WEEK 8_4G's of Carbo Metabolism.docx.pdf

BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Lecturer: Doc. Denzy Rose Tangkusan, MD Date: September 27, 2024 Objectives:...

BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Lecturer: Doc. Denzy Rose Tangkusan, MD Date: September 27, 2024 Objectives:  pyruvate carboxylase which converts pyruvate to The student must be able to: oxaloacetate  Discuss the important reactions in gluconeogenesis.  Phosphoenolpyruvate carboxykinase which converts  Explain the regulation of gluconeogenesis. oxaloacetate to phosphoenolpyruvate  Describe the structure of glycogen Explain the function of - These 2 enzymes reverse pyruvate kinase glycogen  Discuss the two aspects of glycogen metabolism 2. Fructose-6-phosphate to fructose 1,6-bisphosphate glycogenesis and glycogenolysis as to: - Reversed by fructose 1,6-biphosphatase - Reaction steps involved  This enzyme is present in liver, kidney and striated - Enzymes catalyzing the reactions muscle, absent in heart and smooth muscle - Regulatory mechanisms - This enzyme reverses phosphofructokinase-1  Discuss the glycogen storage diseases **Rate limiting step of gluconeogenesis GLUCONEOGENESIS 3. Glucose to glucose-6-phosphate - Reversed by glucose-6-phosphate GLUCONEOGENESIS  present in liver and kidney absent in muscle and - Includes all pathways and mechanisms responsible for adipose tissue converting non-carbohydrates to glucose or glycogen, in order - This enzyme reverses hexokinase to prevent hypoglycemia during a fast **These reactions allow a tissue add glucose to the blood - The two major organs involved in gluconeogenesis: liver (90%) and kidneys (10%) - Occurs in both mitochondria and cytosol Substrates:  Any metabolite that can be converted into pyruvate or a citric acid cycle intermediate can serve as a precursor of glucose  Glucogenic amino acids  Lactate from Cori cycle  Glycerol and propionyl COA from triacylglycerols Regulation of Gluconeogenesis 1. Pyruvate carboxylase reaction  This enzyme is inactive in the absence of acetyl CoA 2. Fructose bisphosphatase reaction  This is inhibited by AMP In Summary: Gluconeogenesis  What hormone is active in fasting? Glucagon  Where does it occur? Mitochondrion and cytosol  What are the substrates? Citric acid cycle intermediate, glucogenic, lactate, Glycerol and propionyl COA  What is the product? Cellulose  Which step is the rate-limiting step? Conversion of fructose 1,6-biphosphatase to fructose 6- phosphate, to glucose-6-phosphate Irreversible reactions in Glycolysis: Reversed in Gluconeogenesis GLYCOGEN METABOLISM 1. Phosphoenolpyruvate to pyruvate (step 1O of glycolysis) GLYCOGEN STRUCTURE 2. Fructose-6-phosphate to fructose 1,6 bisphosphate (step 3)  Excess dietary glucose in animals is stored in the form of 3. Glucose to glucose-6-phosphate (step 1) glycogen (major storage form)  Large, polymeric, highly branched polysaccharide 1. Phosphoenolpyruvate to pyruvate  Contains straight chains with 12 to 14 𐓟-D glucopyranose residues linked by 𐓟 1→4 glycosidic bond - Enzymes used to reverse this reaction includes BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Date: September 27, 2024 BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Lecturer: Doc. Denzy Rose Tangkusan, MD Date: September 27, 2024  Branch points occurs every 8 to 12 glucose indicated by 𐓟1→6 glycosidic bonds GLYCOGEN  Is present in the cytosol as granules GLYCOGENESIS  Glycogen synthesis, degradation, and those that regulate - Occurs in condition wherein the cells in the energy-excess state these processes mainly occurs in the liver and muscle (after a meal) = needing to store glucose rather than use it  Liver glycogen < muscle glycogen (liver mass vs muscle mass) Glycogen Synthase  Important fuel reserve  Forms α-(1→4) glycosidic bonds in glycogen  Serves as a buffer to maintain blood-glucose levels,  