Biochemistry Lecture Notes: Carbohydrates (University of Alkafeel)

Biochemistry 2nd class semester 1 L4:Carbohydrates Assistant professor Ahmed Naseer Kaftan M.B.Ch.B. MSc. F.I.C.M.S Chemical pathology 1 Learning objectives: At the end of the lecture students should be able to: Descri...

Biochemistry 2nd class semester 1 L4:Carbohydrates Assistant professor Ahmed Naseer Kaftan M.B.Ch.B. MSc. F.I.C.M.S Chemical pathology 1 Learning objectives: At the end of the lecture students should be able to: Describe gluconeogenesis pathway Describe control of blood glucose and hypoglycemia Demonstrate fructose and galactose metabolism Illustrate diabetic complications Email :[email protected] Website :http://Alkafeel.edu.iq 2 Gluconoegenesis  Gluconeogenesis Definition: Gluconeogenesis is the formation of glucose from non-carbohydrate sources. Site: Intracellular location: Cytosol & mitochondria. Organ location: 1. Liver (90%). 2. Kidney (10%).  During an overnight fast, -90% of gluconeogenesis occurs in the liver, with the remaining 10% occurring in the kidneys. However, during prolonged fasting, the kidneys become major glucose-producing organs, contributing 40% of the total glucose production. [Note: The small intestine can also make glucose.]  Substrates A. Glycerol Glycerol is released during the hydrolysis of triacylglycerols (TAG) in adipose tissue B. Lactate Lactate from anaerobic glycolysis is released into the blood by exercising skeletal Timmy muscle and William by cells that lack mitochondria such astalk You can RBC. a bit In the You Cori can cycle, talk a bit this lactate is taken about up this by person the hereliver about and this oxidized person here to pyruvate that is converted to glucose, which is released back into the circulation  C. Amino acids: produced by hydrolysis of tissue proteins are the major sources of glucose during a fast. It generates a-keto acids, such as pyruvate that is converted to glucose, or a-ketoglutarate that can enter the tricarboxylic acid (TCA)Timmycycle and form oxaloacetate William D. Propionate: You can talk a bit You can talk a bit from Odd-chain fatty acids enters the about this person here TCA cycle as about this person here succinyl CoA, which forms malate, an intermediate in glucose formation  STEPS The steps of gluconeogenesis are mainly the reversal of glycolysis, except for the three irreversible kinases which are replaced by the following enzymes: Glucokinase : Glucose-6-phosphatase. Timmy William Phosphofructokinase -1: Fructose 1, 6 You can talk a bit You can talk a bit bisphosphatase. about this person here about this person here Pyruvate kinase: Pyruvate carboxylase, Phosphoenol pyruvate carboxykinase.  Pyruvate to phosphoenol pyruvate: Pyruvate should pass first from Cytosol to mitochondria by special transporter. Pyruvate is then converted into oxaloacetate by pyruvate carboxylase (in the presence of biotin, CO2 and ATP). The mitochondrial membrane is impermeable to oxaloacetate. So, oxaloacetate is converted to Malate by (Malate dehydrogenase).  Malate is transported to Cytosol, where it is converted again into oxaloacetate (by Cytosolic Malate dehydrogenase). Oxaloacetate is converted into phosphoenol pyruvate by (phosphoenol pyruvate carboxykinase). N.B. : Pyruvate never goes in the course of citric acid pathway to reach Malate, Because this pathway needs insulin and other factors.  Regulation gluconeogenesis& glycolysis are reciprocally regulated A. Hormonal regulation: Glucagon (+), cortisol(+) , insulin (-) B. Substrate regulation: Acetyl CoA and ATP 1. Stimulate gluconeogenesis by inhibiting glycolysis (through inhibiting PFK-1) and stimulate gluconeogenesis (by stimulating fructose1, 6 bisphosphatase). 2. Acetyl CoA also stimulates pyruvate carboxylase (gluconeogenesis) and inhibit pyruvate dehydrogenase (oxidation). Blood glucose regulation  Sources of blood glucose: A. Dietary carbohydrate: absorbed glucose following digestion of carbohydrate e.g. starch. B. Liver glycogen: through glycogenolysis. Liver glycogen can supply the body with glucose for about 18 hours of fasting. C. Amino acids and other metabolites: (gluconeogenesis): liver and kidney can convert these substrates glucose.  blood glucose in feeding Fate of dietary glucose in liver: Glycogen synthesis Synthesis of triacylglycerols is also stimulated. The triacylglycerols are converted to VLDLs and released into the blood.  Fate of dietary glucose in peripheral tissues a. All cells oxidize glucose for energy. b. Insulin stimulates the transport of glucose into adipose and muscle cells. c. In muscle, insulin stimulates the synthesis of glycogen. d. Adipose cells convert glucose to the glycerol moiety for synthesis of triacylglycerols.  Blood glucose in fasting By 2 hours after a meal, blood glucose has returned to the fasting level By 4 hours after a meal, the liver is supplying glucose to the blood via gluconeogenesis and glycogenolysis Timmy William Glycogenolysis is stimulated as blood You can talk a bit You can talk a bit glucose falls to theabout fasting level this person afterabout this person here here a meal. It is the main source of blood glucose for the next 8 to 12 hours.  