Chem*3560 Lecture 4: Inherited modifications in hemoglobin
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1 Chem*3560 Lecture 4: Inherited modifications in hemoglobin Genetic modifications fall into two classes: Thalassemias, which are the result of failure to express globin genes. Thalassa is Greek for the sea, specifically the Mediterranean sea, and thalassemias are prevalent among people originating from Mediterranean countries Substitution mutations, which alter hemoglobin function. One of the most widespread forms is HbS, sickle cell hemoglobin, occurring among people of African origin Globin genes Myoglobin is on chromosome 22 Genes for a-like globins are on chromosome 16 ζ-globin (zeta), which is expressed in first 4-6 weeks of pregnancy Two almost identical copies of α-globin There are two pseudogenes ψ ζ and ψ α. A pseudogene is an evolutionary relic with partial sequence similarity to a functional gene but incapable of being expressed Genes for b -like globins are on chromosome 11 ε-globin (epsilon) is co-expressed with ζ-globin as ζζεε or embryonic hemoglobin. Two similar copies of γ-globin γa and γg, which differ by one amino acid, and are coexpressed with α-globin during months 2-9 of pregnancy. The tetramer ααγγ is HbF or fetal hemoglobin. A pseudogene ψ β that is most closely related to β. δ-globin, which is functionally identical to β-globin, but only expressed at low level. About 2% of adult hemoglobin is ααδδ. A single functional copy of β-globin is present. The tetramer ααββ is HbA, or adult hemoglobin (although it is expressed from birth onwards.
2 Thalassemias result from the failure to express one of the adult forms of hemoglobin a-thalassemia is the result of failure to express one or more of the a-globin genes. Chromosome 16 contains 2 copies of the α-globin gene, and normal human cells are diploid, meaning that there are two copies of each chromosome (other than the sex chromosomes X and Y). This means that the normal person possesses 4 copies of a-globin genes in total, two copies from each parent. Loss of a-globin expression may be due to: Unequal crossing-over in meiosis (duplicated sequences are prone to this effect). Nonsense mutations in which a codon in mid-gene has been mutated to one of the stop codons UGA UAA or UAG, and which therefore causes an incomplete polypeptide to be released from the ribosome. A mutation in one of the sequences that controls gene expression rather than the coding sequence itself. These may include promoters, polyadenylation sequences or gene splicing sites. Severity of a-thalassemia depends on how many a-globin genes are unexpressed One copy missing: no outward symptoms, perhaps very mild anemia. Two copies missing: minor symptoms with mild anemia (not a candidate for marathon running). Blood contains small amounts of hemoglobin H, a bbbb tetramer. Three copies missing: this is debilitating but not fatal. The blood contains significant amounts of HbH. HbH lacks the proper interactions between α- and β-globins, so it s an example of a tetramer that does not show allosteric behaviour. HbH binds O 2 like myoglobin, and lacks the Bohr effect. Four copies missing is not viable, because both fetal HbF and adult HbA require α-globin, and HbH on its own can t support effective O2 transport. Unfortunately death only occurs after ζ-globin fades out at 8-10 weeks long enough for the mother to know she is pregnant b -Thalassemias may allow survival by continued expression of g-globin in adulthood An individual normally has two functional β-globin genes, one on each copy of chromosome 11 (i.e. one copy from each parent).. If one copy is defective, this results in anemia similar to the case for α-thalassemia.
3 If both copies of b -globin are missing, this is sometimes survivable Small amounts of ααδδ hemoglobin may be made, and this is functionally equivalent to HbA. Expression of γ-globin may persist into adult life. HPFH hereditary persistance of fetal hemoglobin is a compensating mutation that allows survival. The individual has to exist with HbF, which has higher O 2 affinity than HbA, so he or she is unlikely to be able to pursue athletic activities. Thalassemias result in more rapid turnover of red blood cells, with two consequences: Red blood cells are produced in bone marrow. Overdevelopment of bone marrow may lead to bone distortions. Kidney failure due to the overload in processing Fe is another possible complication. Sickle cell anemia is an inherited condition due to a substitution mutation in b-globin Sickle cell anemia occurs with a frequency of 4 per 1000 in people of African origin. Red blood cells change from normal biconcave shape into a spiky or sickle shape, and obstruct blood flow in narrow capillaries There is no sign of any pathological agent or virus The effect is only observed in deoxygenated blood, and when freshly oxygenated, cells appear normal. The hemoglobin was first found to be different by electrophoresis, which showed that HbA was slightly more negative than hemoglobin S (HbS). Hemoglobin S was first isolated in 1949; and deoxy HbS was found to assemble into semicrystalline fibres and form gels in solution, whereas HbA remains soluble. Sickle cell anemia is an example of a molecular disease, due to alteration in a protein s structure rather than due to an infectious agent. When HbS fibres form in cells, this causes the cell to adopt the sickle or spiky shape. Cells containing fibres are more rigid, whereas normal red blood cells are quite flexible and can squeeze into blood capillaries that are smaller than the cell diameter. Spiky cells also tangle with each other, increasing risk of blood clots and stroke.
