Amino acid in hemoglobin

An alternative approach for the analysis of blood samples from the same group of Iranian mustard gas victims has been described (50). As mustard gas alkylates amino acids in hemoglobin, adducts will be formed, which remain in the bloodstream for some time. Selective cleavage of the alkylated N-terminal valine of the a-chain of hemoglobin was carried out by using the modified Edman reagent pentafluorophenyl isothiocyanate. After derivatiza-tion of the adduct-derived pentafluorophenylthio-hydantoin with heptafluorobutyric anhydride, the... 

Even a small change of one amino acid substituted for another can drastically alter the configuration of the protein. On the other hand, some amino acid substitutions have relatively minor effect and the protein may still be able to function nearly normally. The difference between normal red blood cells and sickle cell red blood cells is one strategically placed amino acid in hemoglobin. 

Biological function in polypeptides and proteins requires a specific three-dimensional shape and arrangement of functional groups, which, in turn, necessitate a definite amino acid sequence. One monkey wrench residue in an otherwise normal protein can completely alter its behavior. For example, sickle-ceU anemia, a potentially lethal condition, is the result of changing a single amino acid in hemoglobin (Section 26-8). The determination of the primary structure of a protein, called amino add or polypeptide sequencing, can help us to understand the protein s mechanism of action. 

Figure 2-1 S3. The ViewerLite shows an elaborate depiction of hemoglobin on the right-hand side, with the amino acids in a cascade window on the left.

Normal hemoglobin molecules are complex, three-dimensional structures consisting of four chains of amino acids known as polypeptide chains. Two of these chains are known as alpha subunits with 141 amino acid residues each, and the remaining polypeptide chains are the beta subunits with 146 amino acid residues each. The sequences of amino acids in the alpha and beta subunits are different, but fold up via noncovalent interactions to form similar three-dimensional structures. When a polypeptide chain arranges itself in space, i.e., when it folds, amino acids that were far apart in the chain are brought closer in proximity. The final overall shape of the protein molecule is influenced by (1) the amino acids in the chain, and (2) the interactions that are possible between distant amino acids. 

One of the amino acids in the beta polypeptide chain of hemoglobin is glutamic acid (Fig. 7.11.1). 

Rat hemoglobin has a high affinity for TMT and TET but, because it is highly selective to only two amino acids in the correct sequence, the affinity is quite low in other animals. 

Through the formation of polypeptide bonds between amino acids, very long chains of sequences are obtained. Generally, proteins consist of hundreds and thousands of amino acids. For example, human hemoglobin has four polypeptide chains, of which two are cf-chains and two are j3-chains. There are 141 amino acids in each a-chain with a sequence of... 

Although functioning proteins have very specific amino acid sequences, slight variations can often be tolerated. In some cases, however, a slight variation can be disastrous. For example, some people have a version of hemoglobin—a protein found in red blood cells—that has one incorrect amino acid in about 300. That minor error is responsible for sickle-cell anemia, an inherited condition with painful and often lethal effects. The sickle shape characteristic of this disease is shown in Figure 13.19. 

The important molecule inside these red blood cells is hemoglobin. Hemoglobin is a protein molecule consisting of four long chains of amino acids. In the center of each one is a unit like the one shown here. This porphyrinlike group is a complex of iron the iron atom is the point of attachment of the incoming oxygen molecule. 

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. 

The disease is caused by a mutation of a gene that controls hemoglobin production. A hemoglobin molecule consists of two types of amino acid chains alpha chains and beta chains. At the molecular level, the sickle-cell anemia mutation involves the replacement of one amino acid in the beta chains by another... 

The stability of the hemoglobins depends in great part on the a-helical conformation of their polypeptide chains. If an amino acid in the a-helical region of the protein is replaced by proline, the a helix is broken at that point. When this happens in hemoglobin, it easily becomes denatured. These conditions are again characterized by red cell lysis and the clinical symptoms of hemolytic anemia. Example is Hb Abraham Lincoln, where /332Leu— Pro. 

This metabolic activity is achieved by a turnover of amino acids and proteins that is as rapid as that of lipids and carbohydrates. In an adult human male, 400 g of body proteins is turned over each day. Of this, 50g is used to replace digestive enzymes (Sec. 15.2), and 6g to replace hemoglobin (Sec. 15.8). The concentration of free amino acids in plasma is small (total 3.2mmol L l, of which 25 percent is glutamine), but the turnover of 400g per day of protein is equivalent to the uptake, and release back into the plasma, of 4.6 moles of a-amino-N, so that the average lifetime of an amino... 

Hemoglobin dramatically demonstrates how sensitive the function of a biomolecule is to its structure. In certain people, in the synthesis of the proteins needed for hemoglobin, an improper amino acid is inserted into the protein in two places. This may not seem very serious, since there are several hundred amino acids present. However, because the incorrectly inserted amino acid has a nonpolar substituent instead of the polar one found on the proper amino acid, the hemoglobin drastically changes its shape. The red blood cells are then sickle-shaped rather than disk-shaped, as shown in Fig. 20.37. The misshapen cells can aggregate, causing clogging of tiny capillaries. This condition, known as sickle cell anemia, is the subject of intense research. 

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