Introduction to glucose metabolism

Overview of glucose metabolism

Objectives Recognizing the critical importance of glucose as the main carbohydrate of blood & main fuel of human cells. Recalling the sources of blood glucose in feed & fasting states. Recognizing glucose transport into cells Understand the basic concepts & directions (pathways) of metabolism.

General importance of carbohydrates in human body 1- Provide energy through metabolism pathways and cycles 2- Store energy in the form of: starch (in plants) glycogen (in animals and humans) 3- Supply carbon for synthesis of other compounds. 4- Form structural components in cells and tissues.

Critical importance of glucose A constant source of GLUCOSE is an absolute requirement for human life as it is: 1- Preferred energy of the brain 2- Required energy source for cells with no or few mitochondria (as RBCs) 3- Essential source of energy for exercising muscles (substrate for anerobic glycolysis)

Metabolic Pathways of Glucose Production and Utilization HMP/PPP Glycogenolysis Hexose interconversion Glucose Gluconeogenesis Glycogenesis Hexose interconversion Utilization Production Glycolysis Krebs cycle

Metabolism of Glucose GLUCOSE Glycogen Pyruvate NADPH Acetyl CoA Citric Acid Cycle NADH & FADH2 Electron transport chain (flow of electrons) Formation of ATP (oxidative phosphorylation) HEXOSE MONOPHOSPHATE PATHWAY GLYCOGEN SYNTHESIS Ribose-5 Phosphate Glycogen NADPH GLYCOLYSIS No Oxygen No Mitochondria OR BOTH Metabolism of Glucose Lactate Oxygen & Mitochondria

Pathways of glucose metabolism 1- Catabolic pathways: 1- For providing energy (ATP): Glycolysis Anaerobic Glycolysis: end product is lactate Aerobic Glycolysis: end product is pyruvate 2- For providing synthetic products: Hexose monophosphate pathway (Produces NADPH & Ribose 5-Phosphate) 2- Synthetic pathways: Glycogen synthesis

Sources of Glucose to human Body Glucose can be obtained from three primary sources: Carbohydrate in Diet: Carbohydrates are sources for glucose of the body after meals. Excess glucose is stored in the form of glycogen in liver & skeletal muscles. Glycogen degradation (Glycogenlysis): Glycogen (synthesized from glucose molecules) is stored in liver & skeletal muscles. In cases of fasting, liver glycogen is degraded to yield glucose for blood. In cases of muscular exercise, muscle glycogen is degraded to secure glucose for muscles as a source of energy. Gluconeogenesis (Glucose Synthesis): It is the synthesis of glucose from non carbohydrate sources (as some amino acids) It occurs in prolonged fasting

Sources of glucose of carbohydrate diet 1- Free Monosaccharides: mainly glucose & fructose Fructose is converted into glucose in liver 2- Disaccharides: - Sucrose (glucose & fructose) - Lactose (glucose & galactose) - Maltose (glucose & glucose) They are digested into monosaccharides (glucose, fructose & galactose) in the intestine. Fructose & galactose are converted into glucose in the liver 3-Polysaccharides: - Starch (plant source e.g. rice, potato, flour) - Glycogen (animal source) They are digested into glucose in the GIT

Sources of glucose of carbohydrate diet

Glucose transport into cells 1- Na+-independent facilitated diffusion transport:   Transport occurs with concentration gradient No requirement for ATP It is conducted by a group of at least 14 glucose transporters (GLUT-1 to 14)

Glucose transport into cells

Glucose transport into cells GLUT-1 is abundant in RBCs & Brain GLUT-2 is found in liver, kidney & b-cells of the pancreas Function in both directions (from blood to cells & from cells to blood) GLUT-3 primary glucose transporter in neurons GLUT-4 is abundant in adipose tissue & skeletal muscles Number is increased by insulin GLUT-5 is the primary transporter of fructose GLUT-7 is expressed in gluconeogenic tissue (as the liver) mediates glucose flux across ER membrane

Glucose transport into cells 2- Na+-monosaccharide cotransporter system Energy-requiring process that transports glucose against a concentration gradient from low glucose concentrations outside the cell to higher concentrations within the cell It is a carrier-mediated process in which the movement of glucose is coupled to the concentration gradient of Na+, which is transported into the cell at the same time This type of transport occurs in the epithelial cells of the intestine & renal tubules

GLUCOSE TRANSPORT & INSULIN 16

Glycolysis

Glycolysis Glycolysis is the breakdown of glucose to: 1- Provide energy (in the form of ATP) 2- Provide intermediates for other metabolic pathways. It occurs in cytosols of all tissues All sugars can be converted to glucose & thus can be metabolized by glycolysis.

