Gene/Protein Disease Symptom Drug Enzyme Compound
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Zinc is an essential mineral and deficiency results in abnormal immune function and higher rates of infectious diseases. Randomized controlled trials of zinc supplementation have been conducted in children in developing countries to determine effects on infectious disease morbidity and mortality. Zinc-supplemented children have been found to have lower rates of diarrhea, pneumonia and malaria in comparison with children not given zinc. Zinc used as an adjunct to fluid and dietary management of acute and persistent diarrhea has been found to reduce diarrheal duration and severity. Preliminary evidence suggests that zinc supplementation in children in poor developing country settings may also reduce infant mortality, but larger trials are needed to address this important issue. Preventive and therapeutic interventions should be implemented in developing countries where zinc deficiency is likely to be prevalent.
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PMID:Zinc and childhood infectious disease morbidity and mortality. 1150

Isoprenoids are biosynthesized from isopentenyl diphosphate and the isomeric dimethylallyl diphosphate via the mevalonate pathway or a mevalonate-independent pathway that was identified during the last decade. The non-mevalonate pathway is present in many bacteria, some algae and in certain protozoa such as the malaria parasite Plasmodium falciparum and in the plastids of higher plants, but not in mammals and archaea. Therefore, these enzymes have been recognised as promising drug targets. We report the crystal structure of Escherichia coli 2C- methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), which converts 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate into 2C-methyl-d-erythritol 2,4-cyclodiphosphate and CMP in a Mg-dependent reaction. The protein forms homotrimers that tightly bind one zinc ion per subunit at the active site, which helps to position the substrate for direct attack of the 2-phosphate group on the beta-phosphate.
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PMID:Structure of 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids. 1182 4

The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5'-diphosphate and Mn(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmevalonate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a beta prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn(2+) with tetrahedral coordination. A Mn(2+), with octahedral geometry, is positioned between the alpha and beta phosphates acting in concert with the Zn(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria.
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PMID:Structure of 2C-methyl-D-erythritol 2,4- cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development. 1199 78

Malaria is a leading cause of morbidity and mortality worldwide, and anemia is a common and sometimes serious complication of Plasmodium falciparum infection. Although micronutrient malnutrition is usually highly prevalent in malaria endemic areas, the contribution of micronutrient deficiencies to malarial anemia is often overlooked. Recent investigation suggests that micronutrients such as vitamin A, vitamin E, and zinc, may improve the morbidity of malaria through immune modulation and alteration of oxidative stress. Micronutrients are also involved in the pathogenesis of anemia and likely play a role in malarial anemia, but many clinical trials have not specifically addressed the impact of micronutrient supplementation on malarial anemia. Further work is needed to assess the effect of both clinic and community-based micronutrient interventions on malarial anemia in infants, children, and pregnant women.
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PMID:Micronutrient malnutrition and the pathogenesis of malarial anemia. 1203 72

In 1964, at independence, Zambia's economic future looked brighter than that of most other developing countries. Its copper production accounted for 8% of total world production, and only neighboring Zaire outpaced it in the production of cobalt. Its Central Province around Kabwe held rich deposits of both zinc and lead; uranium deposits also had been found, but their projected yield remained undetermined. Since 1974, the decline in the price of copper and the increase in the price of oil have played havoc with Zambia's balance of payments. Copper, which accounted for 40% of the gross national product (GNP) and 98% of all foreign exchange in 1964, shrank to 12% of the GNP in 1978 while still generating most of the foreign exchange. As a result, imports were cut back markedly from $1.5 billion in 1973 to $690 million in 1983. Although this trend is beginning to make a U-turn, Zambia's economic situation is grave. In 1984 the GNP continued to register negative growth and inflation stood at 25%. With its urbanization rate doubling from 21% in 1964 to 43% in 1985, Zambia is now the most urbanized country south of the Sahara. Zambia's 1985 population is estimated to be 6.8 million. Between 1963 and 1969, the average annual population growth rate was 2.5: it was 3.1% between 1969-80. The current birthrate of about 48/1000 is expected to decline only marginally in the next 15 years, but the death rate is declining more rapidly -- from 19/1000 in the late 1960s to 15/1000 in 1985. Life expectancy is expected to rise from the current 51 years to about 58 years. As a result of the high growth rate, Zambia's population is young, with a median age of about 16.3 years. Traditional African values stress the importance of large families. Zambia's total fertility rate was 6.9 in 1985. According to the World Bank, only 1% of married women of childbearing age in 1982 used contraceptives. Although tribal links are weakening, Zambia still counts 73 officially recognized tribes. Together, they speak about 40 different dialects. Zambia now apportions over 15% of its national budget to education. Despite some noticeable progress, the public health structure remains deficient. Principal health problems include malaria, tuberculosis, and, in Northern Province and Luapula Province, sleeping sickness and river blindness. About 2/3 of the labor force, an estimated 2.2 million persons in 1982, still work in agriculture. Female labor force participation is lower in Zambia than in many African nations.
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PMID:The Republic of Zambia. 1226 4

