Within the cytoplasmic matrix of a red blood cell occurs an anaerobic pathway of glucose catabolism known as glycolysis consisting of 10 reactions (1). The enzyme that catalyzes the last reaction is pyruvate kinase (1). The reaction is one of two that produces ATP and also pyruvate, the molecule generally converted to acetyl CoA for entry into aerobic respiration (1). A deficiency of pyruvate kinase results in low ATP levels (2). It is one of the most common defects of a blood cell (2).
A young red blood cell, or reticulocyte, starts out with organelles and then loses them. While retaining their mitochondria they require a lot more oxygen and if it goes through the spleen while in this stage it could mean its failure, since the spleen is deficient in oxygen and glucose (2).
Lack of sufficient energy causes failure of ion pumps leading to a disrupted intracellular electrolyte concentration (2). The performance of the pentose phosphate pathway is diminished (2). The pathway is necessary for anabolism of glutathione, necessary for the cell’s defense against oxidative stress (2). Membrane injury results in distortion, rigidity and dehydration of the cell (2).
Eventually the red blood cell is filtered out by the spleen or liver (2). A hemolytic anemia occurs due to low blood count resulting from the rate of red blood cells lost outnumbering the rate of production of red blood cells by bone marrow (3). Because red blood cells carry oxygen via their hemoglobin, anemia reduces oxygen distributed in the body (3).
How did a defect such as hemolytic anemia such as sickle cell make it into the human gene pool?
You might find it interesting to learn that the latest research into sickle cell and other hemolytic anemias suggest the diseases may have acted as a protective mechanism against malaria. The theory has been tested in mice and humans (4-6). It is suggested that the rapid elimination of infected red blood cells may have increased overall survival to infection (4;6).
References
1. Dennison KJ, Topping J, Caret RL. General, Organic, and Biochemistry. New York: McGraw-Hill, 2007.
2. Frye, R. E. and Deloughery, T. G. Pyruvate Kinase Deficiency. WebMD . 12-31-2008. Ref Type: Online Source
3. National Heart and Lung Institute. Hemolytic Anemia. Diseases and Conditions Index . 2006. Ref Type: Online Source
4. Min-Oo G, Fortin A, Tam MF, Gros P, Stevenson MM. Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model. Genes Immun 2004;5:168-75.
5. Min-Oo G, Tam M, Stevenson MM, Gros P. Pyruvate kinase deficiency: correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants. Blood Cells Mol Dis 2007;39:63-9.
6. Durand PM, Coetzer TL. Pyruvate kinase deficiency protects against malaria in humans. Haematologica 2008;93:939-40.
