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http://www.as.ua.edu/ant/bindon/ant475/g6pd/g6pd.htm
Human Adaptability
ANT 475/575
Dr. Bindon
[Home | Discussion | Paper]
[ Department of Anthropology | College of Arts and Sciences | University of Alabama ]
Glucose-6-Phosphate Dehydrogenase (G6PD) and Malaria
ANT 570 syllabus
Structure of G6PD
The enzyme, Glucose-6-Phosphate Dehydrogenase, is comprised of a dimer or tetramer of identical polypeptide chains
Each unit consists of 515 amino acids
The single G6PD locus in humans is located on the telomeric region of the long arm of the X-chromosome
Females have two X chromosomes, hence two copies of G6PD, while males have only one X chromosome and one copy of G6PD
Function of G6PD
G6PD is present in the cytoplasm of all cells of the body
In Red Blood Cells (RBC), which lack nuclei, mitochondria, and other organelles, G6PD is particularly significant
G6PD is involved in the first step of the Pentose Phosphate Shunt
Catalyzes the oxidation of Glucose-6-Phosphate to 6-Phosphogluconolactone (Phosphogluconate)
Only source of NADPH and GSH, necessary for the reduction of hydrogen peroxide
Hydrogen Peroxide is a strong oxidant that will degrade the RBC and cause hemolysis if it is not reduced
Red Blood Cell Metabolism
Familial Genetics of G6PD
Five genotypes can form from combinations of one normal (GdB) and one deficient form (e.g., GdA- or GdMed) of G6PD
Females
GdB/GdB, Homozygous Normal; "Normal"
GdB /GdA-, Heterozygous; "Heterozygote"
GdA-/GdA-, Homozygous Deficient; "G6PD Deficient"
Males
GdB, Hemizygous Normal; "Normal"
GdA-, Hemizygous Deficient; "G6PD Deficient"
G6PD Heterozygotes
Because of the random inactivation of one X chromosome in each female body cell, heterozygotes have two kinds of Red Blood Cells
G6PD Normal
G6PD Deficient
Depending on which X chromosome was inactivated in the stem cell giving rise to the particular RBC
G6PD Variants
Four most common variants out of 300+ known
GdB Normal Activity All World Populations
GdA Normal Activity; Aspartic acid substituted for asparagine at position 126, Guanine for adenine at DNA position 376 Africa (most common variant)
GdA- 8 - 20% Normal Activity; Methionine for Valine at position 67 and Aspartic Acid for Asparagine at position 126, Adenine for Guanine at position 202 and Guanine for Adenine at position 376 Africa
GdMed < 5% Normal Activity; Phenylalanine for Serine at position 188; Thymine for Cytosine at position 563 Iran, Iraq, India, Pakistan, Greece, Sardinia
G6PD Activity
Declines with age of RBC
GdB has 62 day half-life for decay of activity
Sustains GSH levels for 100 to 120 day RBC life span
GdA- has normal activity when new, but the activity half-life is only 13 days
Deficiency is due to instability of the enzyme
GdMed has greater instability with 8 day half-life
New cells already have reduced activity, and mature RBC have enzyme levels < 1% normal activity
Symptoms of G6PD deficiency
G6PD deficiency is manifested as anemia, with RBCs being prematurely destroyed
RBCs are also extremely susceptible to oxidative stress
Neonatal jaundice is a yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues
A severe form of this is a direct result of insufficient activity of the G6PD enzyme in the liver
In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage (Beutler, 1994).
