Intermediary metabolism
Pantothenic acid, in the form of coenzyme A, is involved in manifold reactions in intermediary metabolism. This includes energy, carbohydrate, fat, and amino acid metabolism. It is characterized by the metabolic pathways occurring at the interfaces of anabolic and catabolic metabolism. anabolic – building up – processes include the enzymatic synthesis of large-molecule cell components, such as carbohydrates, proteins and fats, from smaller molecules with the help of ATP. Catabolic – degradative – reactions are characterized by the oxidative breakdown of large nutrient molecules, such as carbohydrates, fats, and proteins, to smaller simpler molecules, such as pentoses or hexoses, fatty acids, amino acids, carbon dioxide, and water. Associated with catabolism is the release of energy in the form of ATP.The essential function of coenzyme A is to transfer acyl groups. In this process, CoA establishes, on the one hand, a connection to the acyl residue to be transferred and, on the other hand, connections to important enzymes of intermediary metabolism. In this way, both the acyl groups and the enzymes are activated, enabling them to undergo certain chemical reactions in the body at a sufficient rate. Without coenzyme A, the binding partners would be much more reactive.Acyl group transfer by coenzyme A proceeds as follows. In a first step, coenzyme A, loosely bound to an apoenzyme – protein portion of an enzyme – takes over an acyl group from a suitable donor, such as pyruvate, alkane or fatty acids. The bond between CoA and the acyl occurs between the SH group (thiol group) of the cysteamine residue of the coenzyme A molecule and the carboxyl group (COOH) of the acyl. This bond is called a thioester bond. It is very high in energy and has a high group transfer potential. Known thioester bonds are, for example, acetyl-, propionyl- and malonyl-CoA as well as the fatty acid-CoA thioester.Finally, the SH group of coenzyme A represents its reactive group, which is why coenzyme A is often abbreviated as CoA-SH.In a second step, coenzyme A splits off from one apoenzyme in connection with the acyl residue as acyl-CoA and transfers to another apoenzyme. In a final step, the enzyme-bound CoA transfers the acyl group to a suitable acceptor, such as to oxaloacetate or to fatty acid synthase.Several more enzyme-catalyzed reactions can also occur between the acquisition and release of the acyl group by CoA. For example, the structure of the acyl group may be altered during binding to coenzyme A-for example, the enzymatic conversion of propionic acid to succinate.Contribution of pantothenic acid as coenzyme A to amino acid metabolismEnzymatic synthesis of:
- Leucine, arginine, methionine and lysine.
Enzymatic degradation of:
- Isoleucine, leucine and tryptophan to acetyl-CoA.
- Valine to methylmalonyl-CoA
- Isoleucine to propionyl-CoA
- Phenylalanine, tyrosine, lysine and tryptophan to acetoacetyl-CoA
- Leucine to 3-hydroxy-3-methylglutaryl-CoA
Pantothenic acid continues to play a central role in the
Modification of cellular proteins. Acyl and acetylation reactions, respectively, can strongly influence the activity, structure and localization of proteins. The most common modification is the acetyl group transfer by CoA to the N-terminal end of a peptide chain, usually to methionine, alanine or serine.As a possible function of this acetylation, the protection of cellular proteins against proteolytic degradation is under discussion.Besides acetylcholine, pantothenic acid is essential for the formation of taurine and 2-aminoethanesulfonic acid, respectively. Taurine is a stable end product in the metabolism of the sulfur-containing amino acids cysteine and methionine. The amino acid-like compound acts on the one hand as a neurotransmitter (messenger substance) and on the other hand serves to stabilize the fluid balance in the cells. In addition, taurine participates in the maintenance of the immune system and prevents inflammation.
