Human Adaptability
ANT 475/575
Dr. Bindon
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[ 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 (Gd^B) and one deficient form (e.g., Gd^A- or Gd^Med) of G6PD

Females

Gd^B/Gd^B, Homozygous Normal; "Normal"

Gd^B /Gd^A-, Heterozygous; "Heterozygote"

Gd^A-/Gd^A-, Homozygous Deficient; "G6PD Deficient"

Males

Gd^B, Hemizygous Normal; "Normal"

Gd^A-, 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

G6PD Activity

Declines with age of RBC

Gd^B has 62 day half-life for decay of activity

Sustains GSH levels for 100 to 120 day RBC life span

Gd^A- has normal activity when new, but the activity half-life is only 13 days

Deficiency is due to instability of the enzyme

Gd^Med 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 Gd^Med 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 Gd^Med 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

After several cell cycles the Plasmodium 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: Gd^Med 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 Gd^Med 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 Gd^Med because of resistance to Plasmodium in G6PD RBCs

Combination of Malaria and Fava beans:

Select against Gd^Med 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 Gd^B through increased resistance to Plasmodium from fava beans

Selection in Females

Malaria alone favors the heterozygotes

Selects against Gd^B/Gd^B, most susceptible genotype to Plasmodium

Anemia selects against Gd^Med/Gd^Med, but they are resistant to Plasmodium

Heterozygotes (Gd^B/Gd^Med) are favored

Increased resistance to malaria compared to Gd^B/Gd^B

Less susceptible to hemolytic crises from diet or infection than Gd^Med/Gd^Med

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 Gd^Med/Gd^Med

Favism and increased incidence of hemolytic anemia

Cooking, preparation techniques, and other genes may buffer Gd^Med/Gd^Med from severe hemolytic crises

Decreased selection against Gd^B/Gd^B

Increased resistance to Plasmodium from fava beans

Heterozygotes (Gd^B/Gd^Med) are still most fit

The differential between Gd^B/Gd^Med and Gd^B/Gd^B resistance to malaria is reduced (selection is weaker)

Selection differential may be stronger against Gd^Med/Gd^Med 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.

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Date this page last edited: August 20, 2002
e-mail me at: jbindon@tenhoor.as.ua.edu