Role of heme and localization of the process
Heme biosynthesis occurs in absolutely all cells of our body, as heme is essential for the function of cellular respiratory chain enzymes and antioxidant defense. However, this process is most active in two tissues:
- In the liver — here, heme is massively consumed for the production of cytochromes.
- In the bone marrow — in erythroid cells, heme is synthesized for incorporation into hemoglobin molecules.
The process of creating a heme molecule is compartmentalized: it is strictly divided between cell organelles. The initial stages take place in the mitochondrial matrix, then intermediate metabolites move into the cytoplasm to form a complex ring structure, and the final stage returns to the mitochondria. Simple precursors are required to assemble a complete molecule: the amino acid glycine, succinyl-CoA, and iron ions (Fe²⁺).
Stages of heme biosynthesis
Heme synthesis is a multi-step cascade of reactions. It can be roughly divided into three key stages depending on intracellular localization.
Stage I: Starting in the mitochondria The process begins in the mitochondrial matrix with the condensation of glycine and succinyl-CoA. This reaction is catalyzed by the pyridoxal-dependent enzyme 5-aminolevulinate synthase. Pyridoxal phosphate (a vitamin B6 derivative) acts as a cofactor. The reaction yields carbon dioxide and coenzyme A as byproducts, with 5-aminolevulinic acid (5-ALA) as the main product.
Stage II: Transformations in the cytoplasm The resulting 5-ALA leaves the mitochondria and enters the cytosol. Here, the enzyme 5-aminolevulinate dehydratase comes into play. It combines two molecules of 5-ALA, cleaving off water, and forms a cyclic compound — porphobilinogen. This is followed by a linear sequence of transformations in which porphyrinogens are assembled from four porphobilinogen molecules:
- Hydroxymethylbilane.
- Uroporphyrinogen III.
- Coproporphyrinogen III.
- Protoporphyrinogen IX.
The cytoplasmic stage concludes with the formation of protoporphyrin IX, which is sent back to the mitochondria.
Stage III: Finale in the mitochondria The final stage of assembly takes place in the mitochondrial matrix. The enzyme ferrochelatase inserts a ferrous iron ion (Fe²⁺) into the protoporphyrin IX ring. This results in the formation of a ready heme molecule.
Mechanisms of synthesis regulation
Heme biosynthesis is tightly controlled by the cell via negative feedback and enzymatic induction mechanisms. This prevents both deficiency and toxic excess of porphyrins.
Negative feedback (Inhibition): The pathway end product — heme itself — acts as an allosteric inhibitor. It suppresses the activity of the first two key enzymes of the cascade: 5-aminolevulinate synthase and 5-aminolevulinate dehydratase.
Stimulation (Induction):
- Iron ions (Fe²⁺) in reticulocytes act as a potent inducer, stimulating the synthesis of the main enzyme — 5-aminolevulinate synthase.
- Heme as a coordinator: It induces the translation of α- and β-polypeptide globin chains. This synchronizes the production of the protein part (globin) and the prosthetic group (heme) for hemoglobin assembly.
- Exogenous inducers: A number of medications and hormones (barbiturates, diclofenac, sulfonamides, estrogens, and progestins) can increase heme production by inducing the synthesis of 5-aminolevulinate synthase.
Briefly: answers to topical questions
What diseases occur due to hereditary defects in heme biosynthesis enzymes?
Hereditary defects in heme biosynthesis enzymes lead to primary (hereditary) porphyrias — disorders caused by genetic defects in heme biosynthesis enzymes.
Hereditary porphyrias listed in sources include:
- acute intermittent porphyria;
- congenital erythropoietic porphyria;
- hereditary coproporphyria.
For acute porphyrias, it is noted that patients have a congenital gene defect in one of the heme biosynthesis enzymes. The overwhelming majority of acute porphyrias are inherited in an autosomal dominant manner with incomplete penetrance. An extremely rare form — ALA dehydratase deficiency — is inherited in an autosomal recessive manner. In most mutation carriers, acute porphyrias are asymptomatic, and manifestation as an acute attack occurs upon exposure to specific triggers.
How does heme degradation occur in reticuloendothelial system macrophages?
Heme degradation in bone marrow and spleen macrophages proceeds in two consecutive stages.
- Heme oxygenase reaction — under the influence of the enzyme heme oxygenase, heme is first converted into verdoglobin, after which the green pigment biliverdin is formed. The byproducts of this reaction are iron ions ($Fe^{3+}$) and carbon monoxide (CO).
- Biliverdin reductase reaction — the enzyme biliverdin reductase, with the participation of NADPH and $H^+$, reduces biliverdin to the yellow-red pigment — unconjugated (free) bilirubin.
Subsequently, unconjugated bilirubin binds to albumin for transport via the blood to the liver.
To memorize the localization of heme biosynthesis stages, use the abbreviation "MCP": Mitochondria (start) — Cytoplasm (middle) — Mitochondria (finale).
Class and exam questions
Which vitamins are essential for normal heme biosynthesis?
Pyridoxal phosphate is a required cofactor for the first reaction of synthesis. This is a derivative of vitamin B6, without which the enzyme 5-aminolevulinate synthase cannot function.
In what form is iron incorporated into heme?
Iron is incorporated into the protoporphyrin IX molecule strictly in the ferrous form (Fe²⁺). This reaction is carried out by the enzyme ferrochelatase at the final stage in the mitochondria.
How does heme affect the formation of the protein part of hemoglobin?
Heme acts as an inducer of globin synthesis. It stimulates the translation of α- and β-polypeptide chains, ensuring precise coordination between the formation of the protein and non-protein parts of hemoglobin.
What else to study on this topic
- Structural formulas of intermediate porphyrinogens
- Mechanism of allosteric inhibition of 5-aminolevulinate synthase
- Specifics of heme biosynthesis in bone marrow reticulocytes
- Molecular mechanisms of enzyme induction by barbiturates and estrogens
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