Acetyl coenzyme A
For intermediate metabolism, the most significant ester of coenzyme A is activated acetic acid, acetyl-CoA.It is the end product of catabolic carbohydrate, fat and amino acid or protein metabolism. Acetyl-CoA formed from carbohydrates, fats and proteins can be introduced into the citrate cycle by transfer of the acetyl group to oxaloacetate by CoA-dependent citrate synthase to form citrate, where it can be completely degraded to carbon dioxide and water to yield energy in the form of ATP.The major CoA derivative in the citrate cycle is activated succinic acid, succinyl-CoA. It is formed from alpha-ketoglutarate as a result of a decarboxylation reaction by CoA-dependent alpha-ketoglutarate dehydrogenase. By the action of another CoA-dependent enzyme, the reaction of succinyl-CoA with glycine leads to the formation of delta-aminolevulinic acid. The latter is the precursor of the corrin ring in vitamin B12 and the porphyrin ring in cytochromes as well as heme proteins, such as hemoglobin. In pantothenic acid deficiency, anemia (anemia) occurs in animal experiments due to the deficit of hemoglobin.In addition to catabolic metabolic processes, acetyl-CoA is involved in the following syntheses:
- Fatty acids, triglycerides, and phospholipids.
- Ketone bodies – acetoacetate, acetone and beta-hydroxybutyric acid.
- Steroids, such as cholesterol, bile acids, ergosterol – precursor of ergocalciferol and vitamin D2, respectively, adrenal and sex hormones.
- All components composed of isoprenoid units, such as ubiquinone and coenzyme Q, respectively, with lipophilic isoprenoid side chain – mevalonic acid is the isoprenoid precursor and is formed by condensation of three acetyl-CoA molecules.
- Heme – an iron-containing porphyrin complex found as a prosthetic group in proteins known as cytochromes; major derived hemoproteins include hemoglobin (blood pigment), myoglobin, and the cytochromes of the mitochondrial respiratory chain and drug-degrading systems – P450
- Acetylcholine, one of the most important neurotransmitters in the brain – for example, it mediates the transmission of excitation between nerve and muscle at the neuromuscular endplate and the transmission from the first to the second of the two nerve cells connected in series in the autonomic nervous system, i.e., in both the sympathetic and parasympathetic nervous systems
- Formation of sugars of important components of glycoproteins and glycolipids, such as N-acetylglucosamine, N-acetylgalactosamine and N-acetylneuroamic acid – glycoproteins serve, for example, as structural components of cell membranes, of mucus (mucus) of various mucous membranes, of hormones such as thyrotropin, of immunoglobulins and interferons, and for cell interaction through membrane proteins; glycolipids are also involved in the construction of cell membranes
Furthermore, acetyl-CoA reacts with drugs, such as sulfonamides, which must be acetylated for their excretion in the liver. Thus, acetyl-CoA contributes to the detoxification of drugs.Acetylation of peptide hormones during their cleavage from the polypeptide precursor affects their activity in different ways. For example, epinephrine is inhibited in its activity as a result of the transfer of an acetyl group to the N-terminal end of the peptide chain, whereas melanocyte-stimulating hormone-MHS is activated by acetylation.Examples of CoA-dependent enzymes of intermediary metabolism involved in the formation and degradation of acetyl-CoA:
- Pyruvate dehydrogenase – following glycolysis (glucose breakdown), this enzyme complex leads to the oxidative decarboxylation of pyruvate to acetyl-CoA.
- Acetyl-CoA carboxylase – conversion of acetyl-CoA to malonyl-CoA for fatty acid synthesis.
- Acyl-CoA dehydrogenase, t-enol-CoA hydratase, beta-hydroxyacyl-CoA dehydrogenase, thiolase – degradation of saturated fatty acids in the framework of beta-oxidation to acetyl-CoA; in beta-oxidation, two carbon atoms are always split off from a fatty acid in succession in the form of acetyl-CoA – for example, the degradation of saturated palmitic acid – C16:0 – eight molecules of acetyl-CoA are formed
- Thioloase, 3-hydroxy-3-methylglutaryl-CoA reductase – HMG reductase – the former enzyme leads to the conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA, which can further react to form ketone bodies; HMG reductase reduces HMG-CoA to mevalonate for the synthesis of steroids belonging to lipids, such as cholesterol.
