**6. Erythroenzymopathies**

### **6.1 Glucose-6-phosphate dehydrogenase deficiency (G6PD)**

Worldwide, one of the most frequent polymorphic disorders at the level of erythrocytes is the deficiency of glucose-6-phosphate dehydrogenase (G6PD), a condition that is triggered by the decrease in the activity of glucose-6-phosphate dehydrogenase [92]. This disorder linked to genetics is located in the terminal region of the long arm of chromosome X (Xq28) and characterized by establishing the condition of deficiency or normal in men; and in the case of women, it is established that they can be heterozygous, homozygous, or normal [92, 93]. The heterozygous women have a copy of the gene that synthesizes the normal G6PD and another copy that produces the variant of the enzyme.

The active enzyme consists of identical subunits that form dimers and tetramers, which contain a nicotinamide-adenine dinucleotide phosphate (NADP) binding site [94, 95]. NADP binds to the enzyme, as a structural component and as a substrate for the reaction. As shown in **Figure 4**, G6PD catalyzes the entry of glucose-6-phosphate (G6P) into the pentose phosphate pathway, specifically that of hexose monophosphate, a reaction that produces glucose-6 oxidation, phosphate to 6-phosphogluconolactone, reducing NADP to NADPH [96].

In erythrocytes, it is the only source of NADPH, being essential to protect cells against physiologically high levels of oxidative damage, enzymatic mechanisms

**59**

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria*

associated with increases in reduced glutathione (GSH) [92]. Where glutaredoxin intervenes and by means of which GSH protects the sulfhydryl groups of the hemoglobin and the erythrocyte membrane, but in the presence of oxidizing agents, in the form of free radicals or peroxides, the level of GSH decreases, although it can be restored by the action of glutathione reductase which does have an adequate

Wide mechanisms have been described for the study of role of G6PDdeficiency as elements protective during infection with *P. falciparum*. The distribution in the world with respect to malaria is similar to the mutated alleles G6PD; these observations have evidenced that first studies evaluated the connection between G6PD deficiency and malaria, with contradictory results. However, the allelic heterogeneity of G6PD deficiency may be related with susceptibility of *P. falciparum* when infected erythrocytes are present under this condition. Thereby, studies established by Ruwende and col. have demonstrated that G6PD A- alleles are associated with a reduction in the risk of severe malaria caused by *P. falciparum*, protection that are confer principally in heterozygote individuals [97]. Likewise, experimental investigations have evidenced a diminution in the growth of parasitized-erythrocytes with G6PD A and A- in Mediterranean population when contrast with normal subject. Thus, this has indicated the incidence of mechanism of initial phagocytosis, where infected RBC of G6PD-deficicients is induced to phagocytosis by macrophages in anterior stages of the development of parasite, an aspect that is related with protective mechanism against malaria [98, 99]. Equally, a direct relationship of activation of process as phagocytosis in ring stages of parasite in erythrocytes infected with this condition has been considered [99]. This mechanism is associated with an increased binding of autologous IgG and complements C3 fragments when were compared with infected-RBC normal individuals [100]. Finally, have been associated a succession of phenomena's as the oxidation under increase of ROS into the erythrocytes and formation aggregated of

Pyruvate kinase (PK) is an enzyme engaged in the conversion of phosphoenolpyruvate (PEP) to pyruvate. The catalysis of PK is an important element for formation of ATP in the glycolytic route [102]. PK plays a fundamental role in erythrocyte due to which cells depend on the production of ATP by glycolysis for the metabolic development and functionality of the cells [103]. The PK activity generally is increased in erythrocytes in the infection process. Likewise, have been associated to recognizing and the generation of the target of drug with *P. falciparum* infection [104]. PK deficiency is enzymatic alteration of the glycolytic route inducing non-spherocytic hemolytic anemia. The cause frequently linked is due to punctual mutations (1529A and 1456 T). PK deficiency presents worldwide distribution and

It has been shown that PK deficiency is related to protection against infection in mice with *Plasmodium chabaudi* parasites, suggesting a similar effect of PK deficiency in humans. These effects have shown that PK-deficient human erythrocytes have induced diminution of malaria infection [106]. Other reports have indicated that possibly a protective effect against *P. falciparum* infection is generated, with alterations associated to replication on infected erythrocytes, where an invasive defect of erythrocytes in subjects bearing the homozygous mutation and to a preferential macrophage clearance of ring-infected erythrocytes is evidenced both

*DOI: http://dx.doi.org/10.5772/intechopen.83700*

NADPH supplement [75].

band-3 protein [101].

**6.2 Pyruvate kinase deficiency (PK)**

is commonly prevalent in Caucasian populations [105].

in homozygous and heterozygous individuals [107].

#### Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria DOI: http://dx.doi.org/10.5772/intechopen.83700*

associated with increases in reduced glutathione (GSH) [92]. Where glutaredoxin intervenes and by means of which GSH protects the sulfhydryl groups of the hemoglobin and the erythrocyte membrane, but in the presence of oxidizing agents, in the form of free radicals or peroxides, the level of GSH decreases, although it can be restored by the action of glutathione reductase which does have an adequate NADPH supplement [75].

