Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites.
<h4>Background</h4> <p>Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify ironbound haem. These tasks are executed by haemogl...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2016
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| _version_ | 1797080444629417984 |
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| author | Ponsuwanna, P Kochakarn, T Bunditvorapoom, D Kümpornsin, K Otto, T Ridenour, C Chotivanich, K Wilairat, P White, N Miotto, O Chookajorn, T |
| author_facet | Ponsuwanna, P Kochakarn, T Bunditvorapoom, D Kümpornsin, K Otto, T Ridenour, C Chotivanich, K Wilairat, P White, N Miotto, O Chookajorn, T |
| author_sort | Ponsuwanna, P |
| collection | OXFORD |
| description | <h4>Background</h4> <p>Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify ironbound haem. These tasks are executed by haemoglobin-specific proteases and haem biocrystallization factors that are components of a large multi-subunit complex. Since haemoglobin processing machineries are functionally and genetically linked to the modes of action and resistance mechanisms of several anti-malarial drugs, an understanding of their evolutionary history is important for drug development and drug resistance prevention.</p> <h4>Methods</h4> <p>Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodiumspecies, and with the representatives of Apicomplexan species with various host tropisms, were created. Genetic variants were mapped onto existing three-dimensional structures. Genome-wide single nucleotide polymorphism data were used to analyse the selective pressure and the effect of these mutations at the structural level.</p> <h4>Results</h4> <p>Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparumand P. reichenowilineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodiumspecies, but the other members of the plasmepsin family were evolutionarily conserved with one copy for each sub-group in every Apicomplexan species. Haemoglobin-specific falcipains are separated from invasion-related falcipain, and their expansions within one specific locus arose independently in both P. falciparumand P. vivaxlineages. Gene conversion between P. falciparumfalcipain 2A and 2B was observed in artemisinin-resistant strains. Comparison between the numbers of non-synonymous and synonymous mutations suggests a strong selective pressure at falcipain and plasmepsin genes. The locations of amino acid changes from non-synonymous mutations mapped onto protein structures revealed clusters of amino acid residues in close proximity or near the active sites of proteases.</p> <h4>Conclusion</h4> <p>A high degree of polymorphism at the haemoglobin processing genes implicates an imposition of selective pressure. The identification in recent years of functional redundancy of haemoglobin-specific proteases makes them less appealing as potential drug targets, but their expansions, especially in the human malaria parasite lineages, unequivocally point toward their functional significance during the independent and repetitive adaptation events in malaria parasite evolutionary history.</p> |
| first_indexed | 2024-03-07T01:00:08Z |
| format | Journal article |
| id | oxford-uuid:896ed9ca-552b-4817-81f8-1f27d39deea4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:00:08Z |
| publishDate | 2016 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:896ed9ca-552b-4817-81f8-1f27d39deea42022-03-26T22:24:31ZComparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:896ed9ca-552b-4817-81f8-1f27d39deea4EnglishSymplectic Elements at OxfordBioMed Central2016Ponsuwanna, PKochakarn, TBunditvorapoom, DKümpornsin, KOtto, TRidenour, CChotivanich, KWilairat, PWhite, NMiotto, OChookajorn, T<h4>Background</h4> <p>Malaria parasites have evolved a series of intricate mechanisms to survive and propagate within host red blood cells. Intra-erythrocytic parasitism requires these organisms to digest haemoglobin and detoxify ironbound haem. These tasks are executed by haemoglobin-specific proteases and haem biocrystallization factors that are components of a large multi-subunit complex. Since haemoglobin processing machineries are functionally and genetically linked to the modes of action and resistance mechanisms of several anti-malarial drugs, an understanding of their evolutionary history is important for drug development and drug resistance prevention.</p> <h4>Methods</h4> <p>Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodiumspecies, and with the representatives of Apicomplexan species with various host tropisms, were created. Genetic variants were mapped onto existing three-dimensional structures. Genome-wide single nucleotide polymorphism data were used to analyse the selective pressure and the effect of these mutations at the structural level.</p> <h4>Results</h4> <p>Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparumand P. reichenowilineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodiumspecies, but the other members of the plasmepsin family were evolutionarily conserved with one copy for each sub-group in every Apicomplexan species. Haemoglobin-specific falcipains are separated from invasion-related falcipain, and their expansions within one specific locus arose independently in both P. falciparumand P. vivaxlineages. Gene conversion between P. falciparumfalcipain 2A and 2B was observed in artemisinin-resistant strains. Comparison between the numbers of non-synonymous and synonymous mutations suggests a strong selective pressure at falcipain and plasmepsin genes. The locations of amino acid changes from non-synonymous mutations mapped onto protein structures revealed clusters of amino acid residues in close proximity or near the active sites of proteases.</p> <h4>Conclusion</h4> <p>A high degree of polymorphism at the haemoglobin processing genes implicates an imposition of selective pressure. The identification in recent years of functional redundancy of haemoglobin-specific proteases makes them less appealing as potential drug targets, but their expansions, especially in the human malaria parasite lineages, unequivocally point toward their functional significance during the independent and repetitive adaptation events in malaria parasite evolutionary history.</p> |
| spellingShingle | Ponsuwanna, P Kochakarn, T Bunditvorapoom, D Kümpornsin, K Otto, T Ridenour, C Chotivanich, K Wilairat, P White, N Miotto, O Chookajorn, T Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title | Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title_full | Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title_fullStr | Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title_full_unstemmed | Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title_short | Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites. |
| title_sort | comparative genome wide analysis and evolutionary history of haemoglobin processing and haem detoxification enzymes in malarial parasites |
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