Hemoglobin 3-chain

Figure 38-4. Examples of three types of missense mutations resulting in abnormal hemoglobin chains. The amino acid alterations and possible alterations in the respective codons are indicated. The hemoglobin Hikari p-chain mutation has apparently normal physiologic properties but is electrophoretically altered. Hemoglobin S has a p-chain mutation and partial function hemoglobin S binds oxygen but precipitates when deoxygenated. Hemoglobin M Boston, an a-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so will not bind oxygen at all.

Two additional hemoglobin chains exist which have been termed the e-and the t-chaln. The e-chaln Is found In two hemoglobin components In young human (and animal) embryos ... 

TABLE I. DIVERGENCE OF HEMOGLOBIN CHAINS WITH TIME... 

In addition to oxygen, hemoglobin subunits can also carry carbon dioxide. This is performed by covalent addition of C02 to the N termini of the hemoglobin chains to produce a carbonate structure. Propose reactions for this process utilizing (a) C02 and... 

Hemoglobin chains of one type (a or /J) were substituted with closed shell zinc protoporphyrin (ZnP), and chains of the opposite type were oxidized to the... 

Primary Structure of Proteins The primary structure of a protein is the sequence of amino acids in the peptide chain. The primary structure is immensely important, because it is the sequence of amino acids that determines the higher levels of protein structure and, consequently, the function of the protein. Small changes in the primary structure can cause a protein to be completely nonfunctional. For example, sickle cell anemia is caused by the substitution of a single amino acid in the hemoglobin chain. 

Comparison of the primary sequences of hemoglobin chains from more than 60 different species reveals that only nine residues in the polypeptide chain are invariant (i.e. the same) between all of the species. These nine residues include the proximal and distal histidines which are essential for the correct functioning of the protein. Many of the other residues are replaced from one species... 

Abnormal mRNA splicing can be one cause of /3+-thalassemia in which the production of /3-hemoglobin chains is greatly reduced. The defect appears to be caused by mutations that interfere with the correct removal of introns from the globin pre-mRNAs. 

There are two types of contact between the hemoglobin chains. The contacts within both the a]/3i and a2/32 dimers involve the B, G and H helices and the GH loop (Fig. 5-11). These are known as the packing contacts. The contacts between these two dimers (aj with /32 and a2 with /3i) involve... 

Question Why do hemoglobin chains associate while myoglobin chains do not ... 

In some cases such symmetrical structures extend over large regions of the peptide chain, as in the hemoglobin chain (Sorm, 1962a Keil and Sorm, 1962) (Fig. 11). A symmetrical histidine residue (No. 20, a-chain) is exactly the junction of two a-helix units. 

If the hemoglobin chains are compared with respect to simple amino acid interchanges (within the definition given in the preceding section) the number of matching amino acid residues is increased to 92, i.e., 65%... 

A third embryonic hemoglobin, termed Hb-Portland 1, has recently been described (Cl, C2, H6, T8, W17). The protein was first discovered in a malformed newborn with a complex autosomal chromosomal mosaicism. However, it is probably also present for some 0.5 to 5% in newborn infants with a D, trisomy and in very small amounts (0.1-0.2%) in normal newborns. Hb-Portland 1 does not contain a chains but is composed of one pair of y chains and one pair of chains which have been termed C chains. The C chain is probably a normal embryonic hemoglobin chain. Hb-Portland 1 does react with free a chains to form Hb-F or aayz and a aafa component (T8). It seems, therefore, that the chain can combine with the a chain, but the afiSnity of the a chain for the C chain is apparently lower than for either the e chain or y chain. Embryonic hemoglobins have also been found in several mammalian species, such as the pig, cattle, and sheep (K13, K15). 

The primary structure of the t chain is not established, and only results of preliminary structural analyses have been reported (H30, K15). Extensive studies of the chain have revealed rather unique structural features (C2). Its amino acid composition, for instance, differs from those of all other hemoglobin chains and is, among others, characterized by the presence of five isoleucyl residues. Tryptic hydrolysis produced several peptides with amino acid compositions not observed for any of the tryptic peptides of the a, y, or 8 chain, although other peptides had compositions identical to those of tryptic peptides of the y chain. There seems to be no doubt that the structures of the e and chains are different (C2). 

During development, the synthesis of embryonic hemoglobin polypeptide chain (s) is succeeded by that of the y chains and at a later stage by that of the p and 8 (Fig. 9). The ontogeny of these hemoglobin chains is thoroughly reviewed by Kleihauer (K15), and Fig. 9 is based on information taken from that reference. Hb-Gower-1, or u, is the major... 

What is the mechanism controlling the rate of synthesis of each of these hemoglobin chains during development It has been suggested that the site of red cell production is a major factor however, (and 8) and 7 chains can be synthesized by red cell precursors in the bone marrow as well as in the liver (Fll, T4) whereas the presence of small amounts of Hb-Gower 2 (or 2 2) and of Hb-Portland-1 (or 72 2) in (some) cord blood samples (C2, H22) show that red cell precursors in sites other than in the metamorphosing embryo are able to synthesize these polypeptide chains. 

Tables II, III, IV, and V list abnormal hemoglobins which differ from the normal by the replacement of one amino acid residue by another at a specific position in either the a or the p chain. The total number is 132. Each of these hemoglobin types is produced because of a variation, by mutation, of the hemoglobin chain structural locus governing the synthesis of the specific polypeptide. The amino acid substitutions found in all these variants can be explained by the change of one nucleotide of the triplet which codes for the original residue.

Phenazopyridine may induce methemoglobinemia. Erythrocytes possess four hemoglobin chains, each of... 

Synthesis of the different hemoglobin chains is directed by different genes, at least one for each chain type. The chromosomal arrangement of these genes (Figure 28-12)... 

Thalassemia Is Caused by an Imbalanced Production of Hemoglobin Chains... 

The Accumulation of Free Alpha-Hemoglobin Chains Is Prevented... 

---