Il.Globular Hemeproteins 239 1.Oxygen dissociation curve:A plot of Y measured at different par tial pressures of oxygen (pO2)is called the oxygen dissociation for Hb is ie.The curveolobin and hemoglobin show importan that trates that myoglobin esnond to small affinity changes in POz hemoglobin.The partial pressure of oxygen needed to achieve half-saturation of the binding sites(Pso)is approximately 1 mm Hg for myoglobin and 26 mm Hg for hemoglobin. Myoglobin that myoglobin reversibly binds a single molecule of oxygen. and deoxygenated(Mb)myoglobin Mb +02 MbO2 designed to bind ox P50=1Ps0=25 onomyo Figure3.5 within the muscle cell in response to oxygen demand. b.eealobnbThe xygen esociaean3uncaremeal rate in bindi n co of oxygen by the four subunits of hemoglobin means that the Hb binding of an oxygen molecule at one heme group increases the reme 02 TemehemeInieactionSeebooteetiectsreteredtoas 61Th cult for the first oxygen molecule to bind to hemoglobin,the 2 subsequen 8neeg0pogenoehrin8tgoenarn288 regio mm Hg (see Figure 3.5). E.Allosteric effects The ability of hemoglobin to reversibly bind oxygen is affected by the ough heme-heme interactions as described above),the p pressur tively called allosteric ("other site)effectors,because their interac tion at one site on the hemoglobin molecule affects the binding of f to he on the mol 02 effectors Hb o heme grou nd trans her groups in the h8m8gobiniorhe1astox en bound is (Hb)binds oxygen greater than its affinity for the first oxygen bound
Figure 3.5 Oxygen dissociation curves for myoglobin and hemoglobin (Hb). 0 0 40 80 120 P50 = 1 P50 = 26 The oxygen dissociation curve for Hb is steepest at the oxygen concentrations that occur in the tissues. This permits oxygen delivery to respond to small changes in pO2. Partial pressure of oxygen (pO2) (mm Hg) Figure 3.6 Hemoglobin (Hb) binds oxygen with increasing affinity. O2 O2 O2 O2 Hb Hb Hb Hb Hb O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 Increasing affinity for O2 1. Oxygen dissociation curve: A plot of Y measured at different partial pressures of oxygen (pO2) is called the oxygen dissociation curve. The curves for myoglobin and hemoglobin show important differences (see Figure 3.5). This graph illustrates that myoglobin has a higher oxygen affinity at all pO2 values than does hemoglobin. The partial pressure of oxygen needed to achieve half-saturation of the binding sites (P50) is approximately 1 mm Hg for myoglobin and 26 mm Hg for hemoglobin. The higher the oxygen affinity (that is, the more tightly oxygen binds), the lower the P50. [Note: pO2 may also be represented as PO2.] a. Myoglobin (Mb): The oxygen dissociation curve for myoglobin has a hyperbolic shape (see Figure 3.5). This reflects the fact that myoglobin reversibly binds a single molecule of oxygen. Thus, oxygenated (MbO2) and deoxygenated (Mb) myoglobin exist in a simple equilibrium: Mb + O2 MbO2 The equilibrium is shifted to the right or to the left as oxygen is added to or removed from the system. [Note: Myoglobin is designed to bind oxygen released by hemoglobin at the low pO2 found in muscle. Myoglobin, in turn, releases oxygen within the muscle cell in response to oxygen demand.] b. Hemoglobin (Hb): The oxygen dissociation curve for hemo - globin is sigmoidal in shape (see Figure 3.5), indicating that the subunits cooperate in binding oxygen. Cooperative binding of oxygen by the four subunits of hemoglobin means that the binding of an oxygen molecule at one heme group increases the oxygen affinity of the remaining heme groups in the same hemoglobin molecule (Figure 3.6). This effect is referred to as heme-heme interaction (see below). Although it is more difficult for the first oxygen molecule to bind to hemoglobin, the subsequent binding of oxygen occurs with high affinity, as shown by the steep upward curve in the region near 20–30 mm Hg (see Figure 3.5). E. Allosteric effects The ability of hemoglobin to reversibly bind oxygen is affected by the pO2 (through heme-heme interactions as described above), the pH of the environment, the partial pressure of carbon dioxide, pCO2, and the availability of 2,3-bisphosphoglycerate. These are collectively called allosteric (“other site”) effectors, because their interaction at one site on the hemoglobin molecule affects the binding of oxygen to heme groups at other locations on the molecule. [Note: The binding of oxygen to myoglobin is not influenced by allosteric effectors.] 