In this article we will try to explain in an accessible way what the pyruvate dehydrogenase complex is and the biochemistry of the process, to reveal the composition of enzymes and coenzymes, to indicate the role and significance of this complex in nature and human life. In addition, the possible consequences of violation of the functional purpose of the complex and the time of their manifestation will be considered.
Introduction to the concept
Pyruvate dehydrogenase complex (PDH) is a protein-type complex whose role is to carry out the oxidation of pyruvate as a result of decarboxylation. This complex contains 3 enzymes, as well as two proteins necessary for the implementation of auxiliary functions. For the pyruvate dehydrogenase complex to function, certain cofactors must be present. There are five of them: CoA, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, thiamine pyrophosphate and lipoate.
Localization of PDH in bacterial organisms is concentrated in the cytoplasm, eukaryotic cells store itin the matrix on mitochondria.
Associated with pyruvate decarboxylation
The significance of the pyruvate dehydrogenase complex lies in the oxidation reaction of pyruvate. Consider the essence of this process.
The mechanism of pyruvate oxidation under the influence of decarboxylation is a process of biochemical nature, in which the cleavage of the CO2 molecule in the singular occurs, and then this molecule is added to pyruvate, subjected to decarboxylation and belonging to coenzyme A (CoA). This is how acetyl-KoA is created. This phenomenon occupies an intermediate place between the processes of glycolysis and the tricarboxylic acid cycle. The process of pyruvate dicarboxylation is carried out with the participation of a complex MPC, which, as previously mentioned, includes three enzymes and two auxiliary proteins.
The role of coenzymes
For the pyruvate dehydrogenase complex, enzymes play a crucial role. However, they can start their work only in the presence of five coenzymes or groups of the prosthetic type that were listed above. The process itself will eventually lead to the fact that the acyl group will be included in the CoA-acetyl. Speaking of coenzymes, you need to know that four of them belong to vitamin derivatives: thiamine, riboflavin, niacin and pantothenic acid.
Flavina adenine dinucleotide and nicotinamide adenine dinucleotide are involved in electron transfer, and thiamine pyrophosphate, known to many aspyruvate decarboxylic coenzyme, enters into fermentation reactions.
Activation of the thiol group
Acetylation coenzyme (A) - contains a thiol-type group (-SH), which is very active, it is critical and necessary for CoA to function as a substance that can transfer the acyl group to the thiol and form thioether. Esters of thiols (thioesters) have a fairly high rate of hydrolysis energy of a free nature, therefore they have a high potential for transferring an acyl group to a variety of acceptor molecules. That is why acetyl CoA is periodically called activated CH3COOH.
Electron transfer
In addition to the four cofactors that are derivatives of vitamins, there is a 5th cofactor of the pyruvate dehydrogenase complex, called lipoate. It has 2 thiol-type groups that can undergo reversible oxidation, which results in the formation of a disulfide bond (-S-S-), which is similar to how this process proceeds between amino acids and cysteine residues in proteins. The ability to oxidize and recover gives the lipoate the ability to be a carrier not only of the acyl group, but also of electrons.
Enzymatic kit
Of the enzymes, the pyruvate dehydrogenase complex includes three main components. The first enzyme is pyruvate dehydrosenase (E1). The second enzyme isdihydrolipoyl dehydrogenase (E3). The third is dihydrolipoyltransacetylase (E2). The pyruvate dehydrogenase complex includes these enzymes, storing them in a large number of copies. The number of copies of each enzyme can be different, and therefore the size of the complex can vary greatly. The PDH complex in mammals is about 50 nanometers in diameter. This is 5-6 times larger than the diameter of the ribosome. Such complexes are very large, so they can be distinguished in an electron microscope.
The gram-positive bacillus stearothermophilus bacterium has sixty identical copies of dihydrolipoyl transacetylase in its PDH, which in turn create a pentagonal-type dodecahedron approximately 25 nanometers in diameter. The gram-positive bacterium Escherichia coli contains twenty-four copies of E2, cat. attaches the prosthetic group of the lipoate to itself, and it establishes an amide-type bond with the amino group of the lysine residue included in E2.
Dihydrolipoyltransacetylase is built by the interaction of 3 domains that have functional differences. These are: an aminoterminal lipoyl domain containing a lysine residue and associated with a lipoate; binding domain (central E1- and E3-); internal acyltransferase domain, which includes active type acyltransferase centers.
