title: Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biochemistry Division, CSIR Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. chauhan.indira.indira@gmail.com.
authors.forename: Indira Singh
authors.initials: IS
authors.lastname: Chauhan
authors.affiliation: Department of Biochemistry, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, 243202, India. jaspreet_lko232@yahoo.com.
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Molecular and Structural Biology Division, CSIR Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. krishna.shagun123@gmail.com.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Xcelris Genomics, Ahmedabad, India. arpita.ghosh@xcelrislabs.com.
authors.forename: Arpita
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry, Dayanand Anglo Vedic (P.G.) College, Dehradun, 248001, India. prashantraj86@yahoo.com.
authors.forename: Prashant
authors.initials: P
authors.lastname: Singh
authors.affiliation: Molecular and Structural Biology Division, CSIR Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. mi_siddiqi@cdri.res.in.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Biochemistry Division, CSIR Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. neeloo888@yahoo.com.
authors.forename: Neeloo
authors.initials: N
authors.lastname: Singh
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D018503:Genome, Protozoan; D006801:Humans; D007313:Insecta / Q000469:parasitology; D016830:Kinetoplastida / Q000166:cytology / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D007891:Leishmania / Q000166:cytology / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D007896:Leishmaniasis / Q000469:parasitology; D053858:Metabolic Networks and Pathways; D017368:Protein Prenylation
chemical_list: D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase