Comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites
Background: 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...
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th-mahidol.31052023-03-31T11:52:15Z Comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites Patrath Ponsuwanna Theerarat Kochakarn Duangkamon Bunditvorapoom Krittikorn Kümpornsin Otto, Thomas D. Chase Ridenour Kesinee Chotivanich Prapon Wilairat White, Nicholas J. Olivo Miotto Thanat Chookajorn Mahidol University. Faculty of Tropical Medicine. Genomic and Evolutionary Medicine Unit, Centre of Excellence in Malaria Open Access article malarial parasites haemoglobin Background: 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. Methods: Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within Plasmodium species, 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. Results: Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites especially in the Plasmodium falciparum and P. reichenowi lineage. Expansion of haemoglobin-specific plasmepsins occurred after the separation event of Plasmodium species, 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. falciparum and P. vivax lineages. Gene conversion between P. falciparum falcipain 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. Conclusion: 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. 2017-11-10T02:51:52Z 2017-11-10T02:51:52Z 2017-11-10 2016 Research Article Malaria Journal. Vol.15, (2016), 51 10.1186/s12936-016-1097-9 https://repository.li.mahidol.ac.th/handle/123456789/3105 eng Mahidol University BioMed Central application/pdf |
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Open Access article malarial parasites haemoglobin |
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Open Access article malarial parasites haemoglobin Patrath Ponsuwanna Theerarat Kochakarn Duangkamon Bunditvorapoom Krittikorn Kümpornsin Otto, Thomas D. Chase Ridenour Kesinee Chotivanich Prapon Wilairat White, Nicholas J. Olivo Miotto Thanat Chookajorn Comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites |
description |
Background: 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.
Methods: Maximum likelihood trees of genetic repertoires encoding haemoglobin processing machineries within
Plasmodium species, 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.
Results: Recent expansions in the falcipain and plasmepsin repertoires are unique to human malaria parasites
especially in the Plasmodium falciparum and P. reichenowi lineage. Expansion of haemoglobin-specific plasmepsins
occurred after the separation event of Plasmodium species, 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. falciparum and P. vivax lineages. Gene conversion between P. falciparum falcipain 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. Conclusion: 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. |
author2 |
Mahidol University. Faculty of Tropical Medicine. Genomic and Evolutionary Medicine Unit, Centre of Excellence in Malaria |
author_facet |
Mahidol University. Faculty of Tropical Medicine. Genomic and Evolutionary Medicine Unit, Centre of Excellence in Malaria Patrath Ponsuwanna Theerarat Kochakarn Duangkamon Bunditvorapoom Krittikorn Kümpornsin Otto, Thomas D. Chase Ridenour Kesinee Chotivanich Prapon Wilairat White, Nicholas J. Olivo Miotto Thanat Chookajorn |
format |
Article |
author |
Patrath Ponsuwanna Theerarat Kochakarn Duangkamon Bunditvorapoom Krittikorn Kümpornsin Otto, Thomas D. Chase Ridenour Kesinee Chotivanich Prapon Wilairat White, Nicholas J. Olivo Miotto Thanat Chookajorn |
author_sort |
Patrath Ponsuwanna |
title |
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_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_sort |
comparative genome‑wide analysis and evolutionary history of haemoglobin‑processing and haem detoxification enzymes in malarial parasites |
publishDate |
2017 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/3105 |
_version_ |
1764209783329521664 |