1. Heme-heme interactions: The sigmoidal oxygen dissociation curve reflects specific structural changes that are initiated at one heme group and transmitted to other heme groups in the hemoglobin tetramer. The net effect is that the affinity of hemoglobin for the last oxygen bound is approximately 300 times greater than its affinity for the first oxygen bound. →← II. Globular Hemeproteins 29 168397_P025-042.qxd7.0:03 Hemoglobin 5-20-04 2010.4.4 1:04 PM Page 29
30 3.Globular Proteins LUNGS a.Loading and unloading oxygen:The cooperative binding of CO2 is released 2 binds to tissues in respo cates p in the alveoli of the lung and the capillaries of the tissues.For example.in the lung.the concentration of oxygen metamottis b.Significance of the sigmoidal oxygen dissociation curve:The steep slope of the oxygen dissociation curve over the range of oxygen conce at occur between the lungs anc hyperbolic oxygen dissociation curve.such as myoglobin,could not achieve the same degree of oxygen release partia sures o d have 2.Bohr effect:The release of oxvaen from hemoalobin is enhanced when the pH is lowered or when the hemoglobin is in the pres ence of an increased pCc Both result n a decreased oxyger C,a state.This change in oxyo en binding is called the Bobr effec TISSUES Conversely,raising the pH or lowering the concentration of CO n curve,and stabl Figure 3.7 ax89yHeo80ndcabon lungs,where CO2 is released into the expired air.[Note: ygenrsa8bi8nheri阳tinth 2anmcac5ssuGhasdnctcacaagpioc the tis to H=76 carbonic acid: pH=72 C02+H20 At lower pH,a equ hehs8to9el83bsesaproion,becomingbicarbonaie uratior H2CO HCO+H' Partial pre The H'produc to the low adient dur Fiaure 3.8 h88neas es,and the loading of oxygen in the lung.Thus n th sues,making hemoglobin a more efficient transporter of oxygen
a. Loading and unloading oxygen: The cooperative binding of oxygen allows hemoglobin to deliver more oxygen to the tissues in response to relatively small changes in the partial pressure of oxygen. This can be seen in Figure 3.5, which indicates pO2 in the alveoli of the lung and the capillaries of the tissues. For example, in the lung, the concentration of oxygen is high and hemoglobin becomes virtually saturated (or “loaded”) with oxygen. In contrast, in the peripheral tissues, oxyhemoglobin releases (or “unloads”) much of its oxygen for use in the oxidative metabolism of the tissues (Figure 3.7). b. Significance of the sigmoidal oxygen dissociation curve: The steep slope of the oxygen dissociation curve over the range of oxygen concentrations that occur between the lungs and the tissues permits hemoglobin to carry and deliver oxygen efficiently from sites of high to sites of low pO2. A molecule with a hyperbolic oxygen dissociation curve, such as myoglobin, could not achieve the same degree of oxygen release within this range of partial pressures of oxygen. Instead, it would have maximum affinity for oxygen throughout this oxygen pressure range and, therefore, would deliver no oxygen to the tissues. 2. Bohr effect: The release of oxygen from hemoglobin is enhanced when the pH is lowered or when the hemoglobin is in the presence of an increased pCO2. Both result in a decreased oxygen affinity of hemoglobin and, therefore, a shift to the right in the oxygen dissociation curve (Figure 3.8), and both, then, stabilize the T state. This change in oxygen binding is called the Bohr effect. Conversely, raising the pH or lowering the concentration of CO2 results in a greater affinity for oxygen, a shift to the left in the oxygen dissociation curve, and stabilization of the R state. a. Source of the protons that lower the pH: The concentration of both CO2 and H+ in the capillaries of metabolically active tissues is higher than