Heme is a porphyrin, in the center of the molecule of which there are iron ions Fe2+, which are included in the structure by two covalent and two coordination bonds. Porphyrins are a system of four fused pyrroles having methylene compounds (-CH=).
The heme molecule has a flat structure. The oxidation process converts heme into hematin, designated Fe3+.
Using gems
Heme is a prostatic group of not only hemoglobin and its derivatives, but also myoglobin, catalase, peroxidase, cytochromes, the tryptophan pyrollase enzyme, which catalyzes the oxidation of troptophan to formylkynurenine. There are three leaders in gemma content:
- erythrocytes, consisting of hemoglobin;
- muscle cells that have myoglobin;
- liver cells with cytochrome P450.
Depending on the function of cells, the type of protein changes, as well as porphyrin in the heme. Hemoglobin heme includes protoporphyrin IX, and cytochrome oxidase contains formylporphyrin.
How is heme formed?
Protein production occurs in all tissues of the body, but the most productive heme synthesis occurs in two organs:
- bone marrow produces a non-protein component for the production of hemoglobin;
- hepatocytes produce raw materials for cytochrome P450.
In the mitochondrial matrix, the pyridoxal-dependent enzyme aminolevulinate synthase is a catalyst for the formation of 5-aminolevulinic acid (5-ALA). At this stage, glycine and sucinyl-CoA, a product of the Krebs cycle, are involved in the synthesis of heme. Heme inhibits this reaction. Iron, on the contrary, triggers the reaction in reticulocytes with the help of a binding protein. With a lack of pyridoxal phosphate, the activity of aminolevulinate synthase decreases. Corticosteroids, non-steroidal anti-inflammatory drugs, barbiturates and sulfonamides are stimulants of aminolevulinate synthase. The reactions are caused by an increase in the consumption of heme by cytochrome P450 for the production of this substance by the liver.
5-aminolevulinic acid, or porphobilinogen synthase, enters the cytoplasm from mitochondria. This cytoplasmic enzyme contains, in addition to the porphobilinogen molecule, two more molecules of 5-aminolevulinic acid. During heme synthesis, the reaction is inhibited by heme and lead ions. That is why an increased level in the urine and blood of 5-aminolevulinic acid means lead poisoning.
Deamination of four molecules of porphybilinogen from porphobilinogen deaminase to hydroxymethylbilane occurs in the cytoplasm. Further, the molecule can turn into upoporphyrinogen I and decarboxylate into coproporphyrinogen I. Uroporphyrinogen III is obtained in the process of dehydration of hydroxymethylbilane using the cosynthase enzyme of thismolecules.
Decarboxylation of uroporphyrinogen to coproporphyrinogen III continues in the cytoplasm for further return to the mitochondria of cells. At the same time, coproporphyrinogen III oxidase decarboxylates molecules of protoporphyrinogen IV (+ O2, -2CO2) by further oxidation (-6H+) to protoporphyrin V with the help of protoporphyrin oxidase. The incorporation of Fe2+ at the last stage of the ferrochelatase enzyme into the protoporphyrin V molecule completes the heme synthesis. Iron comes from ferritin.
Features of hemoglobin synthesis
The production of hemoglobin is the production of heme and globin:
- heme refers to a prosthetic group that mediates the reversible binding of oxygen to hemoglobin;
- globin is a protein that surrounds and protects the heme molecule.
In heme synthesis, the enzyme ferrochelatase adds iron to the ring of the protoporphyrin IX structure to produce heme, low levels of which are associated with anemia. Iron deficiency, as the most common cause of anemia, reduces heme production and again reduces the level of hemoglobin in the blood.
A number of drugs and toxins directly block heme synthesis, preventing enzymes from participating in its biosynthesis. Drug inhibition of synthesis is common in children.
Globin formation
Two different globin chains (each with its own heme molecule) combine to form hemoglobin. In the very first week of embryogenesis, the alpha chain combines with the gamma chain. After the birth of the child, the mergeroccurs with the beta chain. It is the combination of two alpha chains and two others that makes up the complete hemoglobin molecule.
The combination of alpha and gamma chains forms fetal hemoglobin. The combination of two alpha and two beta chains gives "adult" hemoglobin, which prevails in the blood for 18-24 weeks from birth.
The connection of two chains forms a dimer - a structure that does not effectively transport oxygen. The two dimers form a tetramer, which is the functional form of hemoglobin. A complex of biophysical characteristics controls the absorption of oxygen by the lungs and its release in tissues.
Genetic mechanisms
Genes encoding alpha globin chains are located on chromosome 16, and not alpha chains - on chromosome 11. Accordingly, they are called "alpha globin locus" and "beta globin locus". The expressions of the two groups of genes are closely balanced for normal erythrocyte function. Imbalance leads to the development of thalassemia.
