Integration of Metabolism Metabolism is a continuous process. Thousands of reactions occur simultaneously in order to maintain homeostasis. It ensures a supply of fuel, to tissues at all times, in fed state as well as absorptive and starved state. Fate of Glucose - The intracellular form of glucose is glucose-6-phosphate. - Glucose-6-phosphate can be oxidised for energy (ATP) and NADH - Glucose-6-phosphate can be converted to Acetyl CoA, which is also used for fat synthesis - Glucose-6-phosphate can be shunted into the pentose phosphate pathway to generate NADPH and ribose-5-phosphate, as well as intermediates of glycolysis. - Excess Glucose-6- phosphate is stored at Glycogen. Glycolysis Glycolysis takes place in the cytosol of all cells in the body. Glycolysis can occur in two form in order to generate ATP. Aerobic Glycolysis occurs in the presence of oxygen. 8 molecules of ATP are produced. Anaerobic Glycolysis occurs when there is lack of oxygen or very scarce amounts. In this process lactate is produced and 2 molecules of ATP is generated.
1- Glucose is first changed to its intracellular for, glucose-6-phosphate. The process of phosphorylation is catalysed by the enzyme Hexokinase in the liver and extra hepatic tissue. ATP is used in this process. The enzyme splits ATP into ADP and Pi and thus adding the Pi to glucose. it is an IRREVERSIBLE reaction. Hexokinase requires Mg2+ for its activity. Hexokinase is regulated by the amount of Glucose-6-phosphate. 2- Glucose-6-phosphate is then isomerized to Fructose-6-phosphate by phosphohexose isomerase. (An aldose- ketose isomerization) 3- Fructose-6-phosphate is phosphorylated to fructose 1,6- bisphosphate. The enzyme phosphfructokinase-1 is used to transfer a phosphate group to fructose-6-phosphate, utilising ATP. This reaction is IRREVERSIBLE. The enzyme phosphofructokinase-1 is the key regulatory enzyme in glycolysis. It is inhibited by high levels of Citrate and ATP and activated by high levels of AMP and fructose 2,6- bisphosphate. 4- Fructose 1,6- bisphosphate (6C) is then cleaved into Glyceraldehyde-3-phosphate (3C) and Dihydroxy acetone phosphate (3C). This reaction is catalysed by the enzyme aldolase. 5- DHAP can interconvert to GAP, by the help of the enzyme triose isomerase. 6- GAP is oxidised to 1,3- bisphosphoglycerate, catalysed by the enzyme glyceraldehyde 3-phosphate dehydrogenase. This reaction is energy-yielding. During this reaction NAD+ is reduced to NADH. 7- The enzyme phosphoglycerate kinase transfers a phosphate group from the carboxyl group of 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate. This type of reaction is substrate- level phosphorylation, where ATP can be produced at substrate level without participating in electron transport chain. 8-3- phosphoglycerate is isomerized to 2- phosphoglycerate by the enzyme phosphglycerate mutase. Mg2+ is required for this reaction. 9- Dehydration of 2- phosphoglycerate to phosphoenol pyruvate by the enzyme enolase 10- Phosphoenol pyruvate is dephosphorylated to pyruvate. It is a substrate level phosphorylation and one mole of ATP is generated. This reaction is IRREVERSIBLE.
Gluconeogenesis Gluconeogenesis is the metabolic pathway that generates glucose from no-carbohydrate carbon substrates such as lactate (from anaerobic glycolysis), glycerol (adipose tissue) and glycogenic amino acids (muscle protein). It maintains blood glucose levels at times of fasting and prolonged exercising. A high protein diet and stress also induces gluconeogenesis. Many pathways of gluconeogenesis are reversible steps of glycolysis. Specific Pathways: 1. Pyruvate > phosphoenol pyruvate 2. Fructose 1,6- phosphate > Fructose-6-phosphate 3. Glucose-6-phosphate > Glucose 1. - Gluconeogenesis begins in the mitochondria, Pyruvate is converted to Oxaloacetate by the enzyme pyruvate carboxylase. ATP, carbon dioxide and biotin are needed for this process. - By the Malate- Aspartate shuttle, Oxaloacetate is transported to the cytosol where it is converted to Phosphoenol pyruvate, by the enzyme phosphoenol pyruvate carboxykinase. This reaction is induced by glucagon, epinephrine and cortisol.
