Heme is a fundamental molecule containing iron, best known for giving blood its characteristic red color. The production of this molecule is a precise, multi-step biological process that occurs within the body’s cells. Its creation is essential for a variety of life-sustaining functions.
The Step-by-Step Assembly of Heme
The synthesis of heme is an eight-step process that can be visualized as a cellular assembly line. It begins inside the mitochondria, moves to the cytoplasm, and then returns to the mitochondria for completion. In the mitochondria, the amino acid glycine and a molecule called succinyl-CoA are combined.
This initial reaction is performed by an enzyme named ALA synthase and is the committed step of the pathway; once it occurs, the cell is dedicated to completing the process. The newly formed molecule, aminolevulinic acid (ALA), then travels out of the mitochondrion into the cell’s main fluid-filled space, the cytosol.
In the cytosol, two ALA molecules are first combined to create a compound called porphobilinogen (PBG). Four of these PBG molecules are then linked together and cyclized to form a ring structure called uroporphyrinogen III. This intermediate is subsequently modified in successive steps, which involve altering the side chains attached to the ring.
For the final stages of production, the maturing molecule is transported back into the mitochondrion. Inside, a couple more enzymatic reactions prepare the molecule to receive its final, defining component. The process culminates when the enzyme ferrochelatase inserts a single atom of ferrous iron into the center of the ring structure, completing the formation of heme.
Essential Roles of Heme in the Body
The primary function of heme is in oxygen transport. As a component of hemoglobin within red blood cells, heme binds to oxygen in the lungs and carries it to tissues throughout the body. A similar molecule, myoglobin, uses heme to store oxygen within muscle cells, providing a ready supply for periods of high activity. About 70% to 80% of all heme synthesis in the body occurs in the bone marrow to produce hemoglobin for new red blood cells.
Beyond its role in moving oxygen, heme is a part of proteins called cytochromes. In the mitochondria, cytochromes are part of the electron transport chain, a system that generates ATP, the main energy currency of the cell. This process, known as cellular respiration, depends on the unique properties of the iron atom held by heme.
Heme also plays a part in detoxification processes, primarily in the liver. A specific family of cytochromes, known as the cytochrome P450 enzymes, break down a wide variety of substances, including metabolic byproducts, pollutants, and drugs. These enzymes utilize heme to facilitate chemical reactions that render potentially harmful compounds water-soluble, allowing them to be excreted. The liver accounts for a significant portion of the body’s remaining heme production for this purpose.
Regulating Heme Production
The body maintains a careful balance of heme through a responsive control system, ensuring production matches demand. This regulation is primarily achieved through a mechanism known as negative feedback inhibition, where the final product of the pathway controls its own starting point. This system is particularly active in the liver, where heme demand can fluctuate.
When the concentration of heme within a cell rises to a sufficient level, the heme molecules themselves act as signals to slow down the production line. They do this by directly inhibiting the activity of ALA synthase, the first enzyme in the biosynthetic pathway. By blocking this initial step, the entire sequence is halted, preventing the synthesis of more heme.
This feedback loop is highly sensitive and efficient. If the cell uses up its heme supply, for instance by producing more cytochrome P450 enzymes to metabolize a drug, the inhibition on ALA synthase is lifted. The decreased concentration of free heme allows the enzyme to become active again, restarting the synthesis pathway to replenish the cell’s supply.
Disorders of Heme Synthesis
When the heme synthesis pathway is disrupted, a group of genetic disorders known as the porphyrias can arise. These conditions are caused by inherited deficiencies in the enzymes responsible for carrying out the eight steps of heme production. Each type of porphyria corresponds to a defect in a specific enzyme.
A deficiency in a particular enzyme creates a bottleneck in the pathway. While the steps before the faulty enzyme proceed normally, the intermediate substance that the deficient enzyme acts on cannot be properly processed. This leads to an accumulation of that specific precursor molecule, called a porphyrinogen, within the body’s tissues and fluids.
The buildup of these intermediate molecules is toxic and gives rise to the symptoms of the porphyrias. Depending on which precursor accumulates, the symptoms can vary significantly. Some intermediates cause severe neurological problems, including pain and psychiatric symptoms, while others lead to extreme photosensitivity, where sunlight causes painful and blistering skin lesions. The urine may also appear unusually dark or reddish in color due to the excretion of these excess porphyrin precursors.