that observed in alveolar capillaries of the lungs, where CO2 is released into the expired air. [Note: Organic acids, such as lactic acid, are produced during anaerobic metabolism in rapidly contracting muscle (see p. 103).] In the tissues, CO2 is converted by carbonic anhydrase to carbonic acid: CO2 + H2O H2CO3 which spontaneously loses a proton, becoming bicarbonate (the major blood buffer): H2CO3 HCO3 – + H+ The H+ produced by this pair of reactions contributes to the lowering of pH. This differential pH gradient (lungs having a higher pH, tissues a lower pH) favors the unloading of oxygen in the peripheral tissues, and the loading of oxygen in the lung. Thus, the oxygen affinity of the hemoglobin molecule responds to small shifts in pH between the lungs and oxygen-consuming tissues, making hemoglobin a more efficient transporter of oxygen. →← →← 30 3. Globular Proteins Figure 3.8 Effect of pH on the oxygen affinity of hemoglobin. Protons are allosteric effectors of hemoglobin. Partial pressure of oxygen (pO2) (mm Hg) 0 0 50 Decrease in pH results in decreased oxygen affinity of hemoglobin and, therefore, a shift to the right in the oxygen dissociation curve. At lower pH, a greater pO2 is required to achieve any given oxygen saturation. Figure 3.7 Transport of oxygen and carbon dioxide by hemoglobin. Fe2+ Fe2+ Fe2+ Fe2+ O2 O2 O2 O2 Oxyhemoglobin Fe2+ Fe2+ Fe2+ Fe2+ NHCOO– NHCOO– Carbaminohemoglobin CO2 binds to hemoglobin O2 is released from hemoglobin O2 binds to hemoglobin CO2 is released from hemoglobin CO2 O2 TISSUES LUNGS CO2 O2 168397_P025-042.qxd7.0:03 Hemoglobin 5-20-04 2010.4.4 1:04 PM Page 30
Il.Globular Hemeproteins 37 Glycolysis proioshanoesowyhemogloin.ThisefiegeCase Glucose avicher yhemooko gro such as specific his ing in a decrease in pH)causes these groups to become pro- tonated (charged)and able to form ionic b piaals8caed ormothemoglobinpioducingaeceas0noygen1hangoy The Bohr effect can be represented schematically as: 2,3-E HbO2+H HbH O2 oxyhemoglobin where an increa orium to the right (favoring deoxyhere po shifts the equn Pyruvate rium to the left. 3.Effect of 2,3-bisphosphoglycerate on oxygen affinity:2,3-Bis- 一2aa受e6amnn。 that of hemoglobin.2.3-BPG is synthesized from an intermediate Figure 3.9 synthesis in glycolysis). glycerate (2.3-DPG). diphospho effect of binding 2.3-BPG can be represented schematically as: Hb02+2,3-BPG2Hb-2.3-BPG+0 oxyhemoglobin deoxyhemoglobin svrchargedmnthaomond d1) with the negatively charged phosphate groups of 2,3-BPG Note on one ab nese res .-isxpllxygntioothehemoon. 23-act oxygen dissociation curve: Hemoglobin from nthe n dssociation curv hg(.) Figure 3.10 hmby deoxy
b. Mechanism of the Bohr effect: The Bohr effect reflects the fact that the deoxy form of hemoglobin has a greater affinity for protons than does oxyhemoglobin. This effect is caused by ionizable groups, such as specific histidine side chains that have higher pKas in deoxy hemoglobin than in oxyhemoglobin. There fore, an increase in the concentration of protons (resulting in a decrease in pH) causes these groups to become protonated (charged) and able to form ionic bonds (also called salt bridges). These bonds preferentially stabilize the deoxy form of hemoglobin, producing a decrease in oxygen affinity. The Bohr effect can be represented schematically as: HbO2 + H+ HbH + O2 oxyhemoglobin deoxyhemoglobin where an increase in protons (or a lower pO2) shifts the equilibrium to the right (favoring deoxyhemoglobin), whereas an increase in pO2 (or a decrease in protons) shifts the equilibrium to the left. 3. Effect of 2,3-bisphosphoglycerate on oxygen affinity: 2,3-Bis - phospho glycerate (2,3-BPG) is an important regulator of the binding of oxygen to hemoglobin. It is the most abundant organic phosphate in the RBC, where its concentration is approximately that of hemoglobin. 