Porphyrins are organic compounds foundational for many biological functions. These molecules are characterized by a large cyclic structure composed of four smaller rings called pyrroles. Their most recognized role is forming heme, the iron-containing component of hemoglobin that transports oxygen throughout the body. Porphyrins are also part of cytochromes, proteins involved in the electron transport chain that generates cellular energy.
Cellular Location of Synthesis
The production of porphyrins is a notable process because it does not occur in a single cellular location. The synthesis pathway is split between two compartments within the cell: the mitochondria and the cytoplasm. This division of labor is an important feature of heme production, with the journey beginning inside the mitochondria before moving to the cytoplasm for intermediate steps.
The initial and final three steps of porphyrin synthesis take place in the mitochondria, while the intermediate reactions happen in the cytoplasm. This movement of molecules between compartments is like a factory’s assembly line that moves between specialized rooms. This shuttle system ensures that each stage of the process occurs in the optimal environment with access to the necessary enzymes.
The transport of these intermediate molecules across the mitochondrial membrane is a complex process. The first molecule, aminolevulinic acid (ALA), is exported from the mitochondria into the cytoplasm. Later in the pathway, another intermediate, coproporphyrinogen III, must be transported back into the mitochondria to complete the synthesis of heme.
The Step-by-Step Synthesis Process
The creation of a porphyrin is an eight-step enzymatic process that begins in the mitochondria. The pathway’s starting materials are the amino acid glycine and succinyl-CoA, an intermediate from the citric acid cycle. These two molecules are condensed by the enzyme ALA synthase to form the first intermediate, aminolevulinic acid (ALA).
Once synthesized, ALA is transported out of the mitochondria and into the cytoplasm. Here, two molecules of ALA are joined by the enzyme ALA dehydratase to form a pyrrole compound called porphobilinogen (PBG). This enzyme contains zinc and is sensitive to inhibition by heavy metals like lead.
Four molecules of PBG are then linked into a linear chain by the enzyme porphobilinogen deaminase, creating a molecule called hydroxymethylbilane. This linear molecule is then circularized by the enzyme uroporphyrinogen III synthase to form an asymmetric ring structure known as uroporphyrinogen III.
With the ring structure formed in the cytoplasm, further modifications occur. The enzyme uroporphyrinogen decarboxylase modifies the side chains of the uroporphyrinogen III molecule, creating coproporphyrinogen III. This intermediate is then transported back into the mitochondria for the final stages of synthesis. Inside the mitochondria, another enzyme, coproporphyrinogen oxidase, modifies it to form protoporphyrinogen IX.
The second to last step involves the enzyme protoporphyrinogen oxidase, which converts protoporphyrinogen IX into protoporphyrin IX. This is the direct precursor to heme. The final step is the insertion of an iron atom into the center of the protoporphyrin IX ring, a reaction catalyzed by the enzyme ferrochelatase to form heme.
Regulation of Porphyrin Production
The body controls the porphyrin synthesis pathway to ensure that the production of heme matches cellular needs without creating a surplus of intermediates. The primary control point is the first enzyme in the pathway, ALA synthase. This enzyme’s activity dictates the overall rate of synthesis and is regulated through a mechanism known as negative feedback inhibition.
In this system, the final product, heme, acts as a regulatory signal. When cellular levels of heme are sufficient, it directly inhibits the activity of ALA synthase. This feedback prevents the cell from expending resources to produce more porphyrins when they are not needed. Heme can also reduce the synthesis of the ALA synthase enzyme itself and block its transport into the mitochondria.
If heme levels drop, the inhibition on ALA synthase is lifted, and the pathway increases production to meet the demand. This regulatory loop ensures a balanced supply of heme for the body’s needs.
Clinical Relevance and Porphyrias
When the porphyrin synthesis pathway does not function correctly, it can lead to a group of genetic disorders called the porphyrias. These conditions arise from a deficiency in one of the eight enzymes required for heme synthesis. The specific enzyme that is deficient determines the type of porphyria and the symptoms that manifest.
A deficiency in a particular enzyme causes a bottleneck in the metabolic assembly line. This leads to the accumulation of the specific porphyrin precursor that comes directly before the non-functional enzyme. These accumulated precursors can be toxic to various tissues in the body, leading to the symptoms associated with these disorders.
The symptoms of porphyrias can be broadly grouped into two main categories. One category involves acute neurological attacks, which can cause severe abdominal pain, psychiatric symptoms, and other nervous system dysfunctions. The other major category is cutaneous photosensitivity, where the buildup of certain porphyrin precursors in the skin leads to extreme sensitivity to sunlight, causing painful blisters and swelling.