The heme molecule is an iron-containing prosthetic group necessary for organisms that utilize oxygen. This structure acts as a cofactor, a non-protein compound bound to a protein required for biological activity. The incorporation of iron gives heme the ability to interact with gases and facilitate electron transfer. The body tightly regulates the creation, utilization, and breakdown of heme to maintain cellular health and function.
The Molecular Architecture of Heme
The structure of the heme molecule (Heme B) is a chemical complex built from two primary components. At its center lies an iron ion, the functional core of the molecule, held securely within a large organic ring structure known as protoporphyrin IX. The protoporphyrin ring is a planar macrocycle composed of four linked pyrrole rings. These rings provide nitrogen atoms that form a tight cage around the central iron ion, creating a coordination complex.
These nitrogen atoms form four of the iron’s six potential coordination bonds. The two remaining coordination sites, called axial positions, are perpendicular to the ring’s plane. These sites are where the iron binds to amino acid residues or small molecules like oxygen. The versatility of heme is tied to the iron’s ability to switch between the ferrous (\(\text{Fe}^{2+}\)) and ferric (\(\text{Fe}^{3+}\)) oxidation states. The ferrous state is associated with the reversible binding of gases, while the transition between states enables electron transfer reactions.
Diverse Biological Roles
Heme serves as a versatile prosthetic group for hemoproteins, supporting diverse functions across the body. One recognized role is in gas transport and storage, primarily within the circulatory and muscular systems. In the blood, four heme groups are incorporated into hemoglobin, where the iron atom reversibly binds to oxygen in the lungs for delivery to distant tissues. In muscle tissue, a single heme group is found within myoglobin, which stores oxygen until needed during high muscular activity. The presence of heme in these proteins allows them to efficiently pick up, hold, and release oxygen. The surrounding protein structure finely tunes the iron’s affinity for oxygen, ensuring proper function in its specific environment.
Heme also plays a role in the body’s energy production through electron transfer. It is a component of cytochromes, which are integral to the electron transport chain located in the mitochondria. Here, the iron atom cycles between its ferrous (\(\text{Fe}^{2+}\)) and ferric (\(\text{Fe}^{3+}\)) states, acting as an electron carrier. This cycling facilitates the movement of electrons, which is harnessed to generate adenosine triphosphate (ATP).
Beyond these roles, heme is a cofactor for enzymes like catalases and cytochrome P450 enzymes. Catalases use heme to break down hydrogen peroxide, a reactive oxygen species, into water and oxygen. Cytochrome P450 enzymes, found predominantly in the liver, utilize heme to carry out oxidation reactions necessary for detoxifying foreign compounds and metabolizing various drugs.
The Heme Life Cycle
The body maintains a constant supply of heme through a controlled metabolic pathway involving synthesis and degradation. Heme synthesis begins with the precursors succinyl-CoA and glycine, which are converted through eight enzymatic steps. This process occurs partly in the mitochondria and partly in the cytoplasm, primarily in the bone marrow and the liver.
The first step, the formation of \(\text{delta-aminolevulinate}\), is catalyzed by \(\text{ALA}\) synthase and is considered the rate-limiting step. The activity of this enzyme is regulated by heme itself, which acts as a negative feedback signal to maintain balance. Once the protoporphyrin ring is formed, the final step is the insertion of the ferrous iron (\(\text{Fe}^{2+}\)) into the ring, catalyzed by the enzyme ferrochelatase.
The life cycle concludes with the degradation of old heme, primarily released from red blood cells after their 120-day lifespan. This breakdown occurs largely within macrophages of the reticuloendothelial system, such as those found in the spleen. The enzyme heme oxygenase cleaves the protoporphyrin ring, releasing the iron for recycling and converting the structure into biliverdin, a green pigment. Biliverdin is then reduced by biliverdin reductase to form bilirubin, a yellow-orange pigment. Bilirubin is transported through the bloodstream bound to serum albumin because it is not water-soluble. In the liver, bilirubin is conjugated to make it water-soluble so it can be excreted in the bile and eliminated from the body in the feces.
When Heme Goes Wrong
Failures in the regulated heme life cycle lead to clinical conditions resulting from the accumulation of metabolic intermediates. Disorders affecting the synthesis pathway are collectively known as Porphyrias, which are inherited genetic conditions caused by defects in one of the eight enzymes. The specific enzyme deficiency determines which toxic precursor molecule accumulates in the body.
Porphyrias are categorized by their primary symptoms, which can be neuro-visceral (severe abdominal pain and neurological issues) or cutaneous (extreme photosensitivity). For example, a defect in \(\text{hydroxymethylbilane}\) synthase leads to Acute Intermittent Porphyria, characterized by acute neurological attacks. The accumulation of light-reactive porphyrin precursors in the skin causes the severe blistering and scarring seen in cutaneous forms.
Issues with the degradation pathway, specifically bilirubin processing, lead to jaundice. Jaundice is a yellow discoloration of the skin and eyes caused by an excessive buildup of bilirubin in the blood. This occurs when the liver cannot clear bilirubin efficiently, due to overproduction, an inability to conjugate it, or a blockage preventing its excretion into the bile.