Heme is a molecule containing iron within a ring-shaped structure called a porphyrin. It is a component of various proteins that perform diverse functions in the body. For example, heme is part of hemoglobin, the protein in red blood cells responsible for transporting oxygen from the lungs to tissues throughout the body.
Heme is also found in cytochromes, which are proteins involved in the electron transport chain, a process that generates energy within cells. Beyond oxygen transport and energy production, heme plays roles in detoxification, gas sensing, and cellular processes like differentiation and proliferation.
How Heme is Made
The body produces heme through a multi-step biochemical pathway, often referred to as the porphyrin synthesis pathway or heme biosynthetic pathway. This process involves a series of enzymatic reactions. The synthesis begins in the mitochondria, then moves to the cytoplasm, and concludes back in the mitochondria.
The initial step of heme synthesis occurs in the mitochondria, where the amino acid glycine combines with succinyl CoA, a molecule derived from the citric acid cycle. This condensation reaction, catalyzed by the enzyme delta-aminolevulinate synthase (ALA synthase), forms 5-aminolevulinic acid (ALA). The ALA then moves out of the mitochondria into the cytoplasm.
In the cytoplasm, two molecules of ALA condense to form porphobilinogen (PBG), a pyrrole ring compound, in a reaction catalyzed by ALA dehydratase. Four molecules of PBG then combine to form a linear molecule called hydroxymethylbilane. This linear structure is then cyclized and modified through several more enzymatic steps in the cytoplasm, leading to the formation of coproporphyrinogen III.
Coproporphyrinogen III then re-enters the mitochondria. Inside the mitochondria, further enzymatic reactions transform coproporphyrinogen III into protoporphyrin IX. The final step in heme synthesis involves the insertion of a ferrous iron ion (Fe2+) into the center of the protoporphyrin IX molecule. This insertion is catalyzed by the enzyme ferrochelatase, resulting in the completed heme molecule.
Controlling Heme Production
The body maintains tight control over heme production to ensure proper levels, preventing both scarcity and overabundance. This regulation is important to avoid the accumulation of intermediate compounds, which can be toxic if present in excess. A primary regulatory point in the heme synthesis pathway is the enzyme delta-aminolevulinate synthase (ALA synthase), which catalyzes the first committed step of heme biosynthesis.
Heme itself acts as a feedback inhibitor of ALA synthase activity. When heme levels are sufficient, heme inhibits ALA synthase, slowing its production. This enzyme’s activity is regulated at multiple levels, including its synthesis in the cytoplasm, its transport into the mitochondria, and its stability.
Other factors also influence heme synthesis. The availability of iron is an important consideration, as iron is incorporated in the final step of heme formation. In erythroid cells, where hemoglobin is produced, heme synthesis is coordinated with the production of globin chains. If heme is not available, globin synthesis can be halted.
Problems with Heme Synthesis
Malfunctions in the heme synthesis pathway can lead to a group of genetic disorders known as porphyrias. These conditions arise from deficiencies in specific enzymes within the pathway, causing intermediate compounds, called porphyrin precursors, to accumulate in the body. The type of porphyria and its characteristic symptoms depend on which enzyme is deficient and which intermediate compounds build up.
Porphyrias often present with neurological problems, which can include severe abdominal pain, nausea, vomiting, psychiatric disturbances like delusion or hallucination, and even seizures. Some porphyrias also cause skin sensitivity to light, known as photosensitivity, leading to blistering rashes, swelling, burning, and itching in sun-exposed areas. The urine of affected individuals may also change color, sometimes turning red or “port wine” colored upon standing.
For example, acute intermittent porphyria (AIP) is linked to a deficiency in porphobilinogen deaminase, resulting in the accumulation of ALA and porphobilinogen. Porphyria cutanea tarda (PCT), the most common type, is associated with a deficiency in uroporphyrinogen decarboxylase, leading to the buildup of uroporphyrin. Most porphyrias are inherited, although some, like porphyria cutanea tarda, can be acquired.
Beyond genetic factors, environmental influences can also disrupt heme synthesis. Lead poisoning, for instance, can inhibit certain enzymes in the pathway, specifically ALA dehydratase and ferrochelatase, by interfering with their zinc cofactors. This inhibition leads to an accumulation of ALA and some protoporphyrin IX, causing symptoms such as abdominal pain, vomiting, fatigue, irritability, and developmental disabilities, particularly in children.