Hemoglobin

Haemoglobin is an iron-containing globular protein responsible for the transport of oxygen in the red blood cells of almost all vertebrates, with the notable exception of the icefish family Channichthyidae. Its central physiological function is to collect oxygen in the respiratory organs and deliver it to the tissues of the body where aerobic respiration occurs. This process underpins the metabolic activity of animals and supports the functioning of every oxygen-dependent cell type. In humans, haemoglobin concentration typically ranges from 12 to 20 grams per 100 millilitres of blood, representing a major component of circulating erythrocytes and playing essential roles beyond oxygen carriage, including the transport of carbon dioxide and the regulation of iron within various tissues.

Structure and Physiological Properties

Haemoglobin is a metalloprotein, chromoprotein, and globulin, composed of four protein subunits known as globins. Each globin contains an embedded haem group, a porphyrin ring with an iron atom capable of binding one molecule of oxygen through ion-induced dipole interactions. In mammals, the tetrameric structure allows each haemoglobin molecule to bind up to four oxygen molecules.
Its oxygen-binding capacity—approximately 1.34 mL of oxygen per gram—enables blood to carry roughly seventy times more oxygen than plasma alone. Haemoglobin constitutes about 96 per cent of the dry mass of mammalian red blood cells and 35 per cent of their wet mass, illustrating its dominant contribution to erythrocyte composition.
Although best known for oxygen transport, haemoglobin also carries approximately 20–25 per cent of the body’s carbon dioxide, taking part in acid-base balance and the removal of respiratory waste. Moreover, haemoglobin is present in several non-erythroid cells, including dopaminergic neurons, macrophages, alveolar cells, hepatocytes, mesangial cells, and epithelial tissues of the eye and reproductive system. In these contexts, it functions as an antioxidant and influences intracellular iron metabolism.
Excessive blood glucose binds irreversibly to haemoglobin to form HbA1c, a clinically significant indicator of long-term glycaemic control.

Occurrence in Other Organisms

Haemoglobin and haemoglobin-like molecules also occur in invertebrates, fungi, and plants. In these organisms, the protein may facilitate oxygen transport, but it can also bind and regulate small signalling molecules such as nitric oxide, hydrogen sulphide, and carbon dioxide. One specialised plant variant, leghemoglobin, scavenges oxygen in the nitrogen-fixing nodules of legumes, protecting oxygen-sensitive biochemical processes from oxidative damage.
A pathological condition associated with haemoglobin is haemoglobinaemia, in which haemoglobin escapes into blood plasma following intravascular destruction of red cells.

Research and Historical Milestones

Scientific understanding of haemoglobin developed across the nineteenth and twentieth centuries through physiological, chemical, and structural investigations. As early as 1825 Johann Friedrich Engelhart observed a consistent proportion of iron to protein in haemoglobin from multiple species, enabling the first estimation of a protein’s molecular mass. Although initially disputed due to the unexpectedly large size of the molecule, later work using osmotic pressure by Gilbert Adair validated the findings.
By the mid-nineteenth century researchers had described haemoglobin’s oxygen-carrying ability, and Otto Funke succeeded in producing haemoglobin crystals by diluting erythrocytes and evaporating the solvent. Felix Hoppe-Seyler later demonstrated the reversible nature of haemoglobin oxygenation.
The advent of X-ray crystallography revolutionised protein chemistry. In 1959 Max Perutz elucidated the molecular structure of haemoglobin, sharing the 1962 Nobel Prize in Chemistry with John Kendrew, who had determined the structure of myoglobin. Haemoglobin’s role in respiration had earlier been explored by Claude Bernard, contributing to the foundation of modern physiology.
The term “haemoglobin” reflects its dual nature: the haem prosthetic group and the globin polypeptide.

Genetic Basis and Variation

Haemoglobin structure is genetically encoded by multiple genes. In humans the predominant adult form, haemoglobin A (HbA), comprises two alpha and two beta globin chains. The alpha subunits are produced from the closely linked HBA1 and HBA2 genes on chromosome 16, while the beta subunit is encoded by HBB on chromosome 11. Differences in the amino acid sequences of globin chains accumulate across species according to evolutionary distance. Humans, bonobos, and chimpanzees share identical alpha and beta sequences, whereas gorillas differ at a single residue in each chain.
Mutations in globin genes give rise to haemoglobin variants, collectively termed haemoglobinopathies. Many variants are benign, but some cause disease. Sickle-cell disease is a classic example, becoming the first human disorder explained at the molecular level. Thalassaemias, caused by reduced synthesis of normal globin chains, represent another major category, resulting in varying degrees of anaemia.
Sequence variation can also serve adaptive functions. High-altitude species often display haemoglobin mutations that enhance oxygen binding under low partial-pressure conditions. Studies in deer mice, mammoths, and Andean hummingbirds have shown specialised globin adaptations that improve oxygen uptake or alter interactions with allosteric regulators such as inositol hexaphosphate. In humans, Tibetan populations exhibit genetic markers associated with increased oxygen saturation during pregnancy at high altitude, improving offspring survival.

Biosynthesis

Haemoglobin synthesis begins in developing erythrocytes within the bone marrow. The haem portion of the molecule is produced through a multi-step biochemical pathway occurring partly in the mitochondria and partly in the cytosol. The globin chains are synthesised by ribosomes in the cytosol.
Production continues from the proerythroblast stage through the reticulocyte stage. In mammals, the maturing erythrocyte eventually loses its nucleus, but residual ribosomal RNA persists for a short period, permitting continued haemoglobin synthesis until the cell completes its maturation.

Adaptive and Functional Diversity

Haemoglobin demonstrates evolutionary flexibility, allowing species to occupy a wide range of ecological niches. Birds inhabiting the Andes benefit from their unique respiratory anatomy coupled with mutations in haemoglobin that increase oxygen affinity at low ambient pressures. Similarly, high-altitude mammals display adaptive substitutions enhancing oxygen binding or modifying responses to temperature.
These adaptive variants underscore haemoglobin’s central role in physiological fitness and illustrate the interplay between molecular evolution and environmental pressures.

Broader Biological Significance

Beyond its role in respiration, haemoglobin participates in redox homeostasis, signalling pathways, and cellular metabolism across a wide range of species. Its discovery, structural characterisation, and functional analysis have shaped biochemistry, molecular biology, evolutionary genetics, and medical science. Haemoglobin continues to serve as a model protein for studying cooperative binding, gene regulation, population adaptation, and hereditary disease, maintaining its relevance as a cornerstone of biological understanding.