Publicação
Characterization of Plasmodium methionine metabolism key enzyme
| Resumo: | Malaria is a disease caused by protozoan parasites of the genus Plasmodium that are transmitted to humans by infected female Anopheles mosquitoes. Despite countless efforts toward eradication malaria still remains one of the most prevalent infectious diseases, constituting a major public health concern. The available antimalarial drugs are insufficient to control and eradicate malaria, mostly due to the emergence of drug-resistant parasites. Thus, the development of novel intervention strategies is critical to achieve eradication. As an obligatory intracellular pathogen, Plasmodium establishes close interactions with its host that are crucial to ensure parasite development and survival, one of such is the methionine metabolism. Methionine is an essential amino acid and, as for most living organisms, Plasmodium lacks the ability to synthesize methionine de novo. During the blood-stage of infection Plasmodium obtains methionine mainly through haemoglobin digestion. However, how Plasmodium obtains methionine during the liver-stage and how the parasite modulates the host cells in order to scavenge this essential amino acid is still unknown. The first step of methionine cycle is the synthesis of S-adenosylmethionine (SAMe) through a reaction catalyzed by the enzyme SAMe synthetase (SAMS). SAMe is a key metabolite in the methionine metabolism being the main biological donor of methyl groups for transmethylation reactions. SAMe is also a key intermediate in the transsulfuration pathway generating homocysteine (Hcy) which is metabolized into glutathione (GSH), being the last step of this pathway catalysed by glutathione synthetase (GS). GSH is a powerful antioxidant that in Plasmodium acts as one of the primary lines of the defense against the damage caused by reactive oxygen species (ROS), ensuring parasite survival. In this work we have explored the role of Plasmodium enzymes responsible for SAMe and GSH synthesis throughout its life cycle and in particular during the liver-stage of infection. The liver is a particular organ in the metabolism of methionine, namely in SAMe-dependent transmethylation reactions and in glutathione synthesis and storage. Thus, we hypothesized that while replicating inside hepatocytes, Plasmodium relies on its host to ensure a sufficient supply of these crucial metabolites. The data obtained in this study suggest that: 1) Plasmodium does not rely on its own SAMS enzyme while developing inside hepatocytes; 2) that the inhibition of SAMS activity during the blood-stage of infection leads to a low parasitemia, preventing the onset of cerebral malaria and 3) the deletion of GS-encoding gene results in the arrest at the oocyst stage, preventing transmission between the mosquito vector and the mammalian host. A detailed knowledge of Plasmodium methionine pathway provides promising tools for the design and development of novel antimalarial drugs. |
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| Autores principais: | Marreiros, Maria Inês Moreira Oliveira Leite |
| Assunto: | Malária Plasmodium Interação patogénio-hospedeiro Metabolismo da metionina ROS Teses de mestrado - 2016 |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria is a disease caused by protozoan parasites of the genus Plasmodium that are transmitted to humans by infected female Anopheles mosquitoes. Despite countless efforts toward eradication malaria still remains one of the most prevalent infectious diseases, constituting a major public health concern. The available antimalarial drugs are insufficient to control and eradicate malaria, mostly due to the emergence of drug-resistant parasites. Thus, the development of novel intervention strategies is critical to achieve eradication. As an obligatory intracellular pathogen, Plasmodium establishes close interactions with its host that are crucial to ensure parasite development and survival, one of such is the methionine metabolism. Methionine is an essential amino acid and, as for most living organisms, Plasmodium lacks the ability to synthesize methionine de novo. During the blood-stage of infection Plasmodium obtains methionine mainly through haemoglobin digestion. However, how Plasmodium obtains methionine during the liver-stage and how the parasite modulates the host cells in order to scavenge this essential amino acid is still unknown. The first step of methionine cycle is the synthesis of S-adenosylmethionine (SAMe) through a reaction catalyzed by the enzyme SAMe synthetase (SAMS). SAMe is a key metabolite in the methionine metabolism being the main biological donor of methyl groups for transmethylation reactions. SAMe is also a key intermediate in the transsulfuration pathway generating homocysteine (Hcy) which is metabolized into glutathione (GSH), being the last step of this pathway catalysed by glutathione synthetase (GS). GSH is a powerful antioxidant that in Plasmodium acts as one of the primary lines of the defense against the damage caused by reactive oxygen species (ROS), ensuring parasite survival. In this work we have explored the role of Plasmodium enzymes responsible for SAMe and GSH synthesis throughout its life cycle and in particular during the liver-stage of infection. The liver is a particular organ in the metabolism of methionine, namely in SAMe-dependent transmethylation reactions and in glutathione synthesis and storage. Thus, we hypothesized that while replicating inside hepatocytes, Plasmodium relies on its host to ensure a sufficient supply of these crucial metabolites. The data obtained in this study suggest that: 1) Plasmodium does not rely on its own SAMS enzyme while developing inside hepatocytes; 2) that the inhibition of SAMS activity during the blood-stage of infection leads to a low parasitemia, preventing the onset of cerebral malaria and 3) the deletion of GS-encoding gene results in the arrest at the oocyst stage, preventing transmission between the mosquito vector and the mammalian host. A detailed knowledge of Plasmodium methionine pathway provides promising tools for the design and development of novel antimalarial drugs. |
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