End products of glycolysis 1- In cells with mitochondria & an adequate supply of oxygen (Aerobic glycolysis) - Pyruvate: enters the mitochondria & is converted into acetyl CoA. Acetyl CoA enters citric acid cycle (Krebs cycle) to yield energy in the form of ATP - NADH: utilizes mitochondria & oxygen to yield energy 2- In cells with no mitochondria or adequate oxygen (or Both) (Anaerobic glycolysis) Lactate: formed from pyruvate (by utilizing NADH)

End products of glycolysis NADH is an end product of aerobic glycolysis Pyruvate is the end product of aerobic glycolysis Lactate is the end product of anaerobic glycolysis

Overall reactions of glycolysis

Key enzymes in glycolysis   1- Hexokinase & Glucokinase Glucose Glucose 6-phosphate 2- Phosphofructokinase (PFK) Fructose 6-phosphate Fructose 1,6 bisphosphate 3- Pyruvate Kinase (PK) Phosphoenel pyruvate Pyruvate

Overall reactions of glycolysis Steps catalyzed By key enzymes

Hexokinase & gluockinase   HEXOKINASE GLUCOKINASE LOCALIZATION Most tissues Hepatocytes & Pancreas Specificity Broad specificity for all hexoses Same Kinetics Km Low Km High Affinity Permits efficient phosph. of glucose even when tissue concentration of glucose is low High Km Low Affinity Requires high concentration of glucose for 1/2 saturation So It permits metabolism of glucose when I.C. concentration of glucose in liver cells are increased Vmax Low Vmax Cannot trap glucose more than cell need High Vmax Allow liver to remove flux of glucose from blood (after absorption) To Reduce hyperglycemia after diet & absorption. Effect of insulin (regulation by insulin) Synthesis not affected by insulin Synthesis is increased by insulin

Energy yield from glycolysis 1- Anerobic glycolysis   2 molecule of ATP for each one molecule of glucose converted to 2 molecules of lactate It is a valuable source of energy under the following conditions 1- Oxygen supply is limited as in muscles during intensive exercise 2- Tissues with no mitochondria Kidney medulla RBCs Leukocytes Lens & cornea cells Testes 2-Aerobic glycolysis 2 moles of ATP for each one mol of glucose converted to 2 moles of pyruvate 2 molecules of NADH for each molecule of glucose 2 or 3 ATPs for each NADH entering electric transport chain (ETC) in mitochondria.

Genetic defects of glycolytic enzymes Pyruvate kinase deficiency (95% of cases) PK deficiency leads to a reduced rate of glycolysis with decreased ATP production. PK deficiency effect is restricted RBCs. As RBCs has no mitochondria & so get ATP only from glycolysis. RBCs needs ATP mainly for maintaining the bio- concave flexible shape of the cell. PK deficiency leads to severe deficiency of ATP for RBCs. So, RBCs fail to maintain bi-concave shape ending in liability to be lysed (hemolysis). Excessive lysis of RBCs leads to chronic hemolytic anemia.

Energy yield from glycolysis In anaerobic glycolysis: 2 ATP for one glucose molecule In aerobic glycolysis Glycolysis: 2 ATP 2 NADH: 2 X 3 = 6 ATP NADH Pyruvate Acetyl CoA 2 Pyruvate produce 2 Acetyl CoA (& 2 NADH): 2 X 3 = 6 ATP 2 Acetl CoA in citric acid cycle: 2 X 12 = 24 ATP

GLUCOSE Energy yield of aerobic glycolysis Energy yield of anaerobic glycolysis GLUCOSE Net = 38 ATP / glucose molecule Net = 2 ATP/ glucose molecule 2NAD+ 2 ATP 2 NADH = 2 X 3 = 6 ATP No Oxygen No Mitochondria OR BOTH Oxygen & Mitochondria 2 Lactate 2 PYRUVATE 2NAD+ 2 NADH = 2 X 3 = 6 ATP 2 ACETYL CoA CITRIC ACID CYCLE = 2 X 12 = 24 ATP

