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Trypanothione synthetase locus in Trypanosoma cruzi CL Brener strain shows an extensive allelic divergence
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2003 (English)In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 87, no 2, 269-278 p.Article in journal (Refereed) Published
Abstract [en]

The protozoan parasite Trypanosoma cruzi, agent of Chagas' disease, displays an extensive genetic heterogeneity among strains and isolates. It is, therefore, important to determine the degree of polymorphism in potential candidates for drug design. Our studies on the organisation of the locus containing the gene encoding trypanothione synthetase (TcTRS) (an enzyme involved in the unique trypanothione pathway and hence a promising drug target) revealed a high degree of sequence polymorphism between the two alleles in the T. cruzi CL Brener strain, the reference clone for the genome project. The genes linked to the synthetase appeared to be involved in diverse cell-functions, not part of the trypanothione metabolism. The gene synteny was conserved at both allelic loci that were found to reside on a pair of homologous chromosomes with a size difference of about 2 Mb. The allelic polymorphism of TcTRS resulted in a protein sequence divergence of 4%, ten-times higher than in trypanothione reductase (TR), another key enzyme in the same pathway. Such allelic divergence observed in T. cruzi genes might have implications for drug design against Chagas' disease and the evolutional impact of the CL Brener strain.

Place, publisher, year, edition, pages
2003. Vol. 87, no 2, 269-278 p.
Keyword [en]
Trypanosoma cruzi, Trypanothione synthetase, CL Brener, TcTRS-1CL, TcTRS-2CL, Sequence polymorphism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90416DOI: 10.1016/S0001-706X(03)00067-6PubMedID: 12826302OAI: oai:DiVA.org:uu-90416DiVA: diva2:162761
Available from: 2003-04-25 Created: 2003-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. A Genetic Survey of the Pathogenic Parasite Trypanosoma cruzi
Open this publication in new window or tab >>A Genetic Survey of the Pathogenic Parasite Trypanosoma cruzi
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Trypanosoma cruzi, the causative agent of Chagas´ disease, is an evolutionarily ancient species with distinct biological and immunological characteristics. A fundamental understanding of the basic biology of the parasite is necessary in order to develop reliable therapeutic and prophylactic agents against T. cruzi. We have, as a part of the T. cruzi genome project launched by the WHO, generated ESTs corresponding to about one third of the functional genes in the parasite. Only about 1/3 of the unique ESTs could be assigned a function upon sequence comparison to all publicly available data. Comparative analysis of the ESTs to functional genes in S. cerevisiae and C. elegans as well as to sequence data from all other kinetoplastids provided primary insights into the evolutionary divergence of T. cruzi.

A novel dispersed gene family (DGC3) was identified and shown to be present specifically on chromosome 3 and its homologue. Sequence analysis of ten isolated DGC3 genes revealed a high sequence similarity of almost 98% among copies. The DGC3 genes were transcribed, trans-spliced with the spliced leader and polyadenylated, but did not seem to have any protein-coding property. These data preliminary suggest that it encodes a novel family of functional RNA.

In the T. cruzi CL Brener strain, the two alleles of a single copy gene encoding the trypanothione synthetase (TcTRS) enzyme appeared to be highly polymorphic. The divergence of the deduced protein sequence was 4%, almost ten-fold higher than another protein, trypanothione reductase, involved in the same pathway. The observed allelic divergence might influence the TcTRS activity thereby having implications for drug design. Moreover, the TcTRS gene was found to be flanked by a number of genes involved in diverse functions and located to a pair of homologous chromosomes with a size difference of about 2 Mbp.

A gene potentially encoding the polypyrimidine-binding protein (TcPTB) was identified and characterised regarding its organisation and function. The deduced amino acid sequence was shown to comprise four RRM domains generally present in other PTBs. Interestingly, the TcPTB gene appeared to be expressed in a stage-specific manner implicating different functions during parasite development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 66 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1264
Keyword
Molecular genetics, Trypanosoma cruzi, Chagas', gene discovery, EST, sequencing, DGC3, repeats, gene family, CL Brener, trypanothione synthetase, TcTRS locus, alleles, polymorphism, RNA-binding protein, TcPTB, stage-specific expression, Genetik
National Category
Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-3425 (URN)91-554-5635-9 (ISBN)
Public defence
2003-05-23, Rudbeck Hall, Rudbeck Laboratory, Uppsala University, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-04-25 Created: 2003-04-25Bibliographically approved

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