Gluconeogenesis is stimulated within a few hours (up to 4 hours) after a meal By 16 hours of fasting, gluconeogenesis and glycogenolysis are about equal as sources of blood glucose. Timmy William You can talk a bit You can talk a bit about this person here about this person here  Blood glucose during exercise 1. Use of endogenous fuels a. ATP is regenerated initially from creatine phosphate. b. Muscle glycogen is oxidized to produce ATP. 2. Use of fuels from the blood a. As blood flow to the exercising muscle increases, blood glucose and fattyTimmy acids are taken up and oxidized William by muscle. You can talk a bit You can talk a bit b. As blood glucose levels about begin this person hereto decrease, thehere about this person liver, by the processes of glycogenolysis and gluconeogenesis, acts to maintain blood glucose level  Hypoglycemia Definition: It is the decrease of blood glucose concentration below normal fasting average concentration: less than 65 mg/dl. Symptoms of hypoglycemia Timmy appear if blood William glucose concentration becomes You can talk a bit less You than45 can talk mg/dl. a bit about this person here about this person here Galactose & fructose metabolism  Galactose metabolism The major dietary source of galactose is lactose obtained from milk and milk products. The digestion of lactose by lactase of the intestinal mucosal cell membrane Some galactose can alsoTimmy be obtained by lysosomal William degradation of glycoproteins You can talk a bit and glycolipids. You can talk a bit Like fructose (and mannose), the transport about this person here of about this person here galactose into cells is not insulin dependent.  Importance of galactose: In the form of UDP-galactose: A. Synthesis of lactose (=milk sugar). B. Synthesis of glycolipids (cerebrosides). C. Synthesis of glycoproteins and proteoglycans. D. Synthesis of glycosaminoglycans.  Galactosemia Definition: It is an increase in blood galactose concentration due to the inability to metabolize galactose. Causes: Inherited enzyme deficiency of: a) Galactokinase. b) Galactose-1-P uridyltransferase.  Effect: a) Cataract (=opacity of eye lens): Galactose in the eye is reduced by an enzyme called aldose reductase into galactitol, which accumulates causing cataract. Timmy William b) Liver failure. You can talk a bit You can talk a bit c) Mental retardation. about this person here about this person here d) Galactosuria: excretion of galactose in urine.  Fructose metabolism The major source of fructose is the disaccharide sucrose, Fructose is also found as a free monosaccharide in many fruits, in honey, and in high-fructose corn syrup Fructose transport into cells is not insulin dependent Importance of fructose A. Energy production: 15% of daily energy is derived from fructose. B. Fructose is the major energy source for spermatozoa in the seminal vesicle.  A. In the liver: Liver contains fructokinase enzyme, which phosphorylates fructose into fructose-1-phosphate. B. In extra-hepatic tissues: Because fructokinase is not available in muscles and adipose tissue, fructose is metabolized by Hexokinase and other enzymes into pyruvate → oxidation  C. In the testis (seminal vesicle): 1. Glucose is converted into fructose through sorbitol formation: 2. Fructose is the main nutrient for sperms. 3. Deficiency of fructose in semen correlates with male infertility. Fructose is rapidly metabolized as compared to glucose because it bypasses PFK-1 step (Rate Limiting Enzyme of glycolysis). So fructose forms acetyl CoA and thus fats. So fructose is regarded as most lipogenic sugar.  Fructose is in the seminal fluid and serves as the main energy source for sperm because: It is readily available in large amounts. Sperm cells are adapted to break down fructose quickly and easily. Fructose can be broken down to make energy even when oxygen is low, which happens in parts of the female reproductive system. Fructose doesn’t need insulin, so sperm can use it freely without relying on hormones.  Essential fructosuria: 1. Cause: Due to deficiency of Fructokinase enzyme. 2. Effect: Not serious condition. The excess accumulated fructose is lost in urine  Diabetes complications Because insulin is not required for the entry of glucose into cells of the retina, lens, kidneys, and peripheral nerves, large amounts of glucose may enter these cells during times of hyperglycemia (for example, in uncontrolled diabetes). Timmy William Elevated intracellular glucose concentrations and an adequate supply ofabout (NADPH) cause You can talk a bit this person here aldose reductase You can talk a bit about this person here to produce a significant increase in the amount of sorbitol,  which cannot pass efficiently through cell membranes and, therefore, remains trapped inside the cell As a result, sorbitol accumulates in these cells, causing strong osmotic effects and cell swelling Timmy William due to water influx and retention. Leading to cataract formation, You can talk a bit about this person here peripheral You can talk a bit about this person here neuropathy, and microvascular problems leading to nephropathy and retinopathy  Discussion ‫ﺗﺧﺻﯾص وﻗت ﻟﻠﻧﻘﺎش اﻟﺗﻔﺎﻋﻠﻲ ﻣﻊ اﻟطﻠﺑﺔ‬ 14/9/202 Email :[email protected] Website :http://Alkafeel.edu.iq 43 3 References Lippincott’s Illustrated Reviews: Biochemistry Textbook of Medical Biochemistry. M.D. Chatterjea, M. N Email :[email protected] Website :http://Alkafeel.edu.iq 44