Hemoglobin, human, mutant

Partial List of Human Mutant and Modified Hemoglobins Used in Research Hemoglobin Properties11... 

Table I gives a partial list of human mutant and modified hemoglobins that have been investigated in our research. Figure 11 shows the location of the mutation in some of the human mutant Hbs used in our research.

Fig. 11. Locations of selected human mutant hemoglobins used in our H NMR studies [Adapted from Dickerson and Geis (1983) illustration copyright by I. Geis].

NUMEROUS MUTANT HUMAN HEMOGLOBINS HAVE BEEN IDENTIFIED... 

Figure 7-23 Folding pattern of the hemoglobin monomers. The pattern shown is for the P chain of human hemoglobin. Some of the differences between this and the a chain and myoglobin are indicated. Evolutionarily conserved residues are indicated by boxes, I I highly conserved, I I invariant. Other markings show substitutions observed in some abnormal human hemoglobins. Conserved residues are numbered according to their location in one of the helices A-H, while mutant hemoglobins are indicated by the position of the substitution in the entire a and P chain.

Azidomethemoglobin the heme iron atoms are in the low-spin ferric state with one unpaired electron per heme iron Human fetal hemoglobin Mutation located in the amino-terminal region of the p chain High-affinity mutant with the mutation located in the 01 2 subunit interface Mutation located in the amino-terminal region of the p chain High-affinity mutant with the mutation located in the a,p2 subunit interface High-affinity mutant with the mutation located in the 01 2 subunit interface... 

There are many abnormal or mutant hemoglobins, some of which cause pathological conditions. One is sickle-cell hemoglobin (HbS), in which the glutamate residue in the sixth position of the normal human hemoglobin (HbA) /3 chain has been replaced by valine. This position, referred to as /36, is on the outside of the hemoglobin molecule. Individuals who... 

A MALDI-TOF mass spectrum of human hemoglobin Hb Miyazono. Two p-globins (one normal and one mutant) are detected. B MALDI spectrum of the tryptic cleavage of the (3-globin from Hb Miyazono mutant of human hemoglobin. Mutated peptides T9m and T8+T9m are detected. By tandem mass spectrometry, the mutation is characterized as the substitution 79D-E. Reproduced (modified) from Wada Y., Journal of Chromatography B, 781, 291-301, 2002, with permission. 

The total number of proteins found in nature is extremely large. The 1992 edition of the Enzyme List (Webb, 1992) lists 3196 enzymes. The total number of proteins in a eukaryotic cell has been estimated to be between 10,000 and 20,000 (Alberts et al., 1989), based upon the number of different messenger RNAs in a typical eukaryotic cell. This number does not reflect the thousands of natural mutants of any one protein that may occur. (Approximately 500 naturally occurring mutants of human hemoglobin have been identified to date.) Nor does it take into account the fact that there are often very substantial differences in homologous proteins that perform the same function in different species. A minimal estimate of the number of different proteins in living systems on earth would be on the order of 10,000 x 500 X the number of species i.e., literally, billions. 

Sickle cell anemia is a human genetic disease that first appeared in tropical west and central Africa. It afflicts about 0.4% of African Americans. These individuals produce a mutant hemoglobin known as sickle cell hemoglobin (Hb S). Sickle cell anemia receives its name from the sickled appearance of the red blood cells that form in this condition (Figure 19.16). The sickled cells are unable to pass through the small capillaries of the circulatory system, and circulation is hindered. This results in damage to many organs, especially bone and kidney, and can lead to death at an early age. 

This mutation in a single codon leads to the change in amino acid sequence at position 6 in the p-chain of human hemoglobin from glutamic acid to valine. The result of this seemingly minor change is sickle cell anemia in individuals who inherit two copies of the mutant gene. 

Each of the mutant forms of hemoglobin exists in only a small fraction of the total human population. Many of the mutant forms are deleterious. Others appear to be harmless, and are often referred to as neutral mutations. A very few may have advantages. Inheritance of globin genes occurs as a result of standard genetic processes (see here for a review of genetics). 

Human cells are diploid, which means they carry two copies of each chromosome. Thus, they carry two copies of each gene, one on each of the paired chromosomes. For a gene such as the adult hemoglobin gene, which can exist in two forms-the "normal" type, and a variant (mutant) type, an individual can have three possible combinations of these genes in the paired chromosomes ... 

Over 100 different kinds of mutant hemoglobin molecules have been detected in humans. Unlike sickle cell anemia (see Exercise 93), not all of these mutations are as serious. In one nonlethal mutation, glutamine substitutes for a single glutamic acid in normal hemoglobin. Rationalize why this substitution is nonlethal. 

Each of these has its drawbacks. The c)rtogenetic method can not detect point mutations, which are probably more important for human welfare than chromosome breakages. Dominant phenotypes are numerous, but traits that would be discovered easily and soon and which would be sufficiently unambiguous in interpretation are very rare. The third, chemical system would require enormous numbers of complicated tests that, even with automation, might be prohibitively expensive. It may also be difficult to distinguish between a child that is a mutant and an illegitimate child whose father had a rare hemoglobin type. 

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