# Adult & Fetal Haemoglobin ## The Oxygen Dissociation Curve - The oxygen dissociation curve is a graph that shows how readily haemoglobin binds to and releases oxygen at different partial pressures of oxygen ($pO_2$) - It reveals critical information about oxygen transport in the blood

Partial pressure of oxygen ($pO_2$) is the pressure exerted by oxygen in a mixture of gases; it's a measure of oxygen concentration

### Key terminology - **Percentage saturation**: the proportion of haemoglobin's oxygen binding sites that are occupied by oxygen - When fully saturated, each haemoglobin molecule carries four oxygen molecules (one per haem group) - **Affinity for oxygen**: describes how readily haemoglobin binds to and releases oxygen - High affinity = binds easily, releases slowly - Low affinity = binds slowly, releases easily ## Structure and Function of Haemoglobin - Haemoglobin is a quaternary protein found in red blood cells (erythrocytes) - Each molecule contains: - Four polypeptide chains (globin subunits) - Four haem groups, each containing an iron ion ($Fe^{2+}$) - Each haem group can bind one oxygen molecule

One haemoglobin molecule can transport four oxygen molecules, or eight oxygen atoms total

### The binding reaction - When oxygen binds to haemoglobin, oxyhaemoglobin is formed: $$\text{Oxygen} + \text{Haemoglobin} \rightleftharpoons \text{Oxyhaemoglobin}$$ $$4O_2 + Hb \rightleftharpoons Hb4O_2$$ ## Cooperative Binding - The shape of the oxygen dissociation curve reflects the way oxygen molecules bind to haemoglobin - Binding doesn't occur at a constant rate; it changes as more oxygen molecules attach ### Why the curve is S-shaped **At low $pO_2$ (bottom left of curve):** - The first oxygen molecule finds it difficult to bind due to haemoglobin's initial shape - Binding occurs slowly - This creates the shallow initial slope **At medium $pO_2$ (steep middle section):** - Once the first oxygen binds, haemoglobin changes shape (conformational change) - This makes it easier for the second and third oxygen molecules to bind - Binding rate increases dramatically - This creates the steep middle section **At high $pO_2$ (top right of curve):** - It becomes harder for the fourth oxygen to bind because there are fewer remaining binding sites - The curve levels off as saturation approaches 100%

Cooperative binding: the binding of one oxygen molecule makes it easier for subsequent oxygen molecules to bind to the same haemoglobin molecule

### The characteristic S-shaped curve The graph below shows the typical oxygen dissociation curve for adult haemoglobin, illustrating the S-shape caused by cooperative binding:

## Interpreting the Curve: Oxygen Loading **Reading left to right shows oxygen binding:** | Region | $pO_2$ | What happens | Significance | |--------|--------|--------------|--------------| | Bottom left | Low | Oxygen binds slowly; low affinity; low saturation | At respiring tissues - haemoglobin doesn't pick up oxygen here | | Middle | Medium | Oxygen binds rapidly; small increase in $pO_2$ causes large increase in saturation | Efficient oxygen loading in lungs | | Top right | High | Oxygen binds easily; high affinity; high saturation approaches 100% | In the lungs - haemoglobin becomes fully saturated | - At high $pO_2$ (in the lungs), haemoglobin has high affinity for oxygen - Large increases in $pO_2$ only slightly increase saturation because most binding sites are already occupied ## Interpreting the Curve: Oxygen Unloading **Reading right to left shows oxygen release:** | Region | $pO_2$ | What happens | Significance | |--------|--------|--------------|--------------| | Top right | High | Very little dissociation | In the lungs - oxygen stays bound to haemoglobin | | Middle | Medium | Rapid dissociation; small decrease in $pO_2$ causes large decrease in saturation | At respiring tissues - efficient oxygen delivery to cells | | Bottom left | Low | Dissociation slows; few oxygen molecules remain | Final oxygen molecules are harder to release | - The steep middle section is crucial: it corresponds to the $pO_2$ found in actively respiring tissues - A small drop in $pO_2$ causes substantial oxygen release - This ensures cells receive plenty of oxygen for aerobic respiration

The steep region of the curve means small changes in tissue oxygen levels cause large changes in oxygen delivery

## Carbon Dioxide Transport - Waste carbon dioxide from respiration must be transported from tissues to the lungs - Three main transport mechanisms exist: ### 1. Dissolved in plasma (smallest amount) - A small percentage of CO₂ dissolves directly in blood plasma - Transported in solution ### 2. Bound to haemoglobin - Carbon dioxide can bind to haemoglobin, forming **carbaminohaemoglobin** - Binds at different sites than oxygen ### 3. As hydrogen carbonate ions (largest amount) - The majority of CO₂ is transported as hydrogen carbonate ions ($HCO_3^-$) - This is the most important transport mechanism ## Formation of Hydrogen Carbonate Ions **Step-by-step process:** 1. Carbon dioxide diffuses from tissues into blood plasma 2. CO₂ diffuses from plasma into red blood cells 3. Inside red blood cells, CO₂ combines with water to form carbonic acid: $$CO_2 + H_2O \rightleftharpoons H_2CO_3$$ 4. The enzyme **carbonic anhydrase** catalyses this reaction - Without this enzyme, the reaction would be too slow - Red blood cells contain high concentrations of carbonic anhydrase - Plasma contains very little, so the reaction is much slower there 5. Carbonic acid dissociates into hydrogen ions and hydrogen carbonate ions: $$H_2CO_3 \rightleftharpoons HCO_3^- + H^+$$ 6. Hydrogen ions bind to haemoglobin, forming **haemoglobinic acid** - This prevents H⁺ ions from lowering blood pH - Haemoglobin acts as a **buffer** 7. Hydrogen carbonate ions diffuse out of red blood cells into plasma - Transported in solution to the lungs