The yeast pyruvate dehydrogenase complex has only one lipoyl-type domain, mammals have two such domains, and the bacterium Escherichia coli has three. The linker sequence of amino acids that areof twenty to thirty amino acid residues, shares E2, while alanine and proline residues are interspersed with amino acid residues that are charged. These linkers most often have extended shapes. This feature affects the fact that they share 3 domains.
Relationship of Origin
E1 establishes a connection with the TTP with its active center, and the active center E3 establishes a connection with FAD. The human body contains the enzyme E1 in the form of a tetramer, which consists of four subunits: two E1alpha and two E1 beta. Regulatory proteins are presented in the form of protein kinase and phosphoprotein phosphatase. This type of structure (E1- E2- E3) remains an element of conservatism in evolutionary teaching. Complexes with a similar structure and structure can participate in a variety of reactions that differ from the standard ones, for example, when α-ketoglutarate is oxidized during the Krebs cycle, α-keto acid is also oxidized, which was formed due to catabolic utilization of branched-type amino acids: valine, leucine and isoleucine.
The pyruvate dehydrogenase complex has the enzyme E3, which is also found in other complexes. The similarity of the protein structure, cofactors and also the reaction mechanisms points to a common origin. The lipoate is attached to the lysine E2, and a kind of “hand” is created that is able to move from the active center E1 to the active centers E 2 andE3, which is approximately 5 nm.
Eukaryotes in the pyruvate dehydrogenase complex contain twelve subunits of E3BP (E3 – a binding protein of non-catalytic nature). The exact location of this protein is not known. There is a hypothesis that this protein replaces some subset of subed. E2 in cow PDH.
Communication with microorganisms
The considered complex is inherent in some types of anaerobic bacteria. However, the number of bacterial organisms that have PDH in their structure is small. The functions performed by the complex in bacteria, as a rule, are reduced to general processes. For example, the role of the pyruvate dehydrogenase complex in the bacterium Zymonomonas mobilis is alcoholic fermentation. Pyruvate bacteria in the amount of up to 98% will be used up for such purposes. The remaining few percent are oxidized to carbon dioxide, nicotinamide adenine dinucleotide, acetyl-CoA, etc. The structure of the pyruvate dehydrogenase complex in Zymomonas mobilis is interesting. This microorganism has four enzymes: E1alpha, E1beta, E2 and E 3. The PDH of this bacterium contains a lipoyl domain within E1beta, which makes it unique. The core of the complex is represented by E2, and the organization of the complex itself takes the form of a pentagonal dodecahedron. Zymomonas mobilis does not have a whole series of enzymes of the tricarboxylic acid cycle, and therefore its PDH is only engaged in anabolic functions.
PDH in man
Man, like other living organisms,has genes encoding PDH. The gene E1alpha – PDHA 1 is localized on the X chromosome. to PDH deficiency. Symptoms of the disease can vary greatly from mild lactic acidosis problems to lethal malformations in the development of the body. Men whose X chromosome includes a similar allele will soon die at a very young age. Female individuals are also affected by this disease, but to a lesser extent, and the problem itself is the inactivation of any X chromosome.
Problems of mutations
E1beta - PDHB - is located on the third chromosome. Only two alleles of the mutant type are known for this gene, which, being in a homozygous position, lead to a lethal outcome throughout the year, which is associated with malformations.
Probably there are other similar alleles that can cause death before the full development of the organism. E2 - DLAT - concentrated on the eleventh chromosome. Mankind knows about two alleles of this gene that will create problems in the future, but the right diet can compensate for this. There is a high chance that the fetus will die inside the womb due to other mutations in this gene. E3 - dld - is located on the seventh chromosome and includes a large number of alleles. Enougha large percentage of them leads to the occurrence of diseases of a genetic nature, which will be associated with a violation of amino acid metabolism.
Conclusion
We have considered how important the pyruvate dehydrogenase complex is for living organisms. The reactions occurring in it are primarily aimed at the decarboxylation of pyruvate by oxidation, and PDH itself is highly specialized, but under different conditions, with certain reasons, it can also perform functions of a different nature, for example, participate in fermentation. We also found that protein-type complexes that are involved in pyruvate oxidation consist of five enzymes that remain functional only in the presence of five cofactors. Any changes in the algorithm of the complex mechanism of decarboxylation can cause serious pathologies and even lead to death of the individual.
