Hemoglobin synthesis is composed of heme synthesis and globin synthesis. Finally, the linkage of the prosthetic heme group with four globins each occurs to form the iron-containing protein complex hemoglobin. Both disorders in heme synthesis and globin synthesis can lead to serious health problems.
What is hemoglobin synthesis?
Hemoglobin is an iron-containing protein complex found in red blood cells. To understand hemoglobin synthesis, it is first necessary to know the structure of hemoglobin. Hemoglobin is an iron-containing protein complex, which consists of four subunits of globin, each with a prosthetic heme group. In adult human hemoglobin, there are both two identical alpha globins and two identical beta globins as subunits. Each of these subunits is attached to a prosthetic heme group, which consists of a porphyrin-iron II complex. Thus, a hemoglobin complex contains four heme groups each. Each heme group can complex an oxygen molecule to the iron II ion depending on the chemical environment. Depending on how many heme groups are loaded with oxygen, we speak of oxyhemoglobin (oxygen-rich) or deoxyhemoglobin (oxygen-poor). The iron II ion is located in the center of the porphyrin ring. To the side of it, there is a complex bond to the histidine residue of globin. To the other side, depending on the energy state of the iron ion, an oxygen molecule may be complex-bound. The energy state is influenced by external physical and chemical conditions due to conformational changes of the globin.
Function and task
The final step in hemoglobin synthesis is the assembly of the prosthetic heme group with the four globin units into an iron-containing protein complex. The individual components are formed by independent biosynthetic pathways. Starting materials for the porphyrin ring of the heme group are the amino acid glycine and succinyl-CoA. Succinyl-CoA is composed of coenzyme A and succinic acid. Succinic acid is an intermediate product in the breakdown of energy-rich ketone bodies as part of energy metabolism. With the help of the enzyme delta-aminolevulinic acid synthase, delta-aminolevulinic acid is synthesized from succinyl-CoA and glycine. With the elimination of one molecule of water, two molecules of delta-aminolevulinic acid condense to form the pyrrole derivative porphobilinogen. With the elimination of ammonia and with the aid of the enzyme uroporphyrinogen I synthetase, four molecules of porphobiliogen react to form hydroxymethylbilane. This is transformed into uroporphyrinogen III with ring formation. Enzymatic decarboxylation and dehydrogenation in the mitochondria produces protoporphyrin. With the enzyme ferrochelatase, an iron II ion is incorporated into this molecule to form heme. In the cytosol of the cell, the heme is linked with the protein globin to form the iron-containing protein complex hemoglobin. Synthesis of the individual globins occurs via normal protein biosynthesis. As mentioned earlier, the adult hemoglobin complex receives two identical subunits each of alpha- and beta-globins. Due to its complex structure, the finished hemoglobin has developed the ability to transport oxygen and supply it to all cells of the organism. However, the binding of the central iron to oxygen is not very strong and is very easily influenced by external chemical and physical factors. This enables hemoglobin both to absorb oxygen rapidly and to release it quickly. Thus, the oxygen loading of hemoglobin depends, among other things, on the factors PH value, carbon dioxide or oxygen partial pressure, or even temperature. These influencing variables change the conformation of globins, for example, so that oxygen binding can be strengthened or weakened via slight changes in the energetic and steric ratios. Thus, at a low PH and a high carbon dioxide partial pressure, oxygen binding to the iron II ion is weakened, favoring oxygen release. It is under these conditions that greater metabolic turnover occurs, which also has an increased oxygen demand. The oxygen transport system is therefore best matched to physical needs via hemoglobin function.
Diseases and ailments
Disturbances in hemoglobin synthesis can lead to various diseases.For example, there are a number of genetic diseases that are based on a disorder of heme synthesis. In this case, heme precursors accumulate in the body, leading among other things to extreme sensitivity to light. In these so-called porphyrias, porphyrins are stored in the blood vessels or even the liver. When exposed to light, some forms of porphyrias store increased radiant energy. When the energy is released, oxygen radicals are formed which attack and destroy the exposed tissue. Severe itching and burning pain develop. There are seven forms of porphyrias. The formation of heme is an eight-step process in which seven enzymes are involved. If an enzyme functions insufficiently, the respective precursor is stored at this point of heme synthesis. Based on the symptoms, porphyrias are divided into two main groups. The so-called cutaneous porphyrias are characterized by painful photosensitivity of the skin. In hepatic porphyrias, liver involvement predominates with severe abdominal pain, nausea and vomiting. In many cases, however, there is overlap of the two symptom complexes. Porphyrias often show an episodic course with acute attacks. Depending on the type of porphyria, these manifest themselves in sudden painful skin reactions, colicky abdominal pain, nausea/vomiting, red coloration of the urine, seizures, neurological deficits or even psychoses. Other disorders of hemoglobin synthesis refer to the defective synthesis of globin molecules due to mutations of the corresponding genes. Examples are the so-called sickle cell anemia or the thalassemias. In sickle cell anemia, the protein of the beta-globin subunit is genetically altered. At position six of this protein, the amino acid glutamic acid is replaced by valine. In the absence of oxygen, the hemoglobin in question deforms into a sickle shape, clumping together and clogging small blood vessels. This results in life-threatening circulatory disorders. Thalassemias are a group of different hemoglobin malformations that result in reduced globin chain formation of alpha or beta globin. The most important symptom is severe anemia.