2,3-BPG is synthesized from an intermediate of the glycolytic pathway (Figure 3.9; see p. 101 for a discussion of 2,3-BPG synthesis in glycolysis). a. Binding of 2,3-BPG to deoxyhemoglobin: 2,3-BPG decreases the oxygen affinity of hemoglobin by binding to deoxy - hemoglobin but not to oxyhemoglobin. This preferential binding stabilizes the taut conformation of deoxyhemoglobin. The effect of binding 2,3-BPG can be represented schematically as: HbO2 + 2,3-BPG Hb–2,3-BPG + O2 oxyhemoglobin deoxyhemoglobin b. Binding site of 2,3-BPG: One molecule of 2,3-BPG binds to a pocket, formed by the two β-globin chains, in the center of the deoxyhemoglobin tetramer (Figure 3.10). This pocket contains several positively charged amino acids that form ionic bonds with the negatively charged phosphate groups of 2,3-BPG. [Note: A mutation of one of these residues can result in hemoglobin variants with abnormally high oxygen affinity.] 2,3-BPG is expelled on oxygenation of the hemoglobin. c. Shift of the oxygen dissociation curve: Hemoglobin from which 2,3-BPG has been removed has a high affinity for oxygen. However, as seen in the RBC, the presence of 2,3-BPG significantly reduces the affinity of hemoglobin for oxygen, shifting the oxygen dissociation curve to the right (Figure 3.11). This reduced affinity enables hemoglobin to release oxygen efficiently at the partial pressures found in the tissues. →← →← II. Globular Hemeproteins 31 Figure 3.9 Synthesis of 2,3-bisphosphoglycerate. [Note: is a phosphoryl group.] In older literature 2,3-bisphosphoglycerate (2,3-BPG) may be referred to as 2,3-diphosphoglycerate (2,3-DPG). 2,3-Bisphosphoglycerate H H C O H C O C O O– P P 1,3-Bisphosphoglycerate Glucose 3-Phosphoglycerate Pyruvate H2O PO4 2– Glycolysis Lactate P –– –– Figure 3.10 Binding of 2,3-BPG by deoxyhemoglobin. β2 α2 A single molecule of 2,3-BPG binds to a positively charged cavity formed by the β-chains of deoxyhemoglobin. α1 168397_P025-042.qxd7.0:03 Hemoglobin 5-20-04 2010.4.4 1:04 PM Page 31
32 3.Globular Proteins d.Response of 2,3-BPG levels to chronic hypoxia or anemia 2,3-BPG=0 C increas ipped 2.3-BP) COPp)like erve high altitudes.where circulating hemoglobin may have diffi culty oxygen.Intracellular levels of 2.3-BPG are BBCs a ronic anem 238PG=8m Elevated 2.3-BPG levels lower the oxvgen affinity of hemo apaedtohghaaeg Figure 3.11). e.Role of 2,3-BPG in transfused blood:2,3-BPG is essential for Panalpram6o9en the normal oxygen transport functic decr2-PRstored plood n Figure 3.11 high oxygen affinity,and fails to unload its bound oxygen prop erly in the tissues. Her 9globndeticentn23- PG thus acts e able s a plies of 2.3-BPG in 6-24 hours.However.severely ill patients ibled (21 to 42 median time of 15 days)by changes in H,phosphate and hexose sugar concentr ation,and by the addition of adenine e p.2 Although the it o was not greatly improved RBC surviva g of CO2:Most C02 oduced in me some co is carried as carbamate bound to the n-terminal amino can be represer Hb-NH2 +CO2 Hb-NH-COO-+H* Zero percent CO-Hb ifty percent CO-H p.28)and a right shift in the oxygen dissociation.In the lungs COa dissociates from the hemoglobin,and is released in the 5.Binding of co:Carbon monoxide(CO)binds tightly(but (mm (p the four heme sites,hemoglobin shifts to the relaxed conforma tion.causing the remaining heme sites to bind oxygen with high 2ea2 idal shape on rd a b 9cfmemgi8nthe result,the affected hemoglobin is unable to release oxygen to the C39 tissues(Figure 3.12).[Note:The affinity of hemoglobin for Co is monoxy. 220 tmes grea for oxygen.C quently.even minut obin in the blood.For am
d. Response of 2,3-BPG levels to chronic hypoxia or anemia: The concentration of 2,3-BPG in the RBC increases in response to chronic hypoxia, such as that observed in chronic obstructive pulmonary disease (COPD) like emphysema, or at high altitudes, where circulating hemoglobin may have difficulty receiving sufficient oxygen. Intracellular levels of 2,3-BPG are also elevated in chronic anemia, in which fewer than normal RBCs are available to supply the body’s oxygen needs. Elevated 2,3-BPG levels lower the oxygen affinity of hemo - globin, permitting greater unloading of oxygen in the capillaries of the tissues (see Figure 3.11). e. Role of 2,3-BPG in transfused blood: 2,3-BPG is essential for the normal oxygen transport function of