New Delhi, March 4: Indian scientists have elucidated in unprecedented detail how the malaria parasite digests haemoglobin in human red blood cells, piecing together a long-standing biological jigsaw that could accelerate the search for new anti-malarial drugs.
Biologists here working with a collaborator in the US have shown that the most lethal of the malaria parasites, Plasmodium falciparum, uses a complex structure of proteins and enzymes to degrade haemoglobin to serve its own nutritional requirements.
The research led by molecular biologist Pawan Malhotra at the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, is described today in the US journal, Proceedings of the National Academy of Sciences.
Medical researchers have known for long that malaria parasites use haemoglobin — a metalloprotein containing iron found in red blood cells — as a source of amino acids for their own growth. Studies in the past have shown that malaria parasites first break up haemoglobin into amino acids and a compound called heme which gets transformed into a dark brown pigment called hemozoin.
“This transformation is a crucial step because heme itself is toxic to malaria parasites — the parasites have to turn heme into harmless hemozoin to be able to survive and grow in the red blood cells,” Malhotra said.
Although numerous earlier studies had identified the multiple molecular components involved in the haemoglobin-to-hemozoin transformation, researchers say, it has never been clearly understood.
“The heme-to-hemozoin transformation has been controversial,” said Govindarajan Padmanabhan, a senior professor of biochemistry at the Indian Institute of Science, Bangalore, who was not associated with the new study.
While researchers knew that a combination of proteins and enzymes would be involved in the hemozoin formation, the precise biochemical pathway through which the process occurred had remained under debate and investigation.
“All the players in the formation of hemozoin are already known — this study has put together the different pieces of the puzzle discovered earlier,” Padmanabhan, who has independently investigated the biology of malaria parasites, told The Telegraph.
In the new research, Malhotra and his colleagues have demonstrated the presence of a complex of multiple proteins and enzymes in the food vacuole of Plasmodium falciparum, and deciphered its role in haemoglobin destruction and hemozoin formation.
The researchers are hoping that this detailed knowledge of the process will spur the search for novel anti-malarial compounds. They point out that no new class of anti-malarial drugs has been introduced since 1996 — and drug-resistant strains of the Plasmodium falciparum parasite have emerged in India and elsewhere in the world.
“Once we understand the pathway, we know where exactly to hit,” Malhotra told this newspaper. The protein complex that plays a role in the haemoglobin-to-hemozoin transformation could be the target for new candidate drugs, he said.
Monika Chugh, Vidhya Sunderaraman, Saravanan Kumar, and Vanga Reddy from the ICGEB, Waseem Siddiqui from Jamia Hamdard, New Delhi and Kenneth Stuart from the Seattle Biomedical Research Institute, Seattle, US, are coauthors of the paper.
Their study has also confirmed through rigorous experiments that two anti-malarial drugs currently in use — chloroquine and artemisinin — interfere with the parasite’s life-cycle by blocking key steps in the haemoglobin transformation process.
The insights from the current study about the haemoglobin-to-hemozoin transformation pathway may “help guide the development” of previously unknown anti-malarial drugs, the scientists said in their research paper.