NFNF1613 Carbohydrate Metabolism II 2024-2025 PDF

NFNF1613 Biokimia Manusia Carbohydrate Metabolism II Dr. Mohd Kaisan Mahadi Fakulti Farmasi, UKM [email protected] Overview Digestion Absorption Catabolism processes glycolysis, pentose-phosphate pathway, glycogenolysis Anab...

NFNF1613 Biokimia Manusia Carbohydrate Metabolism II Dr. Mohd Kaisan Mahadi Fakulti Farmasi, UKM [email protected] Overview Digestion Absorption Catabolism processes glycolysis, pentose-phosphate pathway, glycogenolysis Anabolism processes gluconeogenesis, glycogenesis Cellular respiration Citric acid cycle/TCA cycle/Krebs cycle Gluconeogenesis Formation of glucose from noncarbohydrate precursors 3C compounds (pyruvate, lactate, glycerol) Glucogenic amino acids Occur mainly in liver cells, some extent in kidney Carbohydrate: Digestion, Absorption and Metabolism L.M. Sanders, in Encyclopedia of Food and Health, 2016 Glucogenic AA 18/20 amino acids are glucogenic 2 non-glucogenic AA à Leucine & Lysine Glucogenic AA can undergo conversion to Citric Acid cycle intermediates  Reciprocal process to glycolysis Not directly reversal of glycolysis 3 bypass reactions, other steps are reversible from glycolysis Does not occur readily simultaneous to glycolysis When/why gluconeogenesis occurs? Gluconeogenesis – bypass reactions Why bypass reactions? Irreversible Highly exergonic (spontaneous) 1st bypass: conversion of pyruvate à PEP Oxaloacetate as important intermediate 1st bypass Oxaloacetate transported out of mitochondria in the form of malate Malateàoxaloacetate àPEP NADH produced to be used subsequently in gluconeogenesis  2nd and 3rd bypass 2nd bypass Fructose 1,6-bisphosphateàFructose 6-phosphate Hydrolysis of C-1 phosphate Catalyzed by FBPase-1 3rd bypass Glucose 6-phosphate à glucose Dephosphorylation by hydrolysis Catalyzed by glucose 6-phosphatase (not present in muscle and brain cells). Why?  How is gluconeogenesis regulated? 1) Allosteric regulation of the enzymes involved Acetyl-CoA as one of the regulator Positive modulator of pyruvate carboxylase (an enzyme that converts pyruvate to oxaloacetate - gluconeogenesis) Negative modulator of pyruvate dehydrogenase (an enzyme that converts pyruvate to Acetyl-CoA – TCA cycle) High Acetyl-CoA (indicate an abundance of energy supply), push towards gluconeogenesis Gluconeogenesis TCA cycle Pyruvate carboxylase  Fructose-2,6-bisphosphate (F-2,6- BP): This molecule is a potent regulator that influences both glucose glycolysis and gluconeogenesis: F-2,6-BP stimulates phosphofructokinase-1 (PFK-1) in glycolysis and inhibits fructose-1,6- bisphosphatase (FBPase-1) in PFK-1 gluconeogenesis. High levels of F-2,6-BP favor glycolysis, while low levels favor gluconeogenesis. Glucagon reduces F-2,6-BP levels by activating a specific enzyme, fructose-2,6-bisphosphatase, shifting the balance towards gluconeogenesis. Hormonal Regulation Insulin: Secreted when blood glucose levels are high, insulin inhibits gluconeogenesis. It downregulates the expression of key gluconeogenic enzymes, like phosphoenolpyruvate carboxykinase (PEPCK), thus reducing glucose production. Glucagon: Secreted when blood glucose levels are low, glucagon stimulates gluconeogenesis. It activates protein kinase A (PKA), which phosphorylates and activates key enzymes in the gluconeogenesis pathway. Glucagon also promotes the transcription of gluconeogenic enzymes, enhancing glucose production. Cortisol and Epinephrine: These stress hormones also promote gluconeogenesis during periods of physical or emotional stress, ensuring a steady glucose supply for energy. Important questions! When/why glycolysis occurs? Where does glycolysis occurs? Where does gluconeogenesis occurs? When/why gluconeogenesis occurs? How is glycolysis regulated? How is gluconeogenesis regulated? What is the goal of each process? Section 16.4 Gluconeogenesis and Glycolysis Are Reciprocally Regulated In general, “the amounts and activities of the distinctive enzymes of each pathway are controlled so that both pathways are not highly active at the same time. The rate of glycolysis is also determined by the concentration of glucose, and the rate of gluconeogenesis by the concentrations of lactate and other precursors of glucose” Biochemistry, 5th edition Jeremy M Berg, John L Tymoczko, and Lubert Stryer.  Pentose-phosphate pathway (PPP) Reversible Non-reversible Parallel to glycolysis. 2 phases: Oxidative & Nonoxidative Glucose 6-phosphate dehydrogenase G6PD is a rate limiting step Important products of oxidative phase: Ribose 5-phosphate NADPH Video  Pentose-phosphate pathway Ribose-5-phosphate required for nucelotide synthesis àCaters the need of dividing cells NADPH Required for synthesis of fatty acid, cholesterol, steroid hormones Counteract oxidative damage (by generating GSH) Pentose-phosphate pathway 3 Non oxidative phase Key steps: 1) Isomerization 1 2) Epimerization 3) Transketolase (2C)/Transaldolase (3C) Recycles 6 molecules of ribulose 5- phosphate to glucose 6-phosphate 2 3 How is PPP regulated? Whether the glucose 6-phosphate undergoes glycolysis or PPP? Depending on the cell’s current need eg. not dividing, no need to synthesis nucleotide à glycolysis) Depending on the concentration of NADP+ in the cell High NADP+ allosterically stimulate G6PD (rate limiting step enzyme), favour PPP to occur Glycogen Glycogen Metabolism Glycogenesis = glycogen synthesis Glycogenolysis = glycogen breakdown Insulin Glucagon Organs Liver Muscle Glycogenesis à Occurs during fed state with high blood glucose level. Insulin released to help regulate the blood glucose. Video - Glycogenesis Glycogenesis Video - Glycogenolysis Glycogenