Hemoglobin is the complex protein within red blood cells responsible for transporting oxygen from the lungs to the body’s tissues and carrying carbon dioxide back. This molecule is a tetramer, composed of four subunits, each containing a protein chain called globin and a non-protein component called heme. The heme portion contains an iron atom and is the actual site where oxygen binds and unbinds. The production of this molecule involves a multi-step biochemical process that ensures the correct structure is assembled efficiently.
Cellular Location of Production
Hemoglobin synthesis occurs almost exclusively within developing red blood cells, known as erythroid precursor cells. In adults, this production process, called erythropoiesis, takes place primarily in the red bone marrow (vertebrae, ribs, breastbone, and pelvis). These precursor cells start with a nucleus but gradually lose it as they mature, a process completed before they enter the bloodstream.
Assembly within the cell is divided between the mitochondria and the cytosol. Heme synthesis begins and ends inside the mitochondria, with intermediate steps occurring in the cytosol. Globin protein chains are synthesized entirely in the cytosol by ribosomes. This compartmentalization allows both components to be manufactured simultaneously and brought together for final assembly.
Building the Heme Group
The heme group forms a flat protoporphyrin IX ring, which incorporates a single iron atom. Its creation requires eight enzymatic steps, starting with the amino acid glycine and succinyl coenzyme A (succinyl CoA). This initial step occurs inside the mitochondrion, where ALA synthase catalyzes the condensation of these two molecules to form \(\delta\)-aminolevulinic acid (ALA). This reaction is a primary point of control for the entire pathway in erythroid cells.
The ALA molecule moves into the cytosol, where four subsequent enzymatic reactions occur. These steps involve the condensation of multiple precursor molecules to build the tetrapyrrole ring. The partially formed ring then returns to the mitochondrion for the final three steps of the pathway.
The final step involves the insertion of a ferrous iron ion (\(\text{Fe}^{2+}\)) into the center of the protoporphyrin IX ring. This reaction is catalyzed by the enzyme ferrochelatase, located on the inner mitochondrial membrane. The resulting iron-containing protoporphyrin ring is the finished heme molecule.
Building the Globin Chains
The globin chains are the protein component of hemoglobin. Adult hemoglobin (HbA) is primarily composed of two alpha (\(\alpha\)) and two beta (\(\beta\)) globin chains. Genes encoding alpha-like chains are on chromosome 16, while genes for beta-like chains (including beta, gamma, and delta) are on chromosome 11.
The process begins in the cell nucleus with transcription, copying the DNA sequence for the globin chain into messenger RNA (mRNA). This precursor mRNA undergoes processing, where non-coding sections are removed and coding segments are joined to create a mature mRNA molecule. The mature mRNA then migrates out of the nucleus into the cytosol.
In the cytosol, ribosomes translate the mRNA code, assembling amino acids sequentially in a process called translation to form the complete globin polypeptide chain. Different combinations of these chains are produced at various stages of life. For example, fetal hemoglobin (HbF) uses two alpha and two gamma chains, providing the higher oxygen affinity necessary for oxygen transfer in the womb.
Control and Adjustment of Production Rate
The body maintains balance in hemoglobin production to prevent the accumulation of toxic, free components. Regulation is achieved through a coordinated system that links iron availability and the overall demand for red blood cells. The primary hormone stimulating red blood cell production is erythropoietin (EPO), which is largely produced by the kidneys in response to low tissue oxygen levels.
EPO travels to the bone marrow, stimulating the proliferation and differentiation of erythroid precursor cells. Iron availability is also managed, as it is the most consumed element in erythropoiesis. When red blood cell demand is high, erythroid cells in the bone marrow secrete erythroferrone (ERFE).
Erythroferrone suppresses the liver hormone hepcidin, which normally limits iron absorption and release from storage sites. By suppressing hepcidin, ERFE increases the supply of iron available for incorporation into the heme groups. This coordinated system prevents the unbalanced production of globin chains without enough heme, or vice versa, which could lead to cellular damage.
Clinical Implications of Errors
Disruptions in the synthesis pathway can lead to a variety of hematological disorders. The most common nutritional issue is iron deficiency, which restricts the iron available for heme formation, leading to reduced hemoglobin levels and anemia.
Genetic defects in globin chain production lead to thalassemias. These conditions result from mutations or deletions in the genes on chromosome 16 or 11, causing reduced or absent production of alpha or beta globin chains. The resulting imbalance causes the excess, unmatched chains to precipitate inside the red cell precursors.
Errors in the heme synthesis pathway result in a group of disorders called porphyrias. Depending on the enzyme affected, various heme precursors accumulate in the body, which can be toxic and lead to neurological dysfunction or severe photosensitivity. For example, a ferrochelatase deficiency results in the accumulation of protoporphyrin, causing erythropoietic protoporphyria.