Hemoglobin is the life-giving substance of every red cell, the oxygen-carrying component of the red cell. Each red blood cell is nothing more than a fluid-filled sac, with the fluid being hemoglobin. In 4 months, or 120 days, red cells with normal hemoglobin content submit to the rigors of circulation. Red cells are stretched, twisted, pummeled, and squeezed as they make their way through the circulatory watershed. Each major organ in the human body depends on oxygenation for growth and function, and this process is ultimately under the control of hemoglobin. The hemoglobin molecule consists of two primary structures:
• Heme portion. This structure involves four iron atoms in the ferrous state (Fe2+ because iron in the ferric state, Fe3+, cannot bind oxygen) surrounded by protoporphyrin IX, or the porphyrin ring, a structure formed in the nucleated red cells. Protoporphyrin IX is the final product in the synthesis of the heme molecule. It results from the interaction of succinyl coenzyme A and delta-aminolevulinic acid in the mitochondria of the nucleated red cells. Several intermediate by products are formed: porphobilinogen, uroporphyrinogen, and coproporphyrin. Once iron in incorporated, it combines with protoporphyrin to form the complete heme molecule. Defects in any of the intermediate products can impair hemoglobin function.
• Globin portion. These consist of amino acids linked together to form a polypeptide chain, a bracelet of amino acids. The most significant chains for adult hemoglobins are the alpha and beta chains. Alpha chains have 141 amino acids in a unique arrangement, and beta chains have 146 amino acids in a unique arrangement. The heme and globin portions of the hemoglobin molecule are linked together by chemical bonds.
• An additional structure that supports the hemoglobin molecule is 2,3-diphosphoglyce-rate (2,3-DPG), a substance produced via the Embden-Meyerhof pathway during anaerobic glycolysis.1 This structure is intimately related to oxygen affinity of hemoglobin and is explained in that section.
Each heme molecule consists of four heme structures with iron at the center and two pairs of globin chains (Fig. 4.1). The heme structure sits lodged in the pocket of the globin chains. Hemoglobin begins to be synthesized at the polychromatic normoblast stage of red cell development. This synthesis is visualized by the change in cytoplasmic color from a deep blue to a lavender-tinged cytoplasmic color. Sixty-five percent of hemoglobin is synthesized before the red cell nucleus is extruded, with an additional 35% synthesized by the reticulocyte stage.2 Normal mature red cells have a full complement of hemoglobin, which occupies a little less than one half of the surface area of the red cell.
There are three types of hemoglobin that are synthesized: embryonic hemoglobins, fetal hemoglobin, and the adult hemoglobins. Each of these types of hemoglobins has a specific arrangement of globin chains and each globin chain is under the influence of a specific chromosome. Chromosome 11 contains the genes for the production of epsilon, beta, gamma, and delta chains. Each parent contributes one gene for the production of each of these chains. Therefore, each individual has two genes for the production of any of these chains. Chromosome 16 is responsible for the alpha and zeta genes. There are two genes on the chromosome for the production of alpha chains and one gene for the production of zeta chains (Fig. 4.2). Thus, each parent contributes two genes for the production of alpha chains and one for the zeta chains. Thus, each individual has four genes for the production of alpha chains and two for zeta chains. Alpha chains are a constant component of adult hemoglobin; therefore, each hemoglobin has two obligatory alpha chains as part of its chemical configuration. The epsilon and zeta chains are
reserved for the production of embryonic hemoglobins. As the embryo develops, hemoglobins Gower I and II (a2, e2) and hemoglobin Portland (y252), are synthesized and remain in the embryo for the 3 months. Hemoglobin F (a2y2), fetal hemoglobin, begins to be synthesized at approximately 3 months in fetal development and remains as the majority hemoglobin at birth. Between 3 and 6 months post delivery, the amount of gamma chains declines and the amount of beta chains increases, making hemoglobin A (a2P2) the majority adult hemoglobin, 95% to 98%. Hemoglobin A2 (a252), 1% to 3%, and hemoglobin F, less than 1%, are also part of the normal adult hemoglobin complement. Amino acids are an essential component of each of the globin chains. The unique position of amino acids in each chain, as well as the specificity of the amino acid itself, is essential to the normal function of the hemoglobin molecule. Synthetic or structural abnormalities of the protein chains may lead to hemoglobin defects.
Hb2 Gower II
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