Insilico analysis of hypothetical proteins unveils putative metabolic pathways and essential genes in Leishmania donovani.

Nithin Ravooru,Nitish Sathyanarayanan,Holenarsipur G Nagendra,Sandesh Ganji

doi:10.3389/fgene.2014.00291

Abstract

Leishmaniasis is a parasitic disease caused by the protozoan Leishmania, which is active in two broad forms namely, Visceral Leishmaniasis (VL or Kala Azar) and Cutaneous Leishmaniasis (CL). The disease is most prevalent in the tropical regions and poses a threat to over 70 countries across the globe. About 200 million people are estimated to be at risk of developing VL in the Indian subcontinent, and this refers to around 67% of the global VL disease burden. The Indian state of Bihar alone accounts for 50% of the total VL cases. While no vaccination exists, several pentavalent antimonials and drugs like Paromomycin, Amphotericin, Miltefosine etc. are used in the treatment of Leishmaniasis. However, due to their low efficacies and the resistance developed by the bug to these medications, there is an urgent need to look into newer species specific targets. The proteome information available suggests that among the 7960 proteins in Leishmania donavani, a staggering 65% remains classified as a hypothetical uncharacterized set. In this background, we have attempted to assign probable functions to these hypothetical sequences present in this parasite, to explore their plausible roles as druggable receptors. Thus, putative functions have been defined to 105 hypothetical proteins, which exhibited a GO term correlation and PFAM domain coverage of more than 50% over the query sequence length. Of these, 27 sequences were found to be associated with a reference pathway in KEGG as well. Further, using homology approaches, four pathways viz., Ubiquinone biosynthesis, Fatty acid elongation in Mitochondria, Fatty Acid Elongation in ER and Seleno-cysteine Metabolism have been reconstructed. In addition, 7 new putative essential genes have been mined with the help of Eukaryotic Database of Essential Genes (DEG). All these information related to pathways and essential genes indeed show promise for exploiting the select molecules as potential therapeutic targets.

Highlights

Leishmaniasis is a parasitic disease caused by the protozoan belonging to the genus Leishmania and is transmitted by the vector phlebotomine or sand fly (Alvar et al, 2013)
KEGG Automatic Annotation Server (KAAS) was used to predict Pathway associations for the 105 sequences that have an associated Gene Ontology (GO) term and a domain spanning more than half of its length
Effective utilization of the various available bioinformatics tools has enabled the successful characterization of a set of hypothetical proteins within Leishmania donovani

Summary

Introduction

Leishmaniasis is a parasitic disease caused by the protozoan belonging to the genus Leishmania and is transmitted by the vector phlebotomine or sand fly (Alvar et al, 2013). Visceral Leishmaniasis is the more severe form of the disease, characterized by anemia, splenohepatomegaly, depressed immune response and several secondary infections leading to death (Alvar et al, 2013). The 10 countries with the highest estimated cases namely Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70–75% of global estimated CL incidence (Alvar et al, 2012). In the Indian subcontinent, about 200 million people are estimated to be at risk of developing VL and this area harbors an estimated 67% of the global VL disease burden. The north Indian state of Bihar alone has captured almost 50% of the total cases in the Asian region (Bhunia et al, 2013)

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Conclusion