Carbonic anhydrase is essential; without it, CO₂ transport would be too slow to meet metabolic needs

## The Chloride Shift - A mechanism that maintains electrical balance during CO₂ transport - Occurs when hydrogen carbonate ions are formed **The process:** 1. Carbon dioxide enters red blood cells and forms carbonic acid (catalysed by carbonic anhydrase) $$CO_2 + H_2O \rightleftharpoons H_2CO_3$$ 2. Carbonic acid dissociates: $$H_2CO_3 \rightleftharpoons HCO_3^- + H^+$$ 3. Negatively charged $HCO_3^-$ ions move out of red blood cells via a transport protein 4. To prevent electrical imbalance, negatively charged chloride ions ($Cl^-$) move into red blood cells via the same transport protein 5. This maintains electrical neutrality inside the cell

Without the chloride shift, red blood cells would become positively charged from the buildup of H⁺ ions

**Why it's important:** - Prevents dangerous charge imbalances - H⁺ ions from carbonic acid dissociation would otherwise create a positive charge - Chloride ions balance the loss of negative $HCO_3^-$ ions ## Fetal Haemoglobin - Developing fetuses produce a different type of haemoglobin with special properties - This adaptation is essential for fetal survival ### Key difference - Fetal haemoglobin has a **higher affinity for oxygen** than adult haemoglobin - At any given $pO_2$, fetal haemoglobin has a higher percentage saturation than adult haemoglobin ### Why this matters - Oxygen must transfer from maternal blood to fetal blood at the placenta - At the placenta, $pO_2$ is relatively low - At this low $pO_2$, maternal haemoglobin is releasing oxygen - At the same $pO_2$, fetal haemoglobin is binding oxygen - This ensures efficient oxygen transfer from mother to fetus

Think of it like a relay race: maternal haemoglobin passes the oxygen baton to fetal haemoglobin at the placenta

### The oxygen dissociation curve - On a graph, the fetal haemoglobin curve sits to the **left** of the adult curve - This leftward shift indicates higher oxygen affinity - At any partial pressure, the fetal curve shows higher saturation than the adult curve **Example comparison:** - At a $pO_2$ of 4 kPa (typical at the placenta): - Adult haemoglobin might be 50% saturated (releasing oxygen) - Fetal haemoglobin might be 70% saturated (binding oxygen) The graph below compares adult and fetal haemoglobin curves. Notice how the fetal curve is shifted to the left, showing higher saturation at every partial pressure:

### After birth - After birth, babies gradually replace fetal haemoglobin with adult haemoglobin - Adult haemoglobin has lower affinity, allowing easier oxygen release - This is important because babies become more metabolically active after birth - They need oxygen to be readily released to respiring tissues ## Different Types of Haemoglobin - Haemoglobin structure varies between species - All haemoglobins share the same haem group structure - The **globin polypeptide chains** differ substantially ### What determines haemoglobin properties - The specific amino acid sequence of the globin chains determines: - Oxygen binding affinity - Rate of oxygen association and dissociation - Response to environmental factors - Different species have evolved haemoglobin adapted to their specific needs ### Adaptation to altitude **The challenge:** - Partial pressure of oxygen decreases with altitude - At high altitudes, less oxygen is available in the air **The solution:** - Species living at high altitudes have haemoglobin with higher oxygen affinity - Their haemoglobin binds oxygen more readily **Example: Llamas** - Llamas live in the Andes mountains at high altitude - Their haemoglobin binds oxygen very readily - This allows them to achieve adequate blood oxygen saturation even when $pO_2$ is low - On an oxygen dissociation curve, llama haemoglobin would be shifted to the left of human haemoglobin

A leftward shift on the oxygen dissociation curve always indicates higher affinity for oxygen

The graph below compares haemoglobin from different species, showing how high-altitude animals have leftward-shifted curves:

### Comparing different haemoglobins | Haemoglobin type | Oxygen affinity | Curve position | Adaptation | |------------------|-----------------|----------------|------------| | High-altitude animals (e.g., llama) | Very high | Far left | Binds oxygen at low $pO_2$ | | Fetal | High | Left of adult | Takes oxygen from maternal blood | | Adult human | Medium | Middle | Balanced loading and unloading | | Very active animals | Lower | Right | Releases oxygen more readily to tissues | ### Environmental adaptations - Metabolic rate affects haemoglobin evolution - Highly active animals may have haemoglobin that releases oxygen more easily - This ensures rapidly respiring cells receive sufficient oxygen - Habitat oxygen availability drives adaptation - Aquatic animals may have higher affinity haemoglobin (water contains less dissolved oxygen) - Desert animals in hot environments may have haemoglobin adapted to temperature effects ## Summary: Key Concepts **The oxygen dissociation curve:** - S-shaped due to cooperative binding - Steep middle section allows efficient oxygen delivery at tissues - Plateau at high $pO_2$ ensures full saturation in lungs **Fetal haemoglobin:** - Higher oxygen affinity than adult haemoglobin - Curve shifted left of adult curve - Essential for oxygen transfer at placenta - Replaced by adult haemoglobin after birth **Haemoglobin diversity:** - Globin chains determine oxygen-binding properties - Species adapt haemoglobin to their environment - Altitude, metabolic rate, and habitat drive evolution of different haemoglobin types

When comparing oxygen dissociation curves, remember: left shift = higher affinity; right shift = lower affinity