hemoglobin. However, storing blood in the currently available media results in a decrease in 2,3-PBG. Stored blood displays an abnormally high oxygen affinity, and fails to unload its bound oxygen properly in the tissues. Hemoglobin deficient in 2,3-BPG thus acts as an oxygen “trap” rather than as an oxygen transport system. Transfused RBCs are able to restore their depleted supplies of 2,3-BPG in 6–24 hours. However, severely ill patients may be compromised if transfused with large quantities of such 2,3-BPG–“stripped” blood. [Note: The maximum storage time for red cells has been doubled (21 to 42 days, with median time of 15 days) by changes in H+, phosphate and hexose sugar concentration, and by the addition of adenine (see p. 291). Although the content of 2,3-BPG was not greatly affected by these changes, ATP production was increased and improved RBC survival.] 4. Binding of CO2: Most of the CO2 produced in metabolism is hydrated and transported as bicarbonate ion (see p. 9). However, some CO2 is carried as carbamate bound to the N-terminal amino groups of hemoglobin (forming carbaminohemoglobin, see Figure 3.7), which can be represented schematically as follows: Hb – NH2 + CO2 Hb – NH – COO– + H+ The binding of CO2 stabilizes the T (taut) or deoxy form of hemoglobin, resulting in a decrease in its affinity for oxygen (see p. 28) and a right shift in the oxygen dissociation. In the lungs, CO2 dissociates from the hemoglobin, and is released in the breath. 5. Binding of CO: Carbon monoxide (CO) binds tightly (but reversibly) to the hemoglobin iron, forming carbon monoxy hemo - globin (or carboxyhemoglobin). When CO binds to one or more of the four heme sites, hemoglobin shifts to the relaxed conformation, causing the remaining heme sites to bind oxygen with high affinity. This shifts the oxygen dissociation curve to the left, and changes the normal sigmoidal shape toward a hyperbola. As a result, the affected hemoglobin is unable to release oxygen to the tissues (Figure 3.12). [Note: The affinity of hemoglobin for CO is 220 times greater than for oxygen. Consequently, even minute concentrations of CO in the environment can produce toxic concentrations of carbon monoxyhemoglobin in the blood. For exam- →← 32 3. Globular Proteins % Saturation with O2 (Y) Figure 3.11 Allosteric effect of 2,3-BPG on the oxygen affinity of hemoglobin. Partial pressure of oxygen (mm Hg) 0 0 40 80 120 100 2,3-BPG = 8 mmol/L (Blood from individual adapted to high altitudes) 2,3-BPG = 0 (Hemoglobin stripped of 2,3-BPG) 2,3-BPG = 5 mmol/L (Normal blood) Figure 3.12 Effect of carbon monoxide on the oxygen affinity of hemoglobin. CO-Hb = carbon monoxyhemoglobin. O2 Content (ml/100 ml blood) Partial pressure of oxygen (pO2) (mm Hg) 0 0 40 80 120 20 Fifty percent CO-Hb Zero percent CO-Hb 10 168397_P025-042.qxd7.0:03 Hemoglobin 5-20-04 2010.4.4 1:04 PM Page 32
Il.Globular Hemeproteins ears to result from a com ce 100 HbA 90% atethe dissoction of Co from the hemoglobin.Note: <2% inhibits Complex IV of the electron transport chain(see p.76).]In HbA2 2-5% CO2.and CO.nitric oxide gas (NO)alsosca ea by A1c aBa-glucose up (salvaged)or released from RBCs.thus modulating NO availabil ity and influencina vessel diameter. Figure 3.13 h F.Minor hemoglobins [NC It is important to remember that human hemoglobin A(Hb A)is just r or a nc nly or pro proteins is a tetramer cor posedofhwoa-globinp8lg3ei eptides and two -globin (or B-globin-like)polypeptides.Certain, such as Hb are sized only during feta e although at low levels compared with Hb A.Hb A can also modified by the covalent addition of a hexose.For example.addition 50 of glucose forms the glucosylated hemoglobin derivative,Hb Ae 1.eahenogebngbb5saetanercgnsstng.oftwo The y chains are me bers of the family (see p.35). a.Hb F synthesis during development:In the first month after conception.embryonic hemoglobins such as H ower (E)ch the two B-lik the fifth week of gestation.the site of globin synthesis shifts. and the primary prod s the major 60%of life(Figure 3.14).Hb A synthesis starts in the bone marrow a ntn or pregnancy and graduall replaces 037 of he during fetal and postnatal life.)Note: Months before and after birth F represents less than 1%of the Hb in most adults,and is concentrated in RBCs known as F-cells.] Figure 3.14 changes in hemo b.Binding of 2,3-BPG to Hb F:Under physiologi F has a higher affinity for oxygen than does Hb A,as a result acansot for hi 2-BP chains.I Because 2.3-BPG serves to reduce the affinity of hemoglobin for oxygen,the weaker interaction between 2,3-BPG and F results in a r oxyge en
