Hem is porphyrin, in the center of the molecule which contains iron ions Fe2 +, which enter the structure through two covalent and two coordination bonds. Porphyrins are a system of four condensed pyrroles having methylene compounds (-CH =).
The heme molecule has a flat structure. The oxidation process turns heme into hematin, referred to as Fe3 +.
Gem use
Hem is a prostatic group not only of hemoglobin and its derivatives, but also of myoglobin, catalase, peroxidase, cytochromes, the enzyme tryptophanpyrollase, which catalyzes the oxidation of tropophan to formylkinurenine. There are three leaders in terms of gem content:
- erythrocytes consisting of hemoglobin;
- muscle cells having myoglobin;
- liver cells with cytochrome P450.
Depending on the function of the cells, the type of protein, as well as the porphyrin in the heme, changes. Hemoglobin heme includes protoporphyrin IX, and formylporphyrin is in the composition of cytochrome oxidase.
How is heme formed?
Protein production occurs in all body tissues, but the most productive synthesis of heme is observed in two organs:
- the bone marrow produces a non-protein component for the production of hemoglobin;
- hepatocytes produce raw materials for cytochrome P450.
In the mitochondrial matrix, the pyridoxaldependent aminolevulinate synthase enzyme 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 heme synthesis. Gem suppresses this reaction. Iron, on the contrary, triggers a reaction in reticulocytes with the help of a binding protein. With a lack of pyridoxalphosphate, the activity of aminolevulin synthase decreases. Corticosteroids, non-steroidal anti-inflammatory drugs, barbiturates and sulfonamides are stimulants of aminolevulinase synthase. The reactions are caused by an increase in heme consumption by cytochrome P450 to produce 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. In heme synthesis, the reaction is suppressed by heme and lead ions. That is why an increased level of 5-aminolevulinic acid in urine and blood means lead poisoning.
In the cytoplasm, four molecules of porphibilinogen are deaminated from porphobilinogen deaminase to hydroxymethyl bilane. Further, the molecule can be converted to upoporphyrinogen I and decarboxylated to coproporphyrinogen I. Uroporphyrinogen III is obtained in the process of dehydration of hydroxymethylbilane with the help of the cosintase enzyme of this molecule.
In the cytoplasm, decarboxylation of uroporphyrinogen to coproporphyrinogen III continues for further return to the mitochondria of cells. In this case, coproporphyrinogen III oxidase decarboxylates the protoporphyrinogen IV (+ O2, -2CO2) molecules by further oxidation (-6H +) to protoporphyrin V with protoporphyrin oxidase. The incorporation of Fe2 + at the last stage of the enzyme ferrochelatase into the protoporphyrin V molecule completes the synthesis of heme. 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 hemoglobin reversible oxygen binding;
- Globin is a protein that surrounds and protects a heme molecule.
In heme synthesis, the ferrochelatase enzyme adds iron to the ring of the protoporphyrin IX structure to produce heme, a low level of which is associated with anemia. Iron deficiency, the most common cause of anemia, reduces heme production and again reduces 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 characteristic of children.
Globin formation
Two different globin chains (each with its own gem 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 baby, the merger occurs with the beta chain. It is a combination of two alpha chains and the other two that make 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 the two chains forms a dimer - a structure that does not transport oxygen effectively. Two dimers form a tetramer, which is a 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 the globin alpha chains are located on chromosome 16, and not the alpha chains on chromosome 11. Accordingly, they are called the alpha globin locus and the beta globin locus. Expressions of two groups of genes are closely balanced for the normal function of red blood cells. Imbalance leads to the development of thalassemia.
Each chromosome 16 has two alpha globin genes that are identical. Since each cell has two chromosomes, then normally four of these genes are present. Each of them produces one quarter of the alpha chains of globin necessary for the synthesis of hemoglobin.
The locus genes of the beta-globin locus are located sequentially, starting from the site that is active during embryonic development. The sequence is as follows: epsilon gamma, delta and beta. There are two copies of the gamma gene for each chromosome 11, and the rest are present in single copies. Each cell has two beta globin genes expressing the amount of protein that exactly matches each of the four alpha globin genes.
Hemoglobin transformation
The balancing mechanism at the genetic level is still not known to medicine. A significant amount of fetal hemoglobin is stored in the baby's body for 7 to 8 months after birth. Most people have only a trace of the amounts, if any, of fetal hemoglobin after infancy.
The combination of two alpha and beta genes forms a 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% protein.
ALA ratio
The formation of aminolevulinic acid, or ALA, affects the rate of heme formation. The synthase that starts this process is regulated in two ways:
- allosterically using 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 aminolivulin synthase, forming a negative feedback. Steroid hormones, non-steroidal anti-inflammatory drugs, sulfonamides antibiotics stimulate the production of synthase. While taking drugs, heme absorption in the cytochrome P450 system is increased, which is important for the production of these compounds by the liver.
Gem Factors
Other factors are reflected in the regulation of heme synthesis through the level of ALA synthase. Glucose slows down the process of ALK synthase activity. The amount of iron in the cell affects the synthesis at the translation level.
The mRNA has a hairpin loop at the translation start site - an iron-sensitive element. The decrease in the level of iron synthesis stops, at high - the protein interacts with a complex of iron, cysteine and inorganic sulfur, thereby achieving a balance between the production of gemma and ALA.
Synthesis Disorders
Violation in the synthesis of heme 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, and the acquired one develops under the influence of toxic drugs and salts of heavy metals.
Enzyme deficiency is manifested in the liver or red blood cells, which affects the determination of the porphyria group - hepatic or erythropoietic. The disease can occur in acute or chronic forms.
Violations of heme synthesis are associated with the accumulation of intermediate products - porphyrinogens, which are oxidized. The place of accumulation depends on the location - in red blood cells or hepatocytes. The level of accumulation of products is used to diagnose porphyria.
Toxic porphyrinogens can cause:
- neuropsychiatric disorders;
- skin lesions due to photosensitization;
- disruption of the reticuloendothelial system of the liver.
With an excess of porphyrins, urine acquires a purple hue. An exacerbation of the disease can be caused by an excess of aminolevulinate synthase under the influence of drugs or the production of steroid hormones in adolescence.
Porphyry species
Acute intermittent porphyria is associated with a defect in the gene that encodes 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, and vomiting. The disease can be caused by taking analgesics and antibiotics.
Congenital erythropoietic porphyria is associated with low activity of uroporphyrinogen-III-synthase and a high level 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 oxidizes in the light to coproporphyrin. Patients suffer from heart failure and photosensitivity.
Mosaic porphyria is a disorder in which partial blocking of the enzymatic conversion of protoporphyrinogen to heme occurs. Signs are urine fluorescence and sensitivity to light.
Late cutaneous porphyria appears with liver damage due to alcoholism and excess iron. In the urine, large concentrations of urophorphyrins of type I and III are secreted, which gives it a pinkish color and causes fluorescence.
Erythropoietic protoporphyria is provoked by the low activity of the enzyme ferrochelatase in mitochondria, the source of iron for heme synthesis. Symptoms are acute urticaria under the influence of ultraviolet radiation. High levels of protoporphyrin IX appear in red blood cells, blood, and feces. Immature red blood cells and skin often fluoresce with red light.