Zinc deficiency places children in many low-income countries at increased risk of illness and death from infectious diseases. Randomized controlled trials of zinc supplementation provide the best estimate of this risk through demonstrated preventive benefits. In six of nine trials that evaluated prevention of diarrhea, significantly lower incidence of diarrhea occurred in the zinc group than in the controls; a pooled analysis demonstrated 18% (95% confidence interval, 7-28%) less diarrhea. In five trials, a lower rate of pneumonia infection was found in the zinc-supplemented groups, and there was some indication of a preventive effect in three trials with a clinical malaria outcome. Zinc was also found to have a therapeutic benefit in seven trials of acute diarrhea and five of persistent diarrhea. Studies to evaluate the effect of zinc supplementation on mortality are under way, but a recently published study from India identified a 68% reduction in mortality in small-for-gestational-age term infants that were supplemented with zinc from 1 to 9 mo of age. The important effects of zinc deficiency are now clear, and nutrition programs should address this prevalent problem.
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PMID:Zinc deficiency, infectious disease and mortality in the developing world. 1273 Apr 49

The intraerythrocytic Plasmodium falciparum parasite converts most of host hemoglobin heme into a nontoxic heme crystal. Erythrocyte zinc protoporphyrin IX, normally present at 0.5 microM, which is a ratio of 1:40,000 hemes, can elevate 10-fold in some of the anemias associated with malaria disease protection. This work examines a binding mechanism for zinc protoporphyrin IX inhibition of heme crystallization similar to the antimalarial quinolines. Zinc protoporphyrin IX neither forms crystals alone nor extends on preformed heme crystals. Inhibition of both seed heme crystal formation and crystal extension occurs with an inhibitory concentration (IC)50 of 5 microM. Field emission in-lens scanning electron microscopy depicts the transition and inhibition of heme monomer aggregates to heme crystals with and without seeding of preformed hemozoin templates. In vitro zinc protoporphyrin IX, like the quinolines, binds to heme crystals in a saturable, specific, pH, and time-dependent manner. The ratio at saturation is approximately 1 zinc protoporphyrin IX per 250 hemes of the crystal. Unlike the quinolines, zinc protoporphyrin IX binds measurably in the absence of heme. Isolated ring and trophozoite stage parasites have an elevated zinc protoporphyrin IX to heme ratio 6 to 10 times that in the erythrocyte cytosol, which also corresponds to elevated ratios found in heme crystals purified from Plasmodium parasites. This work implicates protection from malaria by a mechanism where elevated zinc protoporphyrin IX in anemic erythrocytes binds to heme crystals to inhibit further crystallization. In endemic malaria areas, severe iron deficiency anemia should be treated with antimalarials along with iron replenishment.
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PMID:Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum. 1457 25