Transfers glucosyl units from UDP-glucose to C-4 hydroxyl especially in Glucose-6- Phosphate Hexokinase is the first irreversible step in glycolysis. However, it is not the committed step. Instead, PFK1 (phosphofructokinase-1) is the committed step. 2. Isomerization of Glucose-6-Phosphate to Glucose-1- phosphate 3. Glucose-1-phosphate activated to form UDP glucose catalyzed by glucose-1-phosphate uridyltransferase (which makes use of UTP that will attach to the Glucose) —> UDP Glucose 4. UDP Glucose will be used by Glycogenin Synthase & Branching enzyme to attach glucose units into the growing Shows the different enzymes involved glycogen polymer 1. Phosphorylase will hydrolyze/ cleave the α-1,4 linkages In Summary: Glycogenesis until it reaches the last branched glucose molecule  When will you synthesize glycogen? Well-feed 2. Cleaved part will be acted upon by the debranching  What hormone is active? Insulin enzyme (which has 2 functions)  Where does it occur? Muscles and liver a. Glucan transferase will transport 3 glucose units to  What are the substrates? UDP Glucose (Activated) the linear chain  What is the product? Glycogen b. Debranching enzyme will act upon the remaining  Which step is the rate-limiting step? Glycogen unit in the α-1,6 linkage, cleaves it off to form synthase, elongation of α-(1→4) glycosidic bond glucose-1-phosphate 3. The end result will be a straight/ linear chain that is GLYCOGENOLYSIS linked by α-1,4 which will be acted upon by glycogen phosphorylase to cut each glucose molecule from the chain  Breakdown of glycogen = glucose — “Genesis” individually —> forming (many) glucose-1-phosphate synthesis | “lysis” break down  Occurs in conditions wherein the cells in the energy starved state (fasting) = needing to use up stored glucose  Enzymes involved - Glycogen Phosphorylase (opp. of glycogen synthase)  Catalyzes phosphorolysis of glycogen  Pi used to cleave α-(1→4) glycosidic bonds  Product: glucose 1-phosphate  Occurs in the non-reducing terminal - Debranching Enzyme (opp. of branching enzyme)  Bifunctional enzyme 4-α-D-glucanotransferase Glucose-1-phosphate will be isomerized by - removes a strand of 3 glycosyl Phosphoglucomutase back to Glucose-6-phosphate, which can residues from a 4 residue branch enter various metabolic pathways: Amylo-α-1,6 — glucosidase - hydrolyze remaining α-(1→ 6) 1. Glycolysis (in the muscles & brain) glycosidic bonds *has no enzyme to allow glucose to move into circulation so glucose stays within muscle/ brain 2. Glycolysis ( in the liver) Glucose-6-phosphatase can cut phosphate off the glucose-6-phosphate to form a free glucose —> transported back to the blood to be used by other tissues 3. Uronic Acid pathway 4. Pentose Phosphate pathway BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Date: September 27, 2024 BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Lecturer: Doc. Denzy Rose Tangkusan, MD Date: September 27, 2024 In Summary: Glycogenolysis  What is it for? Conversion of glycogen to glucose for muscle energy  Where does it occur? Liver and muscle  What are the substrates? Glycogen  What is the product? Glucose (liver) and Glucose-6- phosphate (muscle)  Which step is the rate-limiting step? Shortening of primary bond by glycogen phosphorylase HORMONAL REGULATION OF GLYCOGEN METABOLISM  Pathway up —> Glycogenesis  Pathway down —> Glycogenolysis  3 Hormones that regulate the enzymes involved in the Glycogen Metabolism  (Fasting State) Glucagon & Epinephrine (↑ Cyclic AMP) — GLYCOGENOLYSIS ➔ Inhibits glycogen synthesis ➔ Promotes glycogen breakdown  (After a meal) Insulin (↓ Cyclic AMP) — GLYCOGENESIS ➔ Promotes glycogen synthesis ➔ Inhibits glycogen breakdown  Cyclic AMP (cAMP) integrates the regulation of glycogenesis & glycogenolysis  The principal enzymes controlling glycogen metabolism are glycogen phosphorylase & glycogen synthase GLYCOGEN STORAGE DISEASES  Group of inherited disorders characterized by a deficient mobilization of glycogen or deposition of abnormal forms of glycogen, leading to muscle weakness.  