Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acquisition of resistance by malaria parasites towards existing antimalarials has necessitated the development of new chemotherapeutic agents. The effect of vitamin B(12) derivatives on the formation of beta-haematin (synthetic haemozoin) was determined under conditions similar to those in the parasitic food vacuole (using chloroquine, a known inhibitor of haemozoin formation for comparison). Adenosylcobalamin (Ado-cbl), methylcobalamin (CH(3)-cbl) and aquocobalamin (H(2)O-cbl) were approximately forty times more effective inhibitors of beta-haematin formation than chloroquine, cyanocobalamin (CN-cbl) was slightly more inhibitory than chloroquine, while dicyanocobinamide had no effect. It is proposed that the cobalamins exert their inhibitory effect on beta-haematin formation by pi-interactions of their corrin ring with the Fe(III)-protoporphyrin ring and by hydrogen-bonding using their 5,6-dimethylbenzimidazole/ribose/sugar side-chain. The antimalarial activity for the cobalamins (Ado-cbl>CH(3)-cbl>H(2)O-cbl>CN-cbl) was found to be less than that for chloroquine or quinine. Ado-cbl, CH(3)-cbl and CN-cbl do not accumulate in the parasite food vacuole by pH trapping, but H(2)O-cbl does. Unlike humans, the malaria parasite has only one enzyme that uses cobalamin as a cofactor, namely methionine synthase, which is important for growth and metabolism. Thus cobalamins in very small amounts are necessary for Plasmodium falciparum growth but in larger amounts they display antimalarial properties.
 ...
PMID:Naturally occurring cobalamins have antimalarial activity. 1734 14

Folate metabolism of the malaria parasites provides two targets for current antimalarials: dihydrofolate reductase and dihydropteroate synthase. Dihydrofolate reductase inhibitors have been used as antimalarials over the past few decades, often in combination with dihydropteroate synthase inhibitors. Resistance to these antifolate drugs developed through mutations in both target enzymes. However, limited mutation possibilities gave opportunities for the development of new drugs. Furthermore, other enzymes in the folate and related pathways are potential new targets that remain to be exploited. These include thymidylate synthase, an enzyme fused with dihydrofolate reductase in the same protein chain, serine hydroxymethyltransferase, methylene tetrahydrofolate dehydrogenase, methionine synthase and enzymes in the glycine cleavage pathway.
 ...
PMID:Folate metabolism as a source of molecular targets for antimalarials. 1766 90

Direct destruction and ineffective erythropoesis does not adequately explain the cause of anaemia in malaria. It is possible that there are more other mechanisms involved besides the causes described till date in malarial anaemia. The effect of NO on erythropoesis and a major haematological abnormality (microcytic/normocytic/megaloblastic picture) can significantly be observed on repeated exposure. In addition, NO can inhibit the enzyme methionine synthase so functional vit B12 deficiency state may occur which can lead to megaloblastic anaemia. This review will focus on causation of malarial anaemia and nitric oxide induced megaloblastic anaemia.
 ...
PMID:Malarial anaemia and nitric oxide induced megaloblastic anaemia: a review on the causes of malarial anaemia. 1950 89