The heme biosynthetic pathway of the malaria parasite is a drug target and the import of host delta-aminolevulinate dehydratase (ALAD), the second enzyme of the pathway, from the red cell cytoplasm by the intra erythrocytic malaria parasite has been demonstrated earlier in this laboratory. In this study, ALAD encoded by the Plasmodium falciparum genome (PfALAD) has been cloned, the protein overexpressed in Escherichia coli, and then characterized. The mature recombinant enzyme (rPfALAD) is enzymatically active and behaves as an octamer with a subunit Mr of 46,000. The enzyme has an alkaline pH optimum of 8.0 to 9.0. rPfALAD does not require any metal ion for activity, although it is stimulated by 20-30% upon addition of Mg2+. The enzyme is inhibited by Zn2+ and succinylacetone. The presence of PfALAD in P. falciparum can be demonstrated by Western blot analysis and immunoelectron microscopy. The enzyme has been localized to the apicoplast of the malaria parasite. Homology modeling studies reveal that PfALAD is very similar to the enzyme species from Pseudomonas aeruginosa, but manifests features that are unique and different from plant ALADs as well as from those of the bacterium. It is concluded that PfALAD, while resembling plant ALADs in terms of its alkaline pH optimum and apicoplast localization, differs in its Mg2+ independence for catalytic activity or octamer stabilization. Expression levels of PfALAD in P. falciparum, based on Western blot analysis, immunoelectron microscopy, and EDTA-resistant enzyme activity assay reveals that it may account for about 10% of the total ALAD activity in the parasite, the rest being accounted for by the host enzyme imported by the parasite. It is proposed that the role of PfALAD may be confined to heme synthesis in the apicoplast that may not account for the total de novo heme biosynthesis in the parasite.
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PMID:Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. 1463 82

Food intake and dietary patterns in Kenyan households have been studied since the 1920s. Reports on breastfeeding, nutrient intake, micronutrient deficiencies and the impacts of malaria and intestinal parasites on nutritional status are reviewed. Diets are mainly cereal-based, with tubers and a variety of vegetables and fruits when available. White maize, sorghum and millet are high in phytate and fiber, which inhibit the absorption of micronutrients such as zinc and iron. Communities growing cash crops have little land for food crops. Although households may own cattle, goats and poultry, commonly these are not consumed. Adults in nomadic communities consume more meat than nonpastoralists. Lakeside and oceanside communities do not consume adequate amounts of fish. Poor households have a limited capacity to grow and purchase food, therefore they have more nutrient deficiencies. Early weaning to cereal porridge deprives the infant of protein and other nutrients from human milk. Other milk is consumed only in small amounts in sweetened tea. Older children eat adult diets, which are extremely bulky and hard to digest. Anemia is mainly due to iron deficiency, malaria and intestinal parasites. In general, Kenyan children have inadequate intakes of energy, fat and micronutrients such as calcium, zinc, iron, riboflavin and vitamins A and B-12. The multiple micronutrient deficiencies may contribute to early onset of stunting and poor child development, whereas lack of calcium together with vitamin D deficiency are responsible for the resurgence of rickets. There is an urgent need to increase the intake of animal source foods by Kenyan children.
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PMID:The need for animal source foods by Kenyan children. 1467 93

A previous longitudinal three-country study in Egypt, Kenya and Mexico found significant positive associations between intake of animal source foods (ASF) and growth, cognitive development and physical activity. To test for a causal relationship, a controlled school feeding intervention study was designed to test the hypotheses that ASF would improve micronutrient status, growth and cognitive function in Kenyan primary school children. Twelve rural Kenyan schools with 554 children were randomized to four feeding interventions using a local vegetable stew as the vehicle. The groups were designated as Meat, Milk, Energy and Control, who received no feedings. Feeding was carried out on school days for seven terms during 21 mo. Preintervention baseline measures included nutritional status, home food intake, anthropometry, biochemical measures of micronutrient status, malaria, intestinal parasites, health status and cognitive and behavioral measures. The measurements of each child were repeated at intervals over 2 y. Baseline data revealed stunting and underweight in approximately 30% of children and widespread inadequate intakes and/or biochemical evidence of micronutrient deficiencies, particularly of iron, zinc, vitamins A and B-12, riboflavin and calcium. Little or no ASF were eaten and fat intake was low. Malaria was present in 31% of children, and hookworm, amebiasis and giardia were widely prevalent. The outcomes measured were rates of change or increase during the intervention in cognitive function, growth, physical activity and behavior and micronutrient status. Hierarchical linear random effects modeling was used for analysis of outcomes.
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PMID:Animal source foods improve dietary quality, micronutrient status, growth and cognitive function in Kenyan school children: background, study design and baseline findings. 1467 94


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