Haemoglobin is the principal oxygen carrying protein found inside red blood cells. It is a specialised globular protein that binds oxygen reversibly, allowing blood to transport oxygen from the lungs to tissues and facilitating the return transport of carbon dioxide through several related mechanisms. In healthy adult humans, the predominant form is adult haemoglobin, usually called haemoglobin A, which consists of four protein subunits, two alpha chains and two beta chains.
Each subunit contains a haem group containing an iron ion in the ferrous state. Each haem group can reversibly bind one oxygen molecule, so a haemoglobin molecule can normally carry up to four oxygen molecules. The iron containing haem groups are responsible for haemoglobin's characteristic association with the red colour of oxygenated blood. Haemoglobin is not simply an oxygen storage substance. Its ability to bind oxygen cooperatively and respond to changes in oxygen pressure, acidity, carbon dioxide concentration and other physiological conditions allows it to function as a dynamic transport system adapted to the differing environments of lungs and metabolically active tissues.
The molecular structure of haemoglobin explains much of its physiological behaviour. Each globin chain folds into a specific three dimensional structure and surrounds a haem prosthetic group. The haem group contains a porphyrin ring with a central iron atom capable of binding oxygen. Oxygen attaches reversibly to the iron, rather than forming an irreversible chemical bond, which permits loading in the lungs and unloading in tissues. Haemoglobin exists in different conformational states depending on whether oxygen is bound.
The transition between these states underlies cooperative oxygen binding. When one oxygen molecule binds, the structural arrangement of the haemoglobin molecule changes in a way that increases the affinity of other haem groups for oxygen. Conversely, release of oxygen promotes a lower affinity state that facilitates further oxygen unloading. This cooperative behaviour produces the characteristic sigmoid oxygen haemoglobin dissociation curve. The curve allows haemoglobin to become highly saturated in the relatively oxygen rich pulmonary environment while still releasing substantial oxygen when tissue oxygen availability falls.
Haemoglobin's oxygen binding is strongly influenced by the partial pressure of oxygen. In the pulmonary alveoli, oxygen partial pressure is relatively high, so haemoglobin becomes highly saturated as oxygen diffuses from alveolar air into pulmonary capillary blood. In systemic tissues, oxygen partial pressure is generally lower, favouring oxygen dissociation from haemoglobin and diffusion into cells. The relationship is not linear. At high oxygen partial pressures, haemoglobin approaches saturation, providing a substantial reserve for oxygen transport.
At lower tissue oxygen pressures, the steep portion of the dissociation curve means relatively modest decreases in oxygen pressure can produce substantial oxygen unloading. This arrangement is physiologically advantageous because active tissues can receive more oxygen when their oxygen availability decreases. Haemoglobin also responds to increased carbon dioxide production and acidity in metabolically active tissues. The Bohr effect describes the reduction in haemoglobin's oxygen affinity associated with increased hydrogen ion concentration and carbon dioxide, promoting oxygen release where metabolism is active.
Haemoglobin also contributes to carbon dioxide transport and acid base regulation. Carbon dioxide generated by cellular metabolism enters the blood and is transported to the lungs in several forms. A substantial proportion is converted inside red blood cells into bicarbonate ions through the action of carbonic anhydrase. Haemoglobin participates in this process by buffering hydrogen ions generated during carbon dioxide conversion and by binding some carbon dioxide directly to globin groups to form carbaminohaemoglobin.
Deoxygenated haemoglobin has a greater capacity to bind hydrogen ions and carbon dioxide than oxygenated haemoglobin, contributing to the Haldane effect. This helps coordinate oxygen unloading in tissues with carbon dioxide uptake and carbon dioxide unloading in the lungs with oxygen loading. Haemoglobin is therefore involved in respiratory gas transport and acid base homeostasis simultaneously. Its behaviour links pulmonary gas exchange, systemic metabolism, blood chemistry and ventilation, making it one of the most important proteins in human physiology.
Haemoglobin concentration is clinically important because it influences the blood's oxygen carrying capacity. Anaemia refers broadly to a reduction in haemoglobin concentration, red cell mass or both, depending on the diagnostic context. Iron deficiency is a common cause and can reduce haem synthesis, producing smaller red blood cells with less haemoglobin. Other causes include vitamin deficiencies, chronic disease, blood loss, inherited disorders and impaired red cell production.
Symptoms depend on severity and rate of development but may include fatigue, reduced exercise tolerance, breathlessness and pallor because tissues receive less oxygen relative to their metabolic requirements. Polycythaemia, by contrast, involves an increased red cell concentration and can increase blood viscosity. Haemoglobin measurements form part of the full blood count and are interpreted alongside red cell indices, clinical findings and other laboratory results. A haemoglobin concentration alone does not identify the cause of an abnormality, because different disorders can produce similar numerical changes through different mechanisms.
Several genetically distinct haemoglobin variants exist. Foetal haemoglobin, or haemoglobin F, predominates before birth and consists of two alpha and two gamma chains. It has a higher oxygen affinity than adult haemoglobin, helping the foetus obtain oxygen from maternal blood across the placenta. After birth, gamma chain production declines and beta chain production increases, leading to predominance of adult haemoglobin. Genetic mutations affecting globin chains can produce inherited disorders such as sickle cell disease and thalassaemias.
In sickle cell disease, a structural change in the beta globin chain can cause deoxygenated haemoglobin to polymerise under appropriate conditions, distorting red blood cells and contributing to haemolysis and vascular obstruction. Thalassaemias involve reduced production of particular globin chains, creating an imbalance in globin synthesis and impaired red cell development. These disorders demonstrate how small molecular changes can have major physiological consequences because haemoglobin is central to oxygen transport.
Haemoglobin also has important relationships with environmental and toxic exposures. Carbon monoxide binds to haemoglobin with much greater affinity than oxygen and forms carboxyhaemoglobin, reducing effective oxygen transport and interfering with oxygen unloading from remaining haemoglobin sites. This explains why carbon monoxide poisoning can cause severe tissue hypoxia even when the lungs contain adequate oxygen. Methemoglobin is another abnormal form in which the haem iron is oxidised from the ferrous to the ferric state.
Ferric iron cannot bind oxygen normally, so excessive methaemoglobin formation impairs oxygen transport. Normally, red cells possess enzyme systems that maintain haemoglobin iron in the appropriate oxidation state. These examples illustrate that haemoglobin function depends not only on its quantity but also on the chemical state of its haem groups and the molecular environment surrounding them.
Haemoglobin is therefore a multifunctional respiratory protein whose structure allows blood to transport oxygen efficiently while also participating in carbon dioxide handling and acid base buffering. Its four subunits, four haem groups and cooperative binding behaviour create a system that responds dynamically to changing physiological conditions. Oxygen loading occurs primarily in pulmonary capillaries, while oxygen unloading occurs throughout systemic tissues according to local oxygen demand and chemical conditions.
The Bohr and Haldane effects help coordinate oxygen and carbon dioxide transport with metabolism and ventilation. Haemoglobin concentration and structure are clinically important because abnormalities can impair oxygen delivery or alter red cell behaviour. The study of haemoglobin also connects molecular biology, genetics, physiology, biochemistry, pathology and medicine, making it a central example of how protein structure determines biological function.