2. Fructose-1,6- bisphosphate is converted to Fructose-6-phosphate by the enzyme Fructose 1,6-bisphosphatase and a phosphate group is released. Fructose 1,6- bisphosphatase is inhabited by Fructose 2,6- phosphate. 3. Glucose-6-phosphate is converted to glucose by the enzyme glucose-6-phosphatase and another phosphate group is released. Fate of Amino Acids - Amino acids are used for the synthesis of enzymes, transporters and other proteins - Amino acid is required for the synthesis of cells genetic information - It is also used for synthesis of neurotransmitters - They are precursors of several hormones, such as insulin and glucagon - Amino acids can be catabolised to acetyl CoA, pyruvate or intermediates of TCA cycle. Glucose- Alanine Cycle The cycle takes place between the skeletal muscle and the liver. - In the skeletal muscle: Glutamate reacts with ammonia to form glutamine (the major source of interurban transport of nitrogen).
This process is catalysed by the enzyme glutamine synthase and it uses ATP in the process. Glutamate + NH4+ + ATP Glutamine + ADP + Pi The glutamate may transfer the amino group to pyruvate, derived from glycolysis, to form alanine and alpha ketoglutarate. This transamination is catalysed by ALT- alanine aminotransferase. Therefore, glutamate leaves the Cahill cycle. Glutamate + Pyruvate Alanine + α-ketoglutarate The alanine produced, as well as the alanine derived from protein breakdown in the muscle, can leave the cell and be transported in the bloodstream to the liver. - In the liver: In the liver, alanine acts as an amino donor and alpha ketoglutarate as an alpha kept acid acceptor. Therefore, transamination occurs by the help of the enzyme alanine aminotransferase. The product of this reaction is pyruvate. Alanine + α-ketoglutarate Glutamate + Pyruvate Glutamate can be catalysed by the glutamate dehydrogenase to form ammonium, which can enter the urea cycle and alpha ketoglutarate, which can enter the krebs cycle. Glutamate can also react with oxaloacetate to form aspartate and alpha ketoglutarate, by the enzyme aspartate aminotransferase. Aspartate is involved in the formation of urea as well as synthesis of purines and pyrimidines. Glutamate + Oxaloacetate Aspartate + α-ketoglutarate Pyruvate can be oxidised for ATP production, thus leaving the glucose-alanine cycle or enter the gluconeogenesis pathway and continue the cycle. The glucose produced can enter different tissues, as skeletal muscle. Transaminases Enzymes catalysing the transamination reaction- the removal of the amino group from amino acids. They require pyridoxal phosphate (PLP), the active form of vitamin B6 or pyridoxine as coenzyme.
Function of Glucose-Alanine Cycle - It transports nitrogen in a non-toxic form from peripheral tissues to the liver - It removes pyruvate from peripheral tissue. - It allows to maintain a high level of alanine in hepatocytes, enough to inhibit protein degradation. - It may play a role in host defence against infectious diseases. Notes- - Alanine and Glutamine are the major sources of nitrogen and carbon in interurban amino acid metabolism. - There is no net synthesis of glucose in the glucose- alanine cycle - The glucose-alanine cycle has an energy cost of 3-5 ATP
Sources- - http://biochemie.lf2.cuni.cz/anglicky/biox2zimni/prednasky/integration%20of %20metabolism.pdf - http://biochemie.lf2.cuni.cz/anglicky/biox2zimni/prednasky/glycolysis%20and %20gluconeogenesis.pdf - http://www.tuscany-diet.net/2017/01/15/glucose-alanine-cycle/ - https://laboratoryinfo.com/glycolysis-steps-diagram-energy-yield-and-significance/ - https://www.sciencedirect.com/topics/medicine-and-dentistry/gluconeogenesis