Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas

BMC Evolutionary Biology, Nov 2015

Background Leptomonas is monogenetic kinetoplastid parasite of insects and is primitive in comparison to Leishmania. Comparative studies of these two kinetoplastid may share light on the evolutionary transition to dixenous parasitism in Leishmania. In order to adapt and survive within two hosts, Leishmania species must have acquired virulence factors in addition to mechanisms that mediate susceptibility/resistance to infection in the pathology associated with disease. Rab proteins are key mediators of vesicle transport and contribute greatly to the evolution of complexity of membrane transport system. In this study we used our whole genome sequence data of these two divergent kinetoplastids to analyze the orthologues/paralogues of Rab proteins. Results During change of lifestyle from monogenetic (Leptomonas) to digenetic (Leishmania), we found that the prenyl machinery remained unchanged. Geranylgeranyl transferase-I (GGTase-I) was absent in both Leishmania and its sister Leptomonas. Farnesyltransferase (FTase) and geranylgeranyl transferase-II (GGTase-II) were identified for protein prenylation. We predict that activity of the missing alpha-subunit (α-subunit) of GGTase-II in Leptomonas was probably contributed by the α-subunit of FTase, while beta-subunit (β-subunit) of GGTase-II was conserved and indicated functional conservation in the evolution of these two kinetoplastids. Therefore the β-subunit emerges as an excellent target for compounds inhibiting parasite activity in clinical cases of co-infections. We also confirmed that during the evolution to digenetic life style in Leishmania, the parasite acquired capabilities to evade drug action and maintain parasite virulence in the host with the incorporation of short-chain dehydrogenase/reductase (SDR/MDR) superfamily in Rab genes. Conclusion Our study based on whole genome sequences is the first to build comparative evolutionary analysis and identification of prenylation proteins in Leishmania and its sister Leptomonas. The information presented in our present work has importance for drug design targeted to kill L. donovani in humans but not affect the human form of the prenylation enzymes.

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Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas

Chauhan et al. BMC Evolutionary Biology Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas Indira Singh Chauhan 2 Jaspreet Kaur 1 Shagun Krishna 0 Arpita Ghosh 4 Prashant Singh 3 Mohammad Imran Siddiqi 0 Neeloo Singh 2 0 Molecular and Structural Biology Division, CSIR Central Drug Research Institute , Jankipuram Extension, Sitapur Road, Lucknow 226031 , India 1 Department of Biochemistry, Shri Ram Murti Smarak Institute of Medical Sciences , Bareilly 243202 , India 2 Biochemistry Division, CSIR Central Drug Research Institute , Jankipuram Extension, Sitapur Road, Lucknow 226031 , India 3 Department of Chemistry , Dayanand Anglo Vedic (P.G. ) College , Dehradun 248001 , India 4 Xcelris Genomics , Ahmedabad , India Background: Leptomonas is monogenetic kinetoplastid parasite of insects and is primitive in comparison to Leishmania. Comparative studies of these two kinetoplastid may share light on the evolutionary transition to dixenous parasitism in Leishmania. In order to adapt and survive within two hosts, Leishmania species must have acquired virulence factors in addition to mechanisms that mediate susceptibility/resistance to infection in the pathology associated with disease. Rab proteins are key mediators of vesicle transport and contribute greatly to the evolution of complexity of membrane transport system. In this study we used our whole genome sequence data of these two divergent kinetoplastids to analyze the orthologues/paralogues of Rab proteins. Results: During change of lifestyle from monogenetic (Leptomonas) to digenetic (Leishmania), we found that the prenyl machinery remained unchanged. Geranylgeranyl transferase-I (GGTase-I) was absent in both Leishmania and its sister Leptomonas. Farnesyltransferase (FTase) and geranylgeranyl transferase-II (GGTase-II) were identified for protein prenylation. We predict that activity of the missing alpha-subunit (α-subunit) of GGTase-II in Leptomonas was probably contributed by the α-subunit of FTase, while beta-subunit (β-subunit) of GGTase-II was conserved and indicated functional conservation in the evolution of these two kinetoplastids. Therefore the β-subunit emerges as an excellent target for compounds inhibiting parasite activity in clinical cases of co-infections. We also confirmed that during the evolution to digenetic life style in Leishmania, the parasite acquired capabilities to evade drug action and maintain parasite virulence in the host with the incorporation of short-chain dehydrogenase/reductase (SDR/MDR) superfamily in Rab genes. Conclusion: Our study based on whole genome sequences is the first to build comparative evolutionary analysis and identification of prenylation proteins in Leishmania and its sister Leptomonas. The information presented in our present work has importance for drug design targeted to kill L. donovani in humans but not affect the human form of the prenylation enzymes. Leishmania donovani; Leptomonas; Prenylation pathway Background Visceral leishmaniasis (VL) is endemic in 98 countries with 350 million people at risk around the world and 300,000 are infected/year (http://www.dndi.org/diseases/ leishmaniasis.php). More than 90 % of visceral leishmaniasis (VL) occurs in seven countries: India, Bangladesh, Nepal, Sudan, Ethiopia, Kenya and Brazil (http:// www.dndi.org/diseases/leishmaniasis.php). Leishmaniasis is caused by protozoan parasites of Leishmania genus. VL also known as kala-azar in India, is the most severe form of leishmaniasis (http://www.dndi.org/diseases-projects/diseases/vl.html) and anthroponotic transmission (human to vector to human) occurs. Whole genome sequencing of clinical isolates of Leishmania donovani and Leptomonas has previously been completed in our lab [ 1 ]. An important insight gained through this effort was the confirmation of co-infection of Leptomonas with the visceralizing Leishmania species. This disturbing trend has been reported so far only in India [ 1–3 ] hinting towards zoonotic spread of the disease and indicates that Leptomonas may be a new pathogen. In such a situation the question remains that a changed paradigm in chemotherapy should be adopted targeting the co-infections. Leptomonas is monogenetic kinetoplastid parasite of insects and primitive in comparison to Leishmania [ 1 ] and these two parasites arose from a common ancestor as shown in Fig. 1 [ 4, 5 ]. At some time during the evolution, Leishmania appears to have lost the ability to be transmitted in nature from invertebrate host to another and adapted to a life cycle alternating between invertebrate and vertebrate host [ 6, 7 ]. With the availability of complete genome sequence with us of these two kinetoplastids [ 1 ] representing important evolutionary branch points viz Leishmania and Leptomonas, in this study we have analyzed the enzymes prenyltransferases (farnesyltransferase and geranylgeranyltransferase) of these kinetoplastids. Cellular organiz (...truncated)


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Indira Chauhan, Jaspreet Kaur, Shagun Krishna, Arpita Ghosh, Prashant Singh, Mohammad Siddiqi, Neeloo Singh. Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas, BMC Evolutionary Biology, 2015, pp. 261, 15, DOI: 10.1186/s12862-015-0538-3