Hemoglobin polypeptides

Figure 7.4 Human hemoglobin polypeptide chains as a function of time during gestation and postnatal development. (Reproduced with permission from Weatherall DJ, Clegg JB. The Thalassemia Syndromes. Boston Blackwell, 1981.)...

In man, a number of different hemoglobin polypeptide chains are synthesized from the time of conception to adult life. The two adult hemoglobins, Hb-A or 2/82 and Hb-Aa or aa a, are first observed in minor amounts in the embryo during the second trimester of pregnancy. After birth they rapidly replace fetal hemoglobin (Hb-F or 2y ), and almost no Hb-F is present in a 6-month-old infant. The Hb-F is the... 

The synthesis of each hemoglobin polypeptide chain is under separate genetic control, Evidence to this effect has been obtained from studies of critical families with (combinations of) specific hemoglobin variants these data are extensively reviewed by Huehns and Shooter (H33). Thus, separate loci exist directing the synthesis of a, p, y, 8, e, and C chains. All data, including data from complete structural analyses (SIS), in-... 

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... 

Fig. 9. Relative amounts of hemoglobin polypeptide chains in different stages of development in man. Data concerning the f chain are not included.

Z2. Zuckerkandl, E., Compensatory effects in the synthesis of hemoglobin polypeptide chains. Cold Spring Harbor Symp. Quant. Biol. 29, 357-374 (1964). 

Thalassemia A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with chnical pictures ranging from barely detectable hematologic abnormahty to severe and fatal anemia, [nih]... 

Attention is attracted to the possibility of reconstructing the amino-acid sequence of ancestral polypeptide chains W virtue of a comparison between the amino-acid sequences of related polypeptide chains foimd in contemporary organisms. A tentative partial structure is proposed for two ancestral hemoglobin polypeptide chains. Some perspectives of paleobio-chemistry are outlined. 

Tables la, lb, and Ic illustrate the procedure Iw presenting two partially and tentatively reconstructed ancestral hemoglobin polypeptide chains. The evidence on which these reconstructions are based are the human a-, / -, y-, and 5-chains, the sperm-whale myoglobin chain (see Schroeder for references and latest information on the structure of these chains), the horse a-chain (Braunitzer and Matsuda, in Cullis et al., and the human myoglobin chain (Hill ). One of us (L. P. ) has listed earlier probable residues for 70 loci in the conunon precursor...

In some proteins, such as hemoglobin, separate polypeptide chains must associate for the chains to be functional. This forms a quaternary stmcture. 

Hemoglobin is a tetramer built up of two copies each of two different polypeptide chains, a- and (5-globin chains in normal adults. Each of the four chains has the globin fold with a heme pocket. Residue 6 in the p chain is on the surface of a helix A, and it is also on the surface of the tetrameric molecule (Figure 3.13). 

Figure 3.13 The hemoglobin molecule is built up of four polypeptide chains two a chains and two (3 chains. Compare this with Figure 1.1 and note that for purposes of clarity parts of the a chains are not shown here. Each chain has a three-dimensional structure similar to that of myoglobin the globin fold. In sicklecell hemoglobin Glu 6 in the (3 chain is mutated to Val, thereby creating a hydrophobic patch on the surface of the molecule. The structure of hemoglobin was determined in 1968 to 2.8 A resolution in the laboratory of Max Perutz at the MRC Laboratory of Molecular Biology, Cambridge, UK.

The terms polypeptide and protein are used interchangeably in discussing single polypeptide chains. The term protein broadly defines molecules composed of one or more polypeptide chains. Proteins having only one polypeptide chain are monomeric proteins. Proteins composed of more than one polypeptide chain are multimeric proteins. Multimeric proteins may contain only one kind of polypeptide, in which case they are homomultimeric, or they may be composed of several different kinds of polypeptide chains, in which instance they are heteromultimeric. Greek letters and subscripts are used to denote the polypeptide composition of multimeric proteins. Thus, an ag type protein is a dimer of identical polypeptide subunits, or a homodimer. Hemoglobin (Table 5.1) consists of four polypeptides of two different kinds it is an hetero-multimer. 

The so-called globin proteins are an important group of a-helical proteins. These include hemoglobins and myoglobins from many species. The globin structure can be viewed as two layers of helices, with one of these layers perpendicular to the other and the polypeptide chain moving back and forth between the layers. 

FIGURE 15.23 The myoglobin and hemoglobin molecules. Myoglobin (sperm whale) one polypeptide chain of 153 aa residues (mass = 17.2 kD) has one heme (mass = 652 D) and binds one O9. Hemoglobin (human) four polypeptide chains, two of 141 aa residues (u) and two of 146 residues (/3) mass = 64.45 kD. Each polypeptide has a heme the Hb tetramer binds four O9. (Irving Geis)... 

FIGURE 19.20 One of the four polypeptide chains that make up the human hemoglobin molecule. The chains consist of alternating regions of a helix and p sheet. The a-helix regions are represented by red helices. The oxygen molecules that we inhale attach to the iron atom (blue sphere) and are curried through the bloodstream. 

Proteins may also Have a quaternary structure, in which neighboring polypeptide units stack together in a specific arrangement. The hemoglobin molecule, for example, has a quaternary structure of four polypeptide units, one of which is shown in Fig. 19.20. 

The Jing group investigated their poly(L-lysine)-6-poly(L-phenylalanine) vesicles for the development of synthetic blood, since PEG-lipid vesicles were previously used to encapsulate hemoglobin to protect it from oxidation and to increase circulation time. They extended this concept and demonstrated that functional hemoglobin could be encapsulated into their vesicles. The same polypeptide material was also used to complex DNA, which caused the vesicles to lose their... 

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