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)

We examined the relative contribution of malaria-associated severe anaemia (parasitaemia and haematocrit < or = 15%) to malaria-related morbidity and mortality among children admitted at 2 hospitals in areas with different seasonal patterns of malaria infection in Malawi. The prevalence of malaria-associated severe anaemia was 8.5% among admissions at the hospital in an area with sustained, year-round infection (Mangochi District Hospital [MDH]), compared to 5.2% at the hospital in an area with a fluctuating pattern of infection (Queen Elizabeth Central Hospital [QECH]). Infants at MDH were nearly twice as likely to have malaria-associated severe anaemia as were those at QECH. Parasite density on admission was not related to the risk of severe anaemia at MDH, but it was at QECH. A similar proportion of all deaths was attributed to malaria at MDH (17.5%) and QECH (20.4%). However, malaria-associated severe anaemia accounted for 54% of malaria-related deaths at MDH compared to only 32% at QECH. Malaria-associated severe anaemia contributed significantly to morbidity and mortality at both sites, but its impact was more marked in the area with a sustained pattern of infection. These findings suggest that seasonal fluctuations in malaria infection may contribute to differences in patterns of malaria disease.
 ...
PMID:In-hospital morbidity and mortality due to malaria-associated severe anaemia in two areas of Malawi with different patterns of malaria infection. 799 35

The malaria parasite thrives on anaerobic fermentation of glucose for energy. Earlier studies from our laboratory have demonstrated that a cytosolic malate dehydrogenase (PfMDH) with striking similarity to lactate dehydrogenase (PfLDH) might complement PfLDH function in Plasmodium falciparum. The N-terminal glycine motif, which forms a characteristic Rossman dinucleotide-binding fold in the co-substrate binding pocket, differentiates PfMDH (GlyXGlyXXGly) from other eukaryotic and prokaryotic malate dehydrogenases (GlyXXGlyXXGly). The amino acids lining the co-substrate binding pocket are completely conserved in MDHs from different species of human, primate and rodent malaria parasites. Based on this knowledge and conserved domains among prokaryotic and eukaryotic MDH, the role of critical amino acids lining the co-substrate binding pocket was analyzed in catalytic functions of PfMDH using site-directed mutagenesis. Insertion of Ala at the 9th or 10th position, which converts the N-terminal GlyXGlyXXGly motif (characteristic of malarial MDH and LDH) to GlyXXGlyXXGly (as in bacterial and eukaryotic MDH), uncoupled regulation of the enzyme through substrate inhibition. The dinucleotide fold GlyXGlyXXGly motif seems not to be responsible for the distinct affinity of PfMDH to 3-acetylpyridine-adenine dinucleotide (APAD, a synthetic analog of NAD), since Ala9 and Ala10 insertion mutants still utilized APADH. The Gln11Met mutation, which converts the signature glycine motif in PfMDH to that of PfLDH, did not change the enzyme function. However, the Gln11Gly mutant showed approximately a 5-fold increase in catalytic activity, and higher susceptibility to inhibition with gossypol. Asn119 and His174 participate in binding of both co-substrate and substrate. The Asn119Gly mutant exhibited approximately a 3-fold decrease in catalytic efficiency, while mutation of His174 to Asn or Ala resulted in an inactive enzyme. These studies provide critical insights into the co-substrate binding pocket of PfMDH, which may be important in design of selective PfMDH/PfLDH inhibitors as potential antimalarials.
 ...
PMID:Structure and function of Plasmodium falciparum malate dehydrogenase: role of critical amino acids in co-substrate binding pocket. 1977 85