Krebs Cycle PDF

Metabolism of Other Monosaccharides Several sugars other than glucose are important in vertebrates. The most notable of these are fructose, galactose, and mannose. Besides glucose, these molecules are the most common sugars found in oligosaccharides and polysaccharides. They are also energy sourc...

Metabolism of Other Monosaccharides Several sugars other than glucose are important in vertebrates. The most notable of these are fructose, galactose, and mannose. Besides glucose, these molecules are the most common sugars found in oligosaccharides and polysaccharides. They are also energy sources. They are converted into glycolytic intermediates. Fructose Metabolism Dietary sources of fructose include fruit, honey, and the disaccharide sucrose. Fructose is a significant source of carbohydrate in the human diet (second to glucose). In the liver, fructose is converted to fructose-1-phosphate by fructokinase. Before fructose-1-phosphate enters the glycolytic pathway, it is split into dihydroxyacetone phosphate (DHAP) and glyceraldehyde by fructose-1-phosphate aldolase (Aldolase-B). DHAP is then converted to glyceraldehyde-3-phosphate by triose phosphate isomerase. The conversion of fructose-1-phosphate into glycolytic intermediates bypasses two regulatory steps (the reactions catalyzed by hexokinase and PFK-1); thus fructose is metabolized more quickly than glucose. Fructosuria: It is an inherited asymptomatic metabolic disorder due to deficiency of fructokinase. Leading to appearance of fructose in urine. Hereditary Fructose Intolerance: It is an inherited metabolic disorder due to deficiency of fructose-1-P-aldolase (aldolase-B). Accumulation of F-1-P will inhibit glycogen phosphorylase enzyme of glycogenolysis. Leading to fasting hypoglycemia especially after ingestion of fructose. Galactose Metabolism Although galactose and glucose have similar structures (i.e., they are C4 epimers), several reactions are required for this sugar to enter the glycolytic pathway. Galactose is initially converted to galactose-1-phosphate by galactokinase: Then galactose-1-phosphate is transformed into UDP-galactose. During fetal development and childhood, this conversion is catalyzed by galactose-1-phosphate uridyltransferase. (The hereditary disorder galactosemia is caused by the absence of this enzyme). Then UDP-glucose is formed by the isomerization of UDP-galactose catalyzed by UDP- galactose-4-epimerase: Depending on the cell's metabolic needs, UDP-glucose is used directly in glycogen synthesis or is converted to glucose-1-phosphate by UDP-glucose pyrophosphorylase. Glucose-1-phosphate enters the glycolytic pathway after its conversion to glucose-6-phosphate by phosphoglucomutase. Galactosemia: It is caused by absence of galactose-1-phosphate uridyltransferase enzyme. Galactose, galactose- 1-phosphate, and galactitol (a sugar alcohol derivative) accumulate and cause liver damage, cataracts, and severe mental retardation. The only effective treatment is early diagnosis and a diet free of galactose. Citric Acid Cycle The citric acid cycle is a series of biochemical reactions aerobic organisms use to release chemical energy stored in acetyl-CoA, which is composed of an acetyl group derived from the breakdown of carbohydrates, lipids, and some amino acid that is linked to the acyl carrier molecule coenzyme A. Acetyl-CoA is synthesized from pyruvate in a series of reactions. Acetyl- CoA is also the product of fatty acid catabolism and certain reactions in amino acid metabolism. In the citric acid cycle, the carbon atoms are oxidized to CO2 and the high-energy electrons are transferred to NAD+ and FAD to form the reduced coenzymes NADH and FADH2, respectively. The net reaction for the citric acid cycle is as follows: Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H2O → 2 CO2 + 3 NADH + FADH2 + CoASH + GTP + 3 H+ Conversion of Pyruvate to Acetyl-CoA After its transport into the mitochondrial matrix, pyruvate is convened to acetyl CoA in a series of reactions catalyzed by the enzymes in the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex is a large multienzyme structure that contains three enzyme activities: pyruvate dehydrogenase, also known as py1uvate decarboxylase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. It requires five coenzymes: thiamine pyrophosphate (TPP), lipoic acid, NAD+, FAD, CoASH. One molecule of NADH is produced from conversion of each molecule of pyruvate to acetyl CoA. Succinate Thiokinase  The reactions of the citric acid cycle are as follows: 1. Introduction of two carbons as acetyl-CoA. The citric acid cycle begins with the condensation of acetyl-CoA with oxaloacetate to form citrate catalyzed by citrate synthase. 