Fate of pyruvate 1- Lactate: in anaerobic glycolysis (in cytosol) 2- Acetyl CoA: in aerobic glycolysis (in mitochondria & available oxygen) 3- Oxalacetate: required for: 1- Citric acid cycle (condenses with acetyl CoA): to yield energy (ATP) OR 2-Gluconeogenesis (to synthesize glucose)

Fate of Pyruvate Glucose ACETYL CoA glycolysis Gluconeogenesis No Oxygen No Mitochondria OR BOTH PYRUVATE LACTATE OXALACETATE Oxygen & Mitochondria ACETYL CoA CITRIC ACID CYCLE

Formation of acetyl CoA from pyruvate Pyruvate (end product of aerobic glycolysis) is transported into the mitochondria. In the mitochondrial matrix, pyruvate is converted to acetyl CoA by pyruvate dehydrogenase complex (multienzyme complex) This reaction is irreversible Pyruvate dehydrogenase complex is composed of three enzymes & five coenzymes Coenzymes of the complex are derived from water soluble vitamins: 1- Thiamine pyruphosphate, TPP (derived from thiamine, vitamin B1) 2- NAD+ (derived from niacin) 3- FAD (derived from riboflavin) 4- Lipoic acid 5- Coenzyme A (derived from pantothenic acid)

Pyruvate dehydrogenase complex ACETYL CoA

Citric acid cycle or,(Krebs cycle)

Citric acid cycle or,(Krebs cycle) Citric acid cycle is the final pathway where the oxidative metabolism of Carbohydrates (as glucose), proteins (amino acids) & lipids (fatty acids) to yield energy (ATP) Acetyl CoA is the end product for oxidation of carbohydrates, lipids & proteins Acetyl CoA condenses with oxalacetate to form citrate (first reaction of the cycle) 3 NADH are produced = 3 X 3 = 9 ATP (by oxidative phosphorylation) One FADH2 is produced = 1 X 2 = 2 ATP (by oxidative phosphorylation) One ATP is produced (by substrate level phosphorylation) Net = 12 ATP / one acetyl CoA

Citric acid cycle or,(Krebs cycle)

GLUCONEOGENESIS   Gluconeogenesis is the synthesis of glucose from glucogenic precursors which are not of carbohydrate origin (gluconeogenic precursors)   It occurs during prolonged fasting to synthesize glucose for tissues requiring continuous supply of glucose as a source of energy: Brain, RBCs, Kidney medulla, Lens, Cornea, Testes, sk.ms Gluconeogenesis occurs ONLY in the liver & kidneys

Gluconeogenic precursors 1- Intermediates of glycolysis by reverse of steps of glycolysis (except 4 steps that need 4 different enzymes) 2- Intermediates of citric acid cycle are converted to oxalacetate then to glucose 3- Lactate Lactic acid formed of anaerobic glycolysis in cells as RBCs & skeletal muscles are transported in blood to liver to be converted to pyruvate then to glucose (Cori cycle) 4- Glycerol Glycerol is derived from the lipid triacylglycerol in adipose tissue. Glycerol is convered into dihydroxyactone phosphate (intermediate of glycolysis) then to glucose. 5- Glucogenic amino acids of proteins Glucogenic amino acids are deaminated to form a-ketoacids a-keto acids are converted to pyruvate or intermediates of citric acid cycle then to glucose

GLUCOSE Triacylglycerol in adipose tissue Precursors of Gluconeogenesis Fatty acids Gluconeogenesis Glycerol Lactate Oxalacetate Pyruvate Intermediate of CITRIC ACID CYCLE Glucogenic amino acids in proteins as sk. ms.

Cori Cycle

Unique enzymes of gluconeogenesis are catalyzed by enzymes Reactions 1, 2, 3 & 4 are catalyzed by enzymes NOT used in glycolysis GLUCOSE 1- Pyruvate to oxalacatate by pyruvate carboxylase 2- oxalacetate to phosphoenol pyruvate by PEP carboxykinase 3- Fructose 1,6 bisphosphate to fructose 6 phosphate by fructose 1,6 bisphosphatase 4- Glucose 6-phosphate to glucose by glucose 6-phosphatase GLUCONEOGENESIS Other reactions of gluconeogenesis are catalyzed by same enzymes of glycolysis in the reverse direction