4 Hemoglobin S contains a modified b-globin Oxygenation prevents HbS fibre formation Valine replaces Glu A3 (Glu 6) in the β-globin. This mutation positions nonpolar Val A3 in a location that is surface-exposed, and therefore represents a sticky patch on the hemoglobin surface. In the HbS tetramer, the β2 Val A3 can insert into a nonpolar recess formed by Phe F1 and Leu F4, on β1-globin of a neighbouring HbS molecule. When HbS is deoxygenated (T-state), the valines and the nonpolar recesses line up, which allows multiple HbS molecules to assemble into a continuous fibre. This is reinforced by the alignment of Glu B4 in β1 of one HbS with His B1 in α2 of a second HbS in the fibre, so that the two make up a stabilizing ion pair. Mutation of β-globin Glu A3 to Isoleucine produces a more severe effect than valine The Ile A3 mutant of b-globin has been created by genetic engineering and was expressed in microorganisms. Ile has one more -CH 2- unit in its side chain than Val, so is more non-polar. The mutant should form fibres more easily than HbS, and this was confirmed by in vitro experiments. The mutation in HbS does not affect O 2 binding affinity. The Val A3 is surface exposed, and is not involved in binding heme, nor is it used in any intersubunit interaction related to the T Ö R switch in HbA. However, whether Hb is in T or R state has a major influence on HbS fibre formation. When HbS binds O 2, the ab-globin pairs rotate into the R-state arrangement, as for normal HbA. In R-state, the Vals and the non-polar recesses do not line up and thus a continous fibre does not form. HbS molecules behave normally if the blood is well oxygenated so that most molecules are in R-state, and if circulation returns deoxygenated blood to lungs quickly enough that fibres don t have time to form inside the cells.
5 Heterozygotes with one HbS gene have sickle cell trait Heterozygotes possess one b S -globin gene from one parent and a normal β-globin from the other parent, and this condition is sickle cell trait. Sickle cell anemia occurs in homozygotes who have both β-globin genes (one from each parent) carrying the HbS Val A3 mutation. Possession of one HbS mutant and one HbA b-globin gene does not result in anemia, A mixture of HbS and HbA does not allow fibre formation. HbA molecules lack the exposed Val, so don t allow propagation of HbS fibres. Hb-Harlem contains Val A3, together with mutation of Asp E17 to Asn; the Asn appears to interferere with the non-polar recess required for fibre formation. Hb-Harlem is a compensating mutation that arose naturally. Carriers of a single HbS gene or thalassemias are protected against malaria Carriers of sickle cell trait are common in certain regions (up to 40% of the population in equatorial Africa). When mutations such as HbS or those causing the various forms of thalassemia spread extensively in a population, this usually indicates that heterozygotes gain some benefit For both sickle cell trait and thalassemia, the lifetime of red blood cells is shorter than the usual 120 days and the short cell lifetime interferes with the life cycle of malaria parasites The disadvantage is that if both parents are carriers, there s a risk of producing a homozygous child who will be severely affected. Therapy for sickle cell anemia The mass of Hb in the adult is about 400 g (g not mg). No drug could be administered in sufficient quantity to bind to and directly affect Hb molecules. Stability can be achieved by lowering the concentration of HbS or by diluting it with another form of hemoglobin. Hydroxyurea H 2 N-CO-NH-OH promotes the production of HbF in adults (by an unknown mechanism). Both γ-globin and β S -globin are expressed, so in addition to HbS, ααβ S γ hybrid Hb is formed as well as ααγγ (HbF); these forms favour R-state and do not make fibres as easily as pure HbS, and effectively dilute out the remaining HbS.
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