ple, increased levels of CO are found in the blood of tobacco smokers. Carbon monoxide toxicity appears to result from a combination of tissue hypoxia and direct CO-mediated damage at the cellular level.] Carbon monoxide poisoning is treated with 100% oxygen at high pressure (hyperbaric oxygen therapy), which facilitates the dissociation of CO from the hemoglobin. [Note: CO inhibits Complex IV of the electron transport chain (see p. 76).] In addition to O2, CO2, and CO, nitric oxide gas (NO) also is carried by hemoglobin. NO is a potent vasodilator (see p. 151). It can be taken up (salvaged) or released from RBCs, thus modulating NO availability and influencing vessel diameter. F. Minor hemoglobins It is important to remember that human hemoglobin A (Hb A) is just one member of a functionally and structurally related family of proteins, the hemoglobins (Figure 3.13). Each of these oxygen-carrying proteins is a tetramer, composed of two α-globin polypeptides and two β-globin (or β-globin-like) polypeptides. Certain hemoglobins, such as Hb F, are normally synthesized only during fetal development, whereas others, such as Hb A2, are synthesized in the adult, although at low levels compared with Hb A. Hb A can also become modified by the covalent addition of a hexose. For example, addition of glucose forms the glucosylated hemoglobin derivative, Hb A1c. 1. Fetal hemoglobin (Hb F): Hb F is a tetramer consisting of two α chains identical to those found in Hb A, plus two γ chains (α2γ2, see Figure 3.13). The γ chains are members of the β-globin gene family (see p. 35). a. Hb F synthesis during development: In the first month after conception, embryonic hemoglobins such as Hb Gower 1, composed of two α-like zeta (ζ) chains and two β-like epsilon (ε) chains (ζ2ε2), are synthesized by the embryonic yolk sac. In the fifth week of gestation, the site of globin synthesis shifts, first to the liver and then to the marrow, and the primary product is Hb F. Hb F is the major hemoglobin found in the fetus and newborn, accounting for about 60% of the total hemoglobin in the erythrocytes during the last months of fetal life (Figure 3.14). Hb A synthesis starts in the bone marrow at about the eighth month of pregnancy and gradually replaces Hb F. (Figure 3.14 shows the relative production of each type of hemoglobin chain during fetal and postnatal life.) [Note: Hb F represents less than 1% of the Hb in most adults, and is concentrated in RBCs known as F-cells.] b. Binding of 2,3-BPG to Hb F: Under physiologic conditions, Hb F has a higher affinity for oxygen than does Hb A, as a result of Hb F binding only weakly to 2,3-BPG. [Note: The γ-globin chains of Hb F lack some of the positively charged amino acids that are responsible for binding 2,3-BPG in the β-globin chains.] Because 2,3-BPG serves to reduce the affinity of hemoglobin for oxygen, the weaker interaction between 2,3-BPG and Hb F results in a higher oxygen affinity for Hb F relative to Hb A. In contrast, if both Hb A and Hb F are stripped of their 2,3-BPG, they then have a similar affinity for oxygen. II. Globular Hemeproteins 33 Figure 3.13 Normal adult human hemoglobins. [Note: The α-chains in these hemoglobins are identical.] HbA α2β2 Form Chain composition Fraction of total hemoglobin HbA1c α2β2-glucose 90% 3–9% α2γ HbF <2% 2 HbA2 α2δ2 2–5% Figure 3.14 Developmental changes in hemoglobin. Months before and after birth Percentage of total globin chains -9 -6 -3 3 6 9 0 25 50 0 25 50 α β δ ε γ ζ α-Globinlike chains β-Globinlike chains Time of birth 0 168397_P025-042.qxd7.0:03 Hemoglobin 5-20-04 2010.4.4 1:04 PM Page 33