Acyl coenzyme A
Acyl-CoA is the name for an activated fatty acid residue.Since fatty acids are relatively inert, they must first be activated by CoA before they can undergo reactions. The enzyme crucial for activation is acyl-CoA synthetase, also known as thiokinase, which is a CoA-dependent enzyme. Thiokinase leads to the formation of acyl adenylate by the addition of ATP to the carboxyl group of the fatty acid with the cleavage of two phosphate residues from the ATP. In this process, the adenosine triphosphate converts to adenosine monophosphate – AMP. Subsequently, the AMP is cleaved from the acyl adenylate and the energy released in this process is used for the esterification of the acyl moiety with coenzyme A. This step is also catalyzed by thiokinase.Fatty acids are capable of reactions, such as beta-oxidation, only in the form of the energy-rich compound with CoA.For beta-oxidation – degradation of saturated fatty acids – the acyl-CoA must be transported into the mitochondrial matrix. Long-chain fatty acids can only cross the inner mitochondrial membrane with the help of the transport molecule L-carnitine. CoA transfers the acyl group to carnitine, which transports the fatty acid residue into the mitochondrial matrix. There, the acyl group is bound by coenzyme A, so that acyl-CoA is again present.In the mitochondrial matrix, the actual beta oxidation begins. It occurs stepwise in a repeating sequence of four individual reactions. The products of a single sequence of the four individual reactions include a fatty acid molecule that is two carbon atoms shorter in the form of acyl-CoA and an acetyl residue bound to coenzyme A, which is composed of the two C atoms of the fatty acid that have been split off.The fatty acid, which is two C atoms smaller, is returned to the first step of beta-oxidation and undergoes a renewed shortening. This reaction sequence is repeated until two acetyl-CoA molecules remain at the end. These can enter the citrate cycle for further degradation or be used for the synthesis of ketone bodies or fatty acids.In addition to the transfer of acetyl groups, the transfer of acyl residues by coenzyme A is also important. Acylations with the saturated C14 fatty acid myristic acid frequently occur, with the acyl residue being bound to an N-terminal glycine residue of a protein, such as cytochrome reductase and protein kinase. CoA also transfers the acyl from the C16 fatty acid palmitic acid to a serine or cysteine residue of proteins, such as the iron transferrin receptor, the insulin receptor, and membrane glycoproteins of cells of the immune system.Presumably, these acylations serve to allow the protein to bind to biomembranes. Furthermore, it is discussed that acyl group transfer affects the protein’s ability to participate in regulatory steps of signal transduction.
4́-Phosphopantetheine as a coenzyme of fatty acid synthase
In addition to its importance as a building block of coenzyme A, pantothenic acid in the form of phosphopantetheine has an important function as a prosthetic group of the acyl carrier protein (ACP) of fatty acid synthase. Fatty acid synthase represents a multifunctional protein that is divided into different spatial sections by folding. Each of these sections possesses one of a total of seven enzymatic activities. One of these sections consists of the acyl-carrier protein, which contains a peripheral SH group formed by a cysteinyl residue and a central SH group. 4́-Phosphopantetheine forms the central SH group by being covalently bonded with its phosphate group to the serine residue of the ACP.The biosynthesis of saturated fatty acids proceeds in an orderly cyclic sequence, with the fatty acid to be synthesized being offered in turn to the individual enzyme sections of fatty acid synthase. During synthesis, the terminal SH group of 4́-phosphopantetheine has the role of acceptor for the malonyl residue to be taken up during each handling. In addition, it serves as a carrier for the growing fatty acid.Coenzyme A is also involved in the formation of fatty acids and their incorporation into, for example, sphingolipids or phospholipids [4, 10. Sphingolipids are building blocks of myelin (myelin sheath of a neuron, i.e., a nerve cell) and are thus important for nerve signal transduction. Phospholipids belong to the membrane lipid family and form the main component of the lipid bilayer of a biomembrane.For the start of fatty acid biosynthesis, CoA transfers an acetyl group to an enzymatic SH group as well as a malonyl residue to the enzyme-bound 4́-phosphopantetheine of fatty acid synthase.Condensation occurs between the acetyl and malonyl radicals, leading to the formation of a beta-ketoacylthioester with the elimination of carbon dioxide. A reduction, elimination of water, and another reduction result in a saturated acylthioester.With each cyclic cycle, the fatty acid chain is lengthened by two carbon atoms.To synthesize one mole of C16 or C18 fatty acid, one mole of acetyl-CoA is required as a starter and seven or eight moles of malonyl-CoA as suppliers of additional C2 units.