Wide mechanisms have been described for the study of role of G6PDdeficiency as elements protective during infection with *P. falciparum*. The distribution in the world with respect to malaria is similar to the mutated alleles G6PD; these observations have evidenced that first studies evaluated the connection between G6PD deficiency and malaria, with contradictory results. However, the allelic heterogeneity of G6PD deficiency may be related with susceptibility of *P. falciparum* when infected erythrocytes are present under this condition. Thereby, studies established by Ruwende and col. have demonstrated that G6PD A- alleles are associated with a reduction in the risk of severe malaria caused by *P. falciparum*, protection that are confer principally in heterozygote individuals [97]. Likewise, experimental investigations have evidenced a diminution in the growth of parasitized-erythrocytes with G6PD A and A- in Mediterranean population when contrast with normal subject. Thus, this has indicated the incidence of mechanism of initial phagocytosis, where infected RBC of G6PD-deficicients is induced to phagocytosis by macrophages in anterior stages of the development of parasite, an aspect that is related with protective mechanism against malaria [98, 99]. Equally, a direct relationship of activation of process as phagocytosis in ring stages of parasite in erythrocytes infected with this condition has been considered [99]. This mechanism is associated with an increased binding of autologous IgG and complements C3 fragments when were compared with infected-RBC normal individuals [100]. Finally, have been associated a succession of phenomena's as the oxidation under increase of ROS into the erythrocytes and formation aggregated of band-3 protein [101].

### **6.2 Pyruvate kinase deficiency (PK)**

Pyruvate kinase (PK) is an enzyme engaged in the conversion of phosphoenolpyruvate (PEP) to pyruvate. The catalysis of PK is an important element for formation of ATP in the glycolytic route [102]. PK plays a fundamental role in erythrocyte due to which cells depend on the production of ATP by glycolysis for the metabolic development and functionality of the cells [103]. The PK activity generally is increased in erythrocytes in the infection process. Likewise, have been associated to recognizing and the generation of the target of drug with *P. falciparum* infection [104]. PK deficiency is enzymatic alteration of the glycolytic route inducing non-spherocytic hemolytic anemia. The cause frequently linked is due to punctual mutations (1529A and 1456 T). PK deficiency presents worldwide distribution and is commonly prevalent in Caucasian populations [105].

It has been shown that PK deficiency is related to protection against infection in mice with *Plasmodium chabaudi* parasites, suggesting a similar effect of PK deficiency in humans. These effects have shown that PK-deficient human erythrocytes have induced diminution of malaria infection [106]. Other reports have indicated that possibly a protective effect against *P. falciparum* infection is generated, with alterations associated to replication on infected erythrocytes, where an invasive defect of erythrocytes in subjects bearing the homozygous mutation and to a preferential macrophage clearance of ring-infected erythrocytes is evidenced both in homozygous and heterozygous individuals [107].

*Malaria*

[90, 91].

**6. Erythroenzymopathies**

studied population [82]. The α-thalassemia is able to induce hemolytic state and be associated with a reduction in erythrocyte survival, with an increased erythrocyte in circulating young erythrocytes [83]. The α-thalassemia is very common in malaria-endemic regions; it is considered to confer protection against clinical manifestations of the disease induced by *P. falciparum*. *In vitro* studies have evidenced that in α-thalassemic erythrocytes infected with *Plasmodium*, high levels of antibodies develop from their surface. Additionally, activation mechanisms in opsonized erythrocytes, complement-induced lysis and inhibition of sequestration of infected erythrocytes have been associated, which result as anti-malarial mecha-

In other studies, the roles of microcytosis have been associated with the protection from *P. falciparum*-related hemoglobin decrease; in patients, a reduction of infection for part of parasite and most notary in homozygous α-thalassemic individuals have been evidenced, where a decline of hemoglobin levels, is observed and likewise, microcytosis is related with oxidative stress induced in altered erythrocytes with the presence of thalassemia and iron-deficiency. Finally, could be linked a development of process as low resetting in infected microcytic RBCs [86]. Likewise, α-thalassemia protects against severe malaria by attenuating the effect of parasite virulence and decreasing the amount of Hb loss during increased parasitemia. The α-thalassemia erythrocytes parasitized may be more susceptible to phagocytosis in vitro culture and unavailable than normal red cells in the formation of rosettes [87, 88]. Alike, has been related the complement receptor 1 (CR1), which is reduced on α-thalassemic erythrocytes infected, the diminution of CR1 expression in this type of cells are associated with a possible mechanism for reduction resetting [89]. Following, with less able to adhere to endothelial cells. Of this mode, studies have suggested that altered cells maintain that membrane band 3 may be a target for enhanced antibody binding to parasitized a-thalassemic cells

nisms that might be promoted by such antibodies [84, 85].

**6.1 Glucose-6-phosphate dehydrogenase deficiency (G6PD)**

another copy that produces the variant of the enzyme.

6-phosphogluconolactone, reducing NADP to NADPH [96].

