Glucose-6-Phosphate Dehydrogenase Deficient Red Cells: Resistance to Infection by Malarial Parasites

Luzzatto, Lucio; Usanga, E. A.; Reddy, S.

doi:10.1126/science.164.3881.839

Cited by 224 publications

(102 citation statements)

References 24 publications

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“…Some years later, it was observed that the parasitation rate in patients heterozygous for G6PD deficiency was 2-80 times higher in normal red blood cells (RBCs) compared with deficient ones. However, the underlying mechanism was not clear and was hypothesized to be either related to decreased invasion, decreased parasite survival or enhanced removal of G6PD-deficient infected RBCs (IRBCs) (23). No differences in invasion of parasites into G6PD-sufficient and -deficient RBCs were reported in 1998 (18).…”

Section: G6pd Deficiencymentioning

confidence: 99%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is responsible for severe malaria and therefore of special interest with regard to drug development. Plasmodium parasites are highly dependent on glucose and very sensitive to oxidative stress; two observations that drew interest to the pentose phosphate pathway (PPP) with its key enzyme glucose‐6‐phosphate dehydrogenase (G6PD). A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections. Plasmodium parasites and the human host possess a complete PPP, both of which seem to be important for the parasites. Interestingly, there are major differences between parasite and human G6PD, making the enzyme of Plasmodium a promising target for antimalarial drug design. This review gives an overview of the current state of research on glucose‐6‐phosphate metabolism in P. falciparum and its impact on malaria infections. Moreover, the unique characteristics of the enzyme G6PD in P. falciparum are discussed, upon which its current status as promising target for drug development is based. © 2012 IUBMB IUBMB Life, 64(7): 603–611, 2012

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Section: G6pd Deficiencymentioning

confidence: 99%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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“…The majority of deficient individuals live in tropical and subtropical regions in which malaria is endemic or where malaria has been eradicated only recently. This distribution of G6PD deficiency as well as functional analysis of deficient erythrocytes and epidemiological data has indicated that G6PD deficiency has a protective role against malaria (Luzzatto et al 1969;Ruwende et al 1995;Mehta et al 2000). Thus, studying the molecular basis of G6PD deficiency in malaria-affected parts of the world is of special interest.…”

Section: Introductionmentioning

confidence: 98%

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

et al. 2005

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency protects from severe forms of malaria. It is interesting therefore to analyze the molecular basis underlying G6PD deficiency in regions such as the Mediterranean basin where malaria was present for a long time in history. Here we report on the genetic characterization of G6PD deficiency among inhabitants of one Mediterranean region-the Dalmatian region of south Croatia. We analyzed 24 unrelated G6PD-deficient male subjects. Molecular testing revealed several different mutations: G6PD Cosenza 9, G6PD Mediterranean 4, G6PD Seattle 3, G6PD Union 3, and G6PD Cassano 1. Furthermore, we have identified one novel G6PD variant that we named G6PD Split. This variant is caused by a nucleotide change 1442 C fi G leading to the amino acid substitution 481 Pro fi Arg and is characterized by moderate enzyme deficiency (class III variant). This study reveals a higher prevalence (37.5%) of the Cosenza mutation in the Dalmatian region than anywhere else previously investigated and overall shows the considerable molecular heterogeneity underlining G6PD deficiency that can be observed in Mediterranean populations.

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“…Consequently, humans that are heterozygous for G6PD, and therefore have variants of this enzyme that yield less than optimum activity, would be resistant to infection by P. falciparum. Furthermore, it is known that the parasitized G6PD-deficient cell is rapidly removed from the circulation, so that the parasite is not afforded the possibility to undergo division (3).…”

Section: Introductionmentioning

confidence: 99%

Glucose-6-phosphate Dehydrogenase Deficiency in Portugal: Biochemical and Mutational Profiles, Heterogeneity, and Haplotype Association

Rodrigues

Freire²,

Martins

et al. 2002

Blood Cells, Molecules, and Diseases

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. This deficiency in erythrocytes has a prevalence of 0.51 Ϯ 0.109 in the Caucasoid male population of Portugal. The frequency for deficiency-conferring genes is 0.39% in the Portuguese population. In the herein study populations males from areas of Portugal presenting with the highest prevalence of G6PD deficiency (Castelo Branco, Setúbal, Faro, and Lisbon) as well as similar subjects located in the border Center/North area of the country (Viseu) have been analyzed for biochemical parameters and screened for mutations and haplotypeassociated mutations commensurate with G6PD deficiency. Six intragenic restriction fragment length polymorphisms (RFLPs) were studied: exon 5, nt 376 A 3 G, FokI; intron 5, nt 611 C 3 G, PvuII; intron 8, nt 163 C 3 T, BspHI; exon 10, nt 116 G 3 A, PstI; exon 11, nt 1311 C 3 T, BclI; and intron 11, nt 93 T 3 C, NlaIII. New haplotypes were constructed with the inclusion of intron 11, nt 93 T 3 C, NlaIII, and only 5 of 64 possible haplotypes were found to show a marked linkage disequilibrium for several RFLPs and also for mutations and specific haplotypes. The control population (n ϭ 168 males) presented the G6PD B variant and corresponded to haplotypes I (Ϫ Ϫ ϩ ϩ Ϫ Ϫ), Ia (Ϫ Ϫ ϩ ϩ Ϫ ϩ), and VIIa (Ϫ Ϫ ϩ ϩ ϩ ϩ), in 91.8, 2.3, and 5.9%, respectively. The PCR and sequencing analysis of extracted DNAs from the deficient G6PD group showed 48.6% (16/33) of individuals with the G6PD AϪ mutation, corresponding to haplotype VIa (ϩ ϩ Ϫ ϩ Ϫ ϩ); 9% (3/33) with the Betica mutation and 18% (6/33) with the Santa Maria mutation, both of them associated with haplotype IVa (ϩ Ϫ Ϫ ϩ Ϫ ϩ); 6.1% (2/33) with the Mediterranean mutation associated with haplotype VIIa; 12.3% (4/33) with the Seattle mutation, 3.0% (1/33) with Gaohe mutation; and a new mutation, 3.0% (1/33), which we designated by G6PD Flores, all of them associated with haplotype I. © 2002 Elsevier Science (USA)

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Glucose-6-Phosphate Dehydrogenase Deficient Red Cells: Resistance to Infection by Malarial Parasites

Cited by 224 publications

References 24 publications

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

Characterization of G6PD deficiency in southern Croatia: description of a new variant, G6PD Split

Glucose-6-phosphate Dehydrogenase Deficiency in Portugal: Biochemical and Mutational Profiles, Heterogeneity, and Haplotype Association

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