HemoglobinEdit

Hemoglobin is the iron-containing protein inside red blood cells that binds oxygen in the lungs and releases it where it is needed in tissues throughout the body. It also collects carbon dioxide, a waste product of metabolism, from tissues and releases it for exhalation. In humans, the vast majority of circulating hemoglobin in adults is HbA, a heterotetramer built from two α-globin chains and two β-globin chains, each associated with a heme group that contains iron. Along the developmental timeline, other forms persist in smaller amounts—HbA2 and fetal Hb (HbF), which has a different pairing of globin chains—but HbA remains the dominant oxygen carrier after birth. The protein’s design enables cooperative binding, allosteric regulation, and the ability to function efficiently across the wide range of oxygen partial pressures encountered in the lungs and tissues. For readers following the broader biology of blood, see also red blood cell and oxygen transport.

Hemoglobin’s function rests on two intertwined systems: the globin protein framework that creates a cooperative, allosterically regulated binding pocket for the heme iron, and the heme prosthetic group that actually binds O2. Each subunit contains a heme group with iron in the Fe2+ state, capable of reversibly binding one molecule of O2. When one subunit binds O2, others undergo conformational changes that increase the affinity of remaining sites for O2, producing the characteristic sigmoidal oxygen dissociation curve. This coordination is modulated by factors such as pH, partial pressure of oxygen, carbon dioxide concentration, temperature, and the level of 2,3-bisphosphoglycerate (2,3-BPG) inside red blood cells. The Bohr effect describes how acidification (lower pH) decreases Hb’s affinity for O2, promoting release in tissues that are metabolically active, while higher pH in the lungs increases oxygen loading. The molecule also participates in carbon dioxide transport, forming carbaminohemoglobin and contributing to acid–base balance.

Structure and biochemistry

The globin tetramer

Hemoglobin is a tetramer formed from two identical α-globin chains and two identical β-globin chains in the common adult form HbA. The globin portion of the molecule is responsible for the protein’s allosteric properties, while the heme groups provide the chemical site of oxygen binding. Across vertebrates, the globin gene family shows evolutionary diversification that underpins different oxygen transport needs and developmental stages. For deeper context on protein families, see globin.

The heme prosthetic group

Each globin chain binds a single heme group, which contains an iron ion that reversibly binds O2. In addition to oxygen binding, the iron can bind carbon monoxide and cyanide with high affinity, which explains the severe toxicity of these gases when inhaled. The heme group links directly to the protein, and the surrounding protein environment modulates the iron’s affinity for oxygen and its susceptibility to oxidation. For more on the chemistry of the iron-containing nonprotein component, see heme.

Oxygen affinity and regulation

Hemoglobin’s oxygen affinity is not fixed; it shifts in response to physiological conditions. The presence of 2,3-BPG inside red blood cells lowers Hb’s affinity for oxygen, favoring release in tissues that require oxygen. Temperature and pH also influence binding, aiding adaptation to varying metabolic states. The interplay between loading in the lungs and unloading in tissues is a central feature of vertebrate physiology and is a classic topic in studies of Oxygen transport.

Genetic variation and development

Globin gene clusters and developmental switching

The genes encoding the globin chains are organized in clusters that reflect their expression patterns over development. Adult HbA consists of α-globin and β-globin gene products, whereas fetal Hb (HbF) uses γ-globin in place of β-globin, giving HbF different oxygen-binding properties and contributing to efficient oxygen transfer from mother to fetus. A small fraction of HbA2—an α2δ2 form—occurs in normal adults as well. The regulation of these genes involves a combination of transcription factors and chromatin modifiers, illustrating how genetics shapes physiology from early life onward.

Evolutionary considerations

Hemoglobin variants have arisen over millions of years and show regional and population-level variation. Some variants alter oxygen affinity or stability in particular environments, which can influence susceptibility to certain diseases or environmental challenges. The study of these variants intersects with broader topics in genetics, population biology, and medicine, including how chromosomes and gene regulation shape protein function.

Pathology and clinical significance

Sickle cell disease

A well-known variant, HbS, results from a single amino acid substitution in the β-globin chain. Under low-oxygen conditions, HbS tends to polymerize, distorting red blood cells into a sickled shape. These abnormally shaped cells can block small vessels, cause pain crises, and lead to organ damage over time. Treatments aim to reduce crises, increase fetal hemoglobin to counterbalance HbS, or cure disease through gene therapy in select cases. For a broader discussion of this and related disorders, see sickle cell disease.

Thalassemias

Thalassemias are caused by imbalances in globin chain production, typically leading to anisopoikilocytosis and anemia due to ineffective erythropoiesis and hemolysis. The clinical picture depends on which globin chain is affected and to what degree, but common themes include reduced hemoglobin content, microcytosis, and lifelong management with monitoring and supportive care. See thalassemia for a detailed overview.

Methemoglobinemia and other dyshemoglobinemias

Methemoglobinemia arises when iron in the heme group is oxidized to the Fe3+ state, which cannot bind oxygen efficiently, shifting the oxygen dissociation profile and producing tissue hypoxia despite normal oxygen tension. Other dyshemoglobinemias involve atypical forms of hemoglobin with altered oxygen-binding properties. These conditions illustrate how delicate the balance is between structure and function in the hemoglobin molecule.

Other red cell disorders and treatment implications

A number of additional conditions affect hemoglobin or red blood cell survival, including various hemolytic anemias and polycythemias. Clinically, management often involves addressing the underlying cause, maintaining adequate oxygen delivery to tissues, and ensuring compatibility in transfusion or transplantation settings. See also erythrocyte and blood transfusion for related topics.

Medical applications and research

Transfusion medicine and blood safety

Modern medicine relies on donor blood to treat acute blood loss and chronic anemias. Across donation systems, careful screening, matching of blood groups, and storage protocols help ensure safety and efficacy. The field continually evolves with improvements in storage longevity, pathogen reduction, and compatibility testing.

Oxygen carriers and blood substitutes

Researchers have explored alternatives to donor blood, including hemoglobin-based oxygen carriers (HBOCs) and other synthetic or engineered systems. While such substitutes hold promise for emergencies or military contexts, early experiences highlighted safety concerns, including vascular effects and oxidative stress. Ongoing research seeks to balance oxygen delivery with biocompatibility and regulatory approval.

Gene therapy and biotechnology

Advances in gene-editing and gene-regulatory approaches aim to correct or compensate for globin-related disorders. Strategies include reactivating fetal Hb production in adults or correcting pathogenic mutations in β-globin genes. These areas illustrate how molecular biology translates into potential therapies for diseases like sickle cell disease and thalassemias.