the Leishmania spp. inferred orthologous groups without hits against the human proteome (Table 4 ) are proteins already described in the literature as possible drug targets, briefly: trypanothione [ 53 ] (K01833.cdhit) – which relates to defense against oxidative stress [ 54 ]; and alpha-1,3-mannosyltransferase [ 55 , 56 ] (K13690.cdhit) – enzyme essential to add mannose on the glycosylphosphatidyl, relates to the growing resistance to miltefosine. However, there are also other proteins, not yet described as drug targets, which should be further studied, briefly: the energy-converting hydrogenase B subunit I [ 55 ] (K14118.cdhit), found in the Archaea organism Methanothermobacter thermautotrophicus , which belongs to a domain related to MnhB subunit of Na+/H+ antiporter and is predicted as an integral membrane protein [ 57 , 58 ]; and galactofuranosyltransferase [ 59 ] (K13672.cdhit), related to the LPG1 gene, which acts as a major ligand for macrophage adhesion [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Improved orthologous databases to ease protozoan targets inference

2015

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BackgroundHomology inference helps on identifying similarities, as well as differences among organisms, which provides a better insight on how closely related one might be to another. In addition, comparative genomics pipelines are widely adopted tools designed using different bioinformatics applications and algorithms. In this article, we propose a methodology to build improved orthologous databases with the potential to aid on protozoan target identification, one of the many tasks which benefit from comparative genomics tools.MethodsOur analyses are based on OrthoSearch, a comparative genomics pipeline originally designed to infer orthologs through protein-profile comparison, supported by an HMM, reciprocal best hits based approach. Our methodology allows OrthoSearch to confront two orthologous databases and to generate an improved new one. Such can be later used to infer potential protozoan targets through a similarity analysis against the human genome.ResultsThe protein sequences of Cryptosporidium hominis, Entamoeba histolytica and Leishmania infantum genomes were comparatively analyzed against three orthologous databases: (i) EggNOG KOG, (ii) ProtozoaDB and (iii) Kegg Orthology (KO). That allowed us to create two new orthologous databases, “KO + EggNOG KOG” and “KO + EggNOG KOG + ProtozoaDB”, with 16,938 and 27,701 orthologous groups, respectively.Such new orthologous databases were used for a regular OrthoSearch run. By confronting “KO + EggNOG KOG” and “KO + EggNOG KOG + ProtozoaDB” databases and protozoan species we were able to detect the following total of orthologous groups and coverage (relation between the inferred orthologous groups and the species total number of proteins): Cryptosporidium hominis: 1,821 (11 %) and 3,254 (12 %); Entamoeba histolytica: 2,245 (13 %) and 5,305 (19 %); Leishmania infantum: 2,702 (16 %) and 4,760 (17 %).Using our HMM-based methodology and the largest created orthologous database, it was possible to infer 13 orthologous groups which represent potential protozoan targets; these were found because of our distant homology approach.We also provide the number of species-specific, pair-to-pair and core groups from such analyses, depicted in Venn diagrams.ConclusionsThe orthologous databases generated by our HMM-based methodology provide a broader dataset, with larger amounts of orthologous groups when compared to the original databases used as input. Those may be used for several homology inference analyses, annotation tasks and protozoan targets identification.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-1090-0) contains supplementary material, which is available to authorized users.

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Molecular modeling and molecular dynamics simulations of GPI 14 in Leishmania major: Insight into the catalytic site for active site directed drug design

Cited by 19 publications

References 34 publications

Mannosyltransferase (GPI-14) overexpression protects promastigote and amastigote forms of Leishmania braziliensis against trivalent antimony

Mannosyltransferase (GPI-14) overexpression protects promastigote and amastigote forms of Leishmania braziliensis against trivalent antimony

The catalytic subunit of the first mannosyltransferase in the GPI biosynthetic pathway affects growth, cell wall integrity and hyphal morphogenesis in Candida albicans

Improved orthologous databases to ease protozoan targets inference

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