Result from a lack of, or abnormal functioning of, one of the enzymes involved in the conversion of glucose to glycogen or the breakdown of glycogen back into glucose A. Von Gierke’s disease (TYPE IA & IB)  Glycogen storage disorders are rare. It is estimated that  Most common glycogen storage disease about one in every 20,000 to 40,000 babies born has a  Enzyme deficient: Glucose-6-phosphatase glycogen storage disorder  Organs involved: Liver, intestinal mucosa and kidney Clinical manifestations: Epidemiology - Fasting hypoglycemia - Lactic Acidemia  The overall GSD incidence is estimated at 1 case per 20,000- - Hyperlipidemia 43,000 live births. - Hyperuricemia with gouty arthritis  No racial or ethnic differences exist for GSD types I, H, IV, V, and VI. GSD type ll highest incidence in Jews in northern B. Pompe’s disease (TYPE II) Africa. GSD type Vl patients are most commonly of Japanese  Enzyme deficient: Lysosomal acid a-1,4 glucosidase (acid and Jewish descent. maltase)  GSD types |-V and VIl affect both sexes with equal  Organs involved: Generalized frequency. Clinical manifestations: - Accumulation of glycogen in lysosomes BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Date: September 27, 2024 BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Lecturer: Doc. Denzy Rose Tangkusan, MD Date: September 27, 2024  The age of onset depends on the clinical form of disease. E. McArdle’s disease (TYPE V) The infantile form develops during the first months of life.  Enzyme deficient: Phosphorylase  In the juvenile form, initial clinical symptoms appear in  Organs involved: skeletal muscle persons aged 1-15 years. The adult form of disease appears  Clinical Manifestations: in persons aged 10-20 years and, less commonly, later. - Symptoms usually start during early childhood. However, it may be difficult to separate these symptoms from those of normal childhood, and diagnosis may not occur until a person’s 20s or 30s. - Burgundy-colored urine (myoglobinuria) - Fatigue - Exercise intolerance, poor stamina - Muscle cramp - Muscle pain - Muscle stiffness - Muscle weakness  Treatment: high protein diet and strenuous exercise Infantile-onset disease - Most severe, with cardiomegaly, hypotonia and death prior to 2 years of age - Infants appear normal at birth - Death occurs from cardiorespiratory failure or aspiration pneumonia C. Cori’s disease (TYPE III)  GSD III, also known as Cori or Forbes disease or limit dextrinosis, is a disorder due to  Enzyme deficient: GDE (Glycogen Debranching Enzyme) F. Hers disease (TYPE VI) - causes storage of glycogen with an  Enzyme deficient: liver glycogen phosphorylase abnormally compact structure, known as - With a deficiency of this enzyme, glycogen cannot be Phosphorylase Limit Dextrin. broken down to glucose, and the accumulating glycogen  Organs affected: both liver and muscle. results in enlarged liver. - Appears to be a benign disorder. G. Tarui’s disease (TYPE VII)  Enzyme deficient: Muscle phosphofructokinase deficiency  Organs involved: muscle  Clinical manifestations: - early onset of fatigue and pain with exercise, vigorous exercise cause severe muscle cramps and myoglobinuria - Treatment: no specific treatment Summary… D. Andersen’s disease (TYPE IV)  Also called amylopectinosis  Enzyme deficient: Branching enzyme. - This results in the accumulation of an abnormal glycogen with poor solubility. - The abnormal glycogen has fewer branch points, more 𐓟-1,4 linked glucose units, and longer outer chains, resulting in a structure resembling amylopectin. BIOCHEMISTRY Week 8: Gluconeogenesis, Glycogen, Glycogenesis, Glycogenolysis Prepared by: Tubat, De Jose, Campos, Maguindra, Valiente Date: September 27, 2024