Worldwide, one of the most frequent polymorphic disorders at the level of erythrocytes is the deficiency of glucose-6-phosphate dehydrogenase (G6PD), a condition that is triggered by the decrease in the activity of glucose-6-phosphate dehydrogenase [92]. This disorder linked to genetics is located in the terminal region of the long arm of chromosome X (Xq28) and characterized by establishing the condition of deficiency or normal in men; and in the case of women, it is established that they can be heterozygous, homozygous, or normal [92, 93]. The heterozygous women have a copy of the gene that synthesizes the normal G6PD and

The active enzyme consists of identical subunits that form dimers and tetramers, which contain a nicotinamide-adenine dinucleotide phosphate (NADP) binding site [94, 95]. NADP binds to the enzyme, as a structural component and as a substrate for the reaction. As shown in **Figure 4**, G6PD catalyzes the entry of glucose-6-phosphate (G6P) into the pentose phosphate pathway, specifically that of hexose monophosphate, a reaction that produces glucose-6 oxidation, phosphate to

In erythrocytes, it is the only source of NADPH, being essential to protect cells against physiologically high levels of oxidative damage, enzymatic mechanisms

**58**

Some phenomena have been associated with the deficiency of pyruvate kinase and infected erythrocytes, such as those established by the pleiotropic effect of the enzyme deficiency in the invasion of the parasite, which favors a substantial reduction of the growth of these and in the same way observes the activation of processes such as phagocytosis of infected erythrocytes in the ring stage that can provide protection against malaria, either by causing a reduction in the parasite burden or by reducing the number of erythrocytes infected with parasites in the trophozoites stages and schizonts that are available to join microvascular beds of vital organs [108].

These result in a reduced level of invasion of *P. falciparum* and erythrocytes of subjects with homozygous mutations. We also indicated that the possible biochemical differences in the intracellular medium, including the accumulation of glycolytic metabolic intermediates, did not cause a difference in the growth of parasites in erythrocytes between homozygotes and heterozygotes [109, 110]. To know even more the hypotheses of the reduction of the invasion observed in the erythrocytes of the subjects with homozygous mutations, it is also due to the capacity of the parasite, including the altered development of merozoites, the invasion of erythrocytes by merozoites was examined. It has been observed that the erythrocyte-tale merozoites had normal levels of invasion and replication in the erythrocytes of the control subjects [110].

We examined the phagocytic uptake of infected erythrocytes with *P. falciparum* (ring phase and mature phase) of case and control matter. Phagocytosis of infected erythrocytes in the ring stage of patients with homozygous mutations was higher than phagocytosis of uninfected erythrocytes. Also, an increased clearance has been observed by macrophages of erythrocytes infected in the ring stage of the parasite derivatives and heterozygotes for the PKLR mutation [108, 110].

Finally, it has led to establish that infected erythrocytes under this condition had a greater phagocytic phenomenon related to the development and deposition of hemichromes, IgG, and complement C3c [111, 112].

#### **7. Conclusions**

Malaria for years has been a study approach for scientists in the approach to the structural and functional study of the constituent proteins of the etiological agent, *Plasmodium falciparum*. A description of important proteins of the parasite has been established, as well as an approach of the main experimental studies that try to explain the molecular basis of each of the main erythrocyte polymorphisms shows a direct and significant resistance against the development of the parasite, and in this way, structural supports and detailed knowledge of some of these polymorphic modifications that show a complete field of study that will lead to the increasingly broad development of new tools for the compression and search for new pharmacological therapies are provided.

#### **Acknowledgements**

The author thanks University of Cartagena and Universitary Corporation Rafael Nuñez.

**61**

**Author details**

Colombia

Neyder Contreras-Puentes

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

University of Cartagena and Corporation Universitary Rafael Núñez, Cartagena,

\*Address all correspondence to: neydercontreras11@gmail.com

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria*

*DOI: http://dx.doi.org/10.5772/intechopen.83700*

AMA1 apical membrane antigen-1

G6PD glucose-6-phosphate dehydrogenase GPI glycosyl-phosphatidyl-inositol protein

6PG 6-phosphogluconate dehydrogenase

KHARP Knobs-proteins rich in histidines

PVM parasitophorous vacuole membrane

PKLR pyruvate kinase isozymes R/L

NADP nicotinamide-adenine dinucleotide phosphate

PfEMP1 *Plasmodium falciparum* erythrocyte membrane protein 1

CR1 complement receptor 1 C3c complement component C3c DBL Duffy binding-like proteins EDV electron-dense vesicles

GPX glutathione peroxidase GR glutathione reductase

GSH glutathione reduced GSSG glutathione oxidized HbAS hemoglobin AS IgG immunoglobulin G MC Maurer's clefts

mi-RNA micro-ribonucleic acid MSP1 merozoite surface protein 1

PV parasitophorous vacuole

TVN tubulovesicular networks

PK pyruvate kinase ROS reactive oxygen species RBP reticulocyte binding proteins

SCT sickle cell trait

**Acronyms and abbreviations**

CAT catalase

### **Conflict of interest**

None.

Plasmodium falciparum *Protein Exported in Erythrocyte and Mechanism Resistance to Malaria DOI: http://dx.doi.org/10.5772/intechopen.83700*
