Chapter 099. Disorders of Hemoglobin (Part 1) pptx

Disorders of Hemoglobin Disorders of Hemoglobin: Introduction Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentratio

Chapter 099 Disorders of

Hemoglobin

(Part 1)

Harrison's Internal Medicine > Chapter 99 Disorders of Hemoglobin

Disorders of Hemoglobin: Introduction

Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero Different forms may present as hemolytic anemia, erythrocytosis, cyanosis, or vasoocclusive stigmata

Hemoglobin Structure

Different hemoglobins are produced during embryonic, fetal, and adult life (Fig 99-1) Each consists of a tetramer of globin polypeptide chains: a pair of α-like chains 141 amino acids long and a pair of β-α-like chains 146 amino acids long The major adult hemoglobin, HbA, has the structure α2β2 HbF (α2β2) predominates during most of gestation, and HbA2 (α2δ2) is minor adult hemoglobin Embryonic hemoglobins need not be considered here

Figure 99-1

The globin genes The α-like genes (α,s) are encoded on chromosome 16;

the β-like genes (β,γ,δ,ε) are encoded on chromosome 11 The s and ε genes encode embryonic globins

Each globin chain enfolds a single heme moiety, consisting of a protoporphyrin IX ring complexed with a single iron atom in the ferrous state (Fe2+) Each heme moiety can bind a single oxygen molecule; a molecule of hemoglobin can transport up to four oxygen molecules

The amino acid sequences of the various globins are highly homologous to

one another Each has a highly helical secondary structure Their globular tertiary

structures can cause the exterior surfaces to be rich in polar (hydrophilic) amino

acids that enhance solubility and the interior to be lined with nonpolar groups, forming a hydrophobic pocket into which heme is inserted The tetrameric

quaternary structure of HbA contains two αβdimers Numerous tight interactions

(i.e., α1β1 contacts) hold the αand βchains together The complete tetramer is held together by interfaces (i.e., α1β2 contacts) between the α-like chain of one dimer and the non-α chain of the other dimer

The hemoglobin tetramer is highly soluble but individual globin chains are insoluble Unpaired globin precipitates, forming inclusions that damage the cell Normal globin chain synthesis is balanced so that each newly synthesized α or non-α globin chain will have an available partner with which to pair

Solubility and reversible oxygen binding are the key properties deranged in hemoglobinopathies Both depend most on the hydrophilic surface amino acids,

the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix, and the amino acids forming the α1β1 and α1β2 contact points Mutations in these strategic regions tend to be the ones that alter clinical behavior

Function of Hemoglobin

To support oxygen transport, hemoglobin must bind O2 efficiently at the partial pressure of oxygen (PO2) of the alveolus, retain it, and release it to tissues at the PO2 of tissue capillary beds Oxygen acquisition and delivery over a relatively narrow range of oxygen tensions depend on a property inherent in the tetrameric arrangement of heme and globin subunits within the hemoglobin molecule called

cooperativity or heme-heme interaction

At low oxygen tensions, the hemoglobin tetramer is fully deoxygenated (Fig 99-2) Oxygen binding begins slowly as O2 tension rises However, as soon

as some oxygen has been bound by the tetramer, an abrupt increase occurs in the slope of the curve Thus, hemoglobin molecules that have bound some oxygen develop a higher oxygen affinity, greatly accelerating their ability to combine with more oxygen This S-shaped oxygen equilibrium curve (Fig 99-2), along which

substantial amounts of oxygen loading and unloading can occur over a narrow

range of oxygen tensions, is physiologically more useful than the high-affinity hyperbolic curve of individual monomers