Each chromosome 16 has two alpha globin genes that are identical. Since each cell has two chromosomes, four of these genes are normally present. Each produces one quarter of the globin alpha chains required for hemoglobin synthesis.
Genes of the beta-globin locus of the locus are located sequentially, starting from the site active during embryonic development. The sequence is as follows: epsilon gamma, delta and beta. There are two copies of the gamma geneeach chromosome 11, and the rest are present in single copies. Each cell has two beta globin genes, expressing an amount of protein that exactly matches each of the four alpha globin genes.
Hemoglobin transformations
Mechanism of balancing at the genetic level is still not known to medicine. A significant amount of fetal hemoglobin is stored in the body of the child for 7 - 8 months after birth. Most people have only trace amounts, if any, of fetal hemoglobin after infancy.
The combination of two alpha and beta genes produces normal adult hemoglobin A. The delta gene, located between gamma and beta on chromosome 11, produces a small amount of delta globin in children and adults - hemoglobin A2, which is less than 3% squirrel.
ALK ratio
The rate of heme formation is affected by the formation of aminolevulinic acid, or ALA. The synthase that starts this process is regulated in two ways:
- allosterically with the help of effector enzymes that are produced during the reaction itself;
- at the genetic level of enzyme production.
The synthesis of heme and hemoglobin inhibits the production of aminolivulinate synthase, forming a negative feedback. Steroid hormones, non-steroidal anti-inflammatory drugs, antibiotics sulfonamides stimulate the production of synthase. Against the background of taking drugs, the uptake of heme in the cytochrome P450 system, which is important for the production of these compounds by the liver, increases.
Heme production factors
Onregulation of heme synthesis through the level of ALA synthase is reflected by other factors. Glucose slows down the process of ALA synthase activity. The amount of iron in the cell affects the synthesis at the level of translation.
MRNA has a hairpin loop at the translation start site - an iron-sensitive element. A decrease in the level of iron synthesis stops, at a high level, the protein interacts with a complex of iron, cysteine and inorganic sulfur, which achieves a balance between the production of heme and ALA.
Synthesis disorders
Violation in the process of heme synthesis of biochemistry is expressed in a deficiency of one of the enzymes. The result is the development of porphyria. The hereditary form of the disease is associated with genetic disorders, while the acquired form develops under the influence of toxic drugs and s alts of heavy metals.
Enzyme deficiencies are manifested in the liver or erythrocytes, which affects the definition of the group of porphyria - hepatic or erythropoietic. The disease can occur in acute or chronic forms.
Disturbances in heme synthesis are associated with the accumulation of intermediate products - porphyrinogens, which are oxidized. The place of accumulation depends on localization - in erythrocytes or hepatocytes. The level of accumulation of products is used to diagnose porphyria.
Toxic porphyrinogens can cause:
- neuropsychiatric disorders;
- skin lesions due to photosensitivity;
- disruption of the reticuloendothelial system of the liver.
Urine turns purple with excess porphyrinsshade. An excess of aminolevulinate synthase under the influence of drugs or the production of steroid hormones during adolescence can cause an exacerbation of the disease.
Porphyria species
Acute intermittent porphyria is associated with a defect in the gene that codes for deaminase and leads to the accumulation of 5-ALA and porphobilinogen. Symptoms are dark urine, paresis of the respiratory muscles, heart failure. The patient complains of abdominal pain, constipation, vomiting. The disease can be caused by taking analgesics and antibiotics.
Congenital erythropoietic porphyria is associated with low uroporphyrinogen-III-cosynthase activity and high levels of uroporphyrinogen-I-synthase. Symptoms are photosensitivity, which is manifested by cracks in the skin, bruising.
Hereditary coproporphyria is associated with a lack of coproporphyrinogen oxidase, which is involved in the conversion of coproporphyrinogen III. As a result, the enzyme is oxidized in the light to coproporphyrin. Patients suffer from heart failure and photosensitivity.
Mosaic porphyria is a disorder in which there is a partial blockage of the enzymatic conversion of protoporphyrinogen to heme. Signs are urine fluorescence and sensitivity to light.
Tardor cutaneous porphyria appears with liver damage on the background of alcoholism and excess iron. Large concentrations of type I and III uroporphyrins are excreted in the urine, giving it a pinkish color and causing fluorescence.
Erythropoietic protoporphyria is provoked by lowferrochelatase enzyme activity in mitochondria, a source of iron for heme synthesis. Symptoms are acute urticaria under the influence of ultraviolet radiation. High levels of protoporphyrin IX appear in erythrocytes, blood and feces. Immature red blood cells and skin often fluoresce with red light.