2. Citrate is isomerized to form isocitrate that can be easily oxidized. Citrate is reversibly convened to isocitrate by aconitase. 3. Isocitrate is oxidized to α-ketoglutarate. The oxidative decarboxylation of isocitrate, catalyzed by isocitrate dehydrogenase, produces the first NADH and CO2. 4. α-Ketoglutarate is oxidized to succinyl-CoA. The conversion of α-ketoglutarate to succinyl- CoA is catalyzed by the α-ketoglutarate dehydrogenase complex: α-ketoglutarate dehydrogenase, dihydrolipoyl transsuccinylase, and dihydrolipoyl dehydrogenase. It requires five coenzymes: thiamine pyrophosphate (TPP), lipoic acid, NAD+, FAD, CoASH. This reaction produces the second NADH and CO2. 5. The cleavage of succinyl-CoA to succinate. The cleavage of the high-energy thioester bond of succinyl-CoA to form succinate, catalyzed by succinate thiokinase, is coupled in mammals to the substrate-level phosphorylation of GDP to produce GTP, which can be converted to ATP. 6. Succinate is oxidized to form fumarate. This is catalyzed by succinate dehydrogenase. Unlike the other citric acid cycle enzymes, succinate dehydrogenase is not found within the mitochondrial matrix. Instead, it is tightly bound to the inner mitochondrial membrane. Succinate dehydrogenase is a flavoprotein using FAD to drive the oxidation of succinate to fumarate. This produces FADH2. 7. Fumarate is converted to L-malate. This is a reversible stereospecific hydration reaction catalyzed by fumarase. 8. Malate is oxidized to form oxaloacetate. This is catalyzed by malate dehydrogenase. The third NADH is produced from this reaction. Malate OAA The Amphibolic Citric Acid Cycle Amphibolic pathways can function in both anabolic and catabolic processes. The citric acid cycle is obviously catabolic, because acetyl groups are oxidized to form CO2 and energy is conserved in reduced coenzyme molecules. The citric acid cycle is also anabolic, because several citric acid cycle intermediates are precursors in biosynthetic pathways. For example, α-Ketoglutarate plays an important role in amino acid synthesis. Anabolic processes drain the citric acid cycle of the molecules required to sustain its role in energy generation. Several reactions, referred to as anaplerotic reactions, replenish them. One of the most important anaplerotic reactions is catalyzed by pyruvate carboxylase. A high concentration of acetyl-CoA, an indicator of an insufficient oxaloacetate concentration, activates pyruvate carboxylase. As a result, oxaloacetate concentration increases. Any excess oxaloacetate that is not used within the citric acid cycle is used in gluconeogenesis. Pyruvate carboxylase deficiency A fatal disease caused by a missing or defective enzyme that converts pyruvate to oxaloacetate. It is characterized by varying degrees of mental retardation and disturbances in several metabolic pathways, especially those involving amino acids and their degradation products. A prominent symptom of this malady is lactic aciduria. Citric Acid Cycle Regulation The citric acid cycle enzymes citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase are closely regulated because they catalyze reactions that represent important metabolic branch points. Citrate synthase: The rate of citrate synthesis is stimulated by high concentrations of acetyl-CoA and oxaloacetate. However, high concentrations of succinyl-CoA and citrate inhibit citrate synthase by acting as allosteric inhibitors. lsocitrate dehydrogenase: Its activity is stimulated by high concentrations of ADP and NAD+ and inhibited by ATP and NADH. α-ketoglutarate dehydrogenase: It is strictly regulated because of its important role in several metabolic processes. When a cell's energy stores are low, α-ketoglutarate dehydrogenase is activated and α-ketoglutarate is retained within the cycle at the expense of biosynthetic processes. As the cell's supply of NADH rises, the enzyme is inhibited, and α-ketoglutarate molecules become available for biosynthetic reactions.