Outside areas where dietary components cause hemolytic crises, infection is the most common cause of hemolysis and anemia in subjects with G6PD deficiency
Oxidative metabolites produced by bacterial, viral, and rickettsial cause an anemic response
Viral hepatitis, pneumonia, and typhoid fever are particularly likely to precipitate a hemolytic episode in G6PD deficient individuals
G6PD Hemolysis
Red blood cells will hemolyze or burst when the oxidant stress level becomes too high
Hemolysis occurs in G6PD deficient individuals due to the consumption of certain foods or drugs
Substances that increase the oxidation of glutathione, thereby reducing the available GSH for oxidation of peroxide, creating a potential for hemolysis
Fava Beans contains vicine and convicine which can cause a hemolytic crisis in GdMed individuals
Many anti-malarial drugs, sulfonamides, sulfones and other drugs produce the same reaction in severely deficient individuals
Also leads to the oxidation of hemoglobin, making it lose the ability to be a reversible oxygen carrier
Favism
The Fava Bean (Vicia faba) is a favored cultigen in areas where the GdMed allele is common
Vicine and convicine make up approximately 0.5% of the wet weight of the Fava bean
These compounds metabolize to divicine and isouramil in the intestine
These metabolites decrease RBC reduced glutathione (GSH)
Produce hydrogen peroxide and free radicals
Creates a severe oxidant stress in G6PD deficient cells
G6PD and Fava Beans
Plasmodium in the RBC
Plasmodium preferentially attack immature RBC but P. falciparum can invade RBC of all ages
Plasmodium oxidizes RBC NADPH from the Pentose Phosphate pathway for its metabolism
This results in a deficiency of RBC GSH, most severe in G6PD deficient individuals, leading to peroxide-induced hemolysis which curtails the development of Plasmodium(Malaria parasites
After several cell cycles the Plasmodium (Malaria parasites)can adapt to produce its own G6PD, reducing the adaptive benefit of G6PD deficiency
G6PD and Malaria
Fava Beans and Malaria
Recall that fava beans contain compounds that metabolize to powerful oxidants
In a cell that is oxidant-stressed by Plasmodium infection, the addition of another strong oxidant can lead a rapid build-up of peroxide
In vitro and in vivo (mouse) studies indicate a suppressant effect of divicine and isouramil on Plasmodium in G6PD normals
This effect would be expected to be even greater in G6PD deficient individuals
G6PD, Fava Beans, and Malaria
Distribution of G6PD, Fava Beans, and Malaria
Case Study: GdMed and Favism
Fava bean cultivation is widespread, especially throughout the circum-Mediterranean region
There is substantial overlap between the cultivation of fava beans and the GdMed allele
Serious cases of hemolytic favism are described more than 2,000 years ago by Greeks
About 1 in 12 cases of favism results in mortality
Mostly affects children (up to 95% of cases)
Why continue to cultivate fava beans?
Nutrition and Fava Beans
Fava beans are only one of several legumes cultivated in the Mediterranean including chick peas, kidney beans, and lentils
Fava beans are a highly productive crop and produce a high yield of protein by dry weight
However, kidney beans and chick peas are more efficient in terms of the ratio of weight of protein consumed to weight gained in growing individuals
Lentils are as efficient as fava beans
Continued use where Favism rates are high must be due to other factors
Responses to Favism
Mediterranean populations have developed several responses including food taboos, preparation techniques, and folk remedies
Highly susceptible groups including children and pregnant women are frequently forbidden to consume fava beans
Drying, soaking, and removing the skins appear to reduce toxicity
Increasing sugar consumption reduces the severity of an impending hemolytic crisis
Continued Cultivation
There are three lines of evidence that suggest continued cultivation of Fava Beans in the face of Favism is related to malaria
The association of divicine and isouramil with the suppression of Plasmodium growth
The clinal association of fava beans cultivation and malaria
The overlap of the peak fava bean harvest and consumption times with the peak Anopheles mosquito breeding season
Selection in Males
Males are G6PD deficient or Normal
Malaria alone:
Select for an increase in GdMed because of resistance to Plasmodium in G6PD RBCs
Combination of Malaria and Fava beans:
Select against GdMed through favism and hemolytic anemia
Cooking and preparation techniques may buffer the favism selection
Other genes may also buffer favism
Acid Phosphatase B and b -Thallasemia reduce severity
Decreased selection against GdB through increased resistance to Plasmodium from fava beans
Selection in Females
Malaria alone favors the heterozygotes
Selects against GdB/GdB, most susceptible genotype to Plasmodium
Anemia selects against GdMed/GdMed, but they are resistant to Plasmodium
Heterozygotes (GdB/GdMed) are favored
Increased resistance to malaria compared to GdB/GdB
Less susceptible to hemolytic crises from diet or infection than GdMed/GdMed
The balance is complicated by the random deactivation of an X chromosome in the cells producing the RBCs
Heterozygotes will range widely from about 20% normal to about 80% normal RBCs, and the response to malaria and other hemolytic crises will vary accordingly
Combination of Malaria and Fava beans complicates selection
Fava beans intensify selection against GdMed/GdMed
Favism and increased incidence of hemolytic anemia
Cooking, preparation techniques, and other genes may buffer GdMed/GdMed from severe hemolytic crises
Decreased selection against GdB/GdB
Increased resistance to Plasmodium from fava beans
Heterozygotes (GdB/GdMed) are still most fit
The differential between GdB/GdMed and GdB/GdB resistance to malaria is reduced (selection is weaker)
Selection differential may be stronger against GdMed/GdMed because of the increased incidence of hemolytic crises due to favism
References
http://rialto.com/g6pd/index.htm
Green L (1993) G6PD deficiency as protection against falciparum malaria: an epidemiologic critique of population and experimental studies. Yearbook of Physical Anthropology, 36:153-178.
Katz SH, and Schall J (1979) Fava bean consumption and biocultural evolution. Medical Anthropology, 3:459-476.
top
Date this page last edited: August 20, 2002
e-mail me at: jbindon@tenhoor.as.ua.edu
Human Adaptability
ANT 475/575
Dr. Bindon
[Home | Discussion | Paper]
[ Department of Anthropology | College of Arts and Sciences | University of Alabama ]
Glucose-6-Phosphate Dehydrogenase (G6PD) and Malaria
ANT 570 syllabus
Structure of G6PD
The enzyme, Glucose-6-Phosphate Dehydrogenase, is comprised of a dimer or tetramer of identical polypeptide chains
Each unit consists of 515 amino acids
The single G6PD locus in humans is located on the telomeric region of the long arm of the X-chromosome
Females have two X chromosomes, hence two copies of G6PD, while males have only one X chromosome and one copy of G6PD
Function of G6PD
G6PD is present in the cytoplasm of all cells of the body
In Red Blood Cells (RBC), which lack nuclei, mitochondria, and other organelles, G6PD is particularly significant
G6PD is involved in the first step of the Pentose Phosphate Shunt
Catalyzes the oxidation of Glucose-6-Phosphate to 6-Phosphogluconolactone (Phosphogluconate)
Only source of NADPH and GSH, necessary for the reduction of hydrogen peroxide
Hydrogen Peroxide is a strong oxidant that will degrade the RBC and cause hemolysis if it is not reduced
Red Blood Cell Metabolism
Familial Genetics of G6PD
Five genotypes can form from combinations of one normal (GdB) and one deficient form (e.g., GdA- or GdMed) of G6PD
Females
GdB/GdB, Homozygous Normal; "Normal"
GdB /GdA-, Heterozygous; "Heterozygote"
GdA-/GdA-, Homozygous Deficient; "G6PD Deficient"
Males
GdB, Hemizygous Normal; "Normal"
GdA-, Hemizygous Deficient; "G6PD Deficient"
G6PD Heterozygotes
Because of the random inactivation of one X chromosome in each female body cell, heterozygotes have two kinds of Red Blood Cells
G6PD Normal
G6PD Deficient
Depending on which X chromosome was inactivated in the stem cell giving rise to the particular RBC
G6PD Variants
Four most common variants out of 300+ known
GdB Normal Activity All World Populations
GdA Normal Activity; Aspartic acid substituted for asparagine at position 126, Guanine for adenine at DNA position 376 Africa (most common variant)
GdA- 8 - 20% Normal Activity; Methionine for Valine at position 67 and Aspartic Acid for Asparagine at position 126, Adenine for Guanine at position 202 and Guanine for Adenine at position 376 Africa
GdMed < 5% Normal Activity; Phenylalanine for Serine at position 188; Thymine for Cytosine at position 563 Iran, Iraq, India, Pakistan, Greece, Sardinia
G6PD Activity
Declines with age of RBC
GdB has 62 day half-life for decay of activity
Sustains GSH levels for 100 to 120 day RBC life span
GdA- has normal activity when new, but the activity half-life is only 13 days
Deficiency is due to instability of the enzyme
GdMed has greater instability with 8 day half-life
New cells already have reduced activity, and mature RBC have enzyme levels < 1% normal activity
Symptoms of G6PD deficiency
G6PD deficiency is manifested as anemia, with RBCs being prematurely destroyed
RBCs are also extremely susceptible to oxidative stress
Neonatal jaundice is a yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues
A severe form of this is a direct result of insufficient activity of the G6PD enzyme in the liver
In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage (Beutler, 1994).
Outside areas where dietary components cause hemolytic crises, infection is the most common cause of hemolysis and anemia in subjects with G6PD deficiency
Oxidative metabolites produced by bacterial, viral, and rickettsial cause an anemic response
Viral hepatitis, pneumonia, and typhoid fever are particularly likely to precipitate a hemolytic episode in G6PD deficient individuals
G6PD Hemolysis
Red blood cells will hemolyze or burst when the oxidant stress level becomes too high
Hemolysis occurs in G6PD deficient individuals due to the consumption of certain foods or drugs
Substances that increase the oxidation of glutathione, thereby reducing the available GSH for oxidation of peroxide, creating a potential for hemolysis
Fava Beans contains vicine and convicine which can cause a hemolytic crisis in GdMed individuals
Many anti-malarial drugs, sulfonamides, sulfones and other drugs produce the same reaction in severely deficient individuals
Also leads to the oxidation of hemoglobin, making it lose the ability to be a reversible oxygen carrier
Favism
The Fava Bean (Vicia faba) is a favored cultigen in areas where the GdMed allele is common
Vicine and convicine make up approximately 0.5% of the wet weight of the Fava bean
These compounds metabolize to divicine and isouramil in the intestine
These metabolites decrease RBC reduced glutathione (GSH)
Produce hydrogen peroxide and free radicals
Creates a severe oxidant stress in G6PD deficient cells
G6PD and Fava Beans
Plasmodium in the RBC
Plasmodium preferentially attack immature RBC but P. falciparum can invade RBC of all ages
Plasmodium oxidizes RBC NADPH from the Pentose Phosphate pathway for its metabolism
This results in a deficiency of RBC GSH, most severe in G6PD deficient individuals, leading to peroxide-induced hemolysis which curtails the development of Plasmodium(Malaria parasites
After several cell cycles the Plasmodium (Malaria parasites)can adapt to produce its own G6PD, reducing the adaptive benefit of G6PD deficiency
G6PD and Malaria
Fava Beans and Malaria
Recall that fava beans contain compounds that metabolize to powerful oxidants
In a cell that is oxidant-stressed by Plasmodium infection, the addition of another strong oxidant can lead a rapid build-up of peroxide
In vitro and in vivo (mouse) studies indicate a suppressant effect of divicine and isouramil on Plasmodium in G6PD normals
This effect would be expected to be even greater in G6PD deficient individuals
G6PD, Fava Beans, and Malaria
Distribution of G6PD, Fava Beans, and Malaria
Case Study: GdMed and Favism
Fava bean cultivation is widespread, especially throughout the circum-Mediterranean region
There is substantial overlap between the cultivation of fava beans and the GdMed allele
Serious cases of hemolytic favism are described more than 2,000 years ago by Greeks
About 1 in 12 cases of favism results in mortality
Mostly affects children (up to 95% of cases)
Why continue to cultivate fava beans?
Nutrition and Fava Beans
Fava beans are only one of several legumes cultivated in the Mediterranean including chick peas, kidney beans, and lentils
Fava beans are a highly productive crop and produce a high yield of protein by dry weight
However, kidney beans and chick peas are more efficient in terms of the ratio of weight of protein consumed to weight gained in growing individuals
Lentils are as efficient as fava beans
Continued use where Favism rates are high must be due to other factors
Responses to Favism
Mediterranean populations have developed several responses including food taboos, preparation techniques, and folk remedies
Highly susceptible groups including children and pregnant women are frequently forbidden to consume fava beans
Drying, soaking, and removing the skins appear to reduce toxicity
Increasing sugar consumption reduces the severity of an impending hemolytic crisis
Continued Cultivation
There are three lines of evidence that suggest continued cultivation of Fava Beans in the face of Favism is related to malaria
The association of divicine and isouramil with the suppression of Plasmodium growth
The clinal association of fava beans cultivation and malaria
The overlap of the peak fava bean harvest and consumption times with the peak Anopheles mosquito breeding season
Selection in Males
Males are G6PD deficient or Normal
Malaria alone:
Select for an increase in GdMed because of resistance to Plasmodium in G6PD RBCs
Combination of Malaria and Fava beans:
Select against GdMed through favism and hemolytic anemia
Cooking and preparation techniques may buffer the favism selection
Other genes may also buffer favism
Acid Phosphatase B and b -Thallasemia reduce severity
Decreased selection against GdB through increased resistance to Plasmodium from fava beans
Selection in Females
Malaria alone favors the heterozygotes
Selects against GdB/GdB, most susceptible genotype to Plasmodium
Anemia selects against GdMed/GdMed, but they are resistant to Plasmodium
Heterozygotes (GdB/GdMed) are favored
Increased resistance to malaria compared to GdB/GdB
Less susceptible to hemolytic crises from diet or infection than GdMed/GdMed
The balance is complicated by the random deactivation of an X chromosome in the cells producing the RBCs
Heterozygotes will range widely from about 20% normal to about 80% normal RBCs, and the response to malaria and other hemolytic crises will vary accordingly
Combination of Malaria and Fava beans complicates selection
Fava beans intensify selection against GdMed/GdMed
Favism and increased incidence of hemolytic anemia
Cooking, preparation techniques, and other genes may buffer GdMed/GdMed from severe hemolytic crises
Decreased selection against GdB/GdB
Increased resistance to Plasmodium from fava beans
Heterozygotes (GdB/GdMed) are still most fit
The differential between GdB/GdMed and GdB/GdB resistance to malaria is reduced (selection is weaker)
Selection differential may be stronger against GdMed/GdMed because of the increased incidence of hemolytic crises due to favism
References
http://rialto.com/g6pd/index.htm
Green L (1993) G6PD deficiency as protection against falciparum malaria: an epidemiologic critique of population and experimental studies. Yearbook of Physical Anthropology, 36:153-178.
Katz SH, and Schall J (1979) Fava bean consumption and biocultural evolution. Medical Anthropology, 3:459-476.
top
Date this page last edited: August 20, 2002
e-mail me at: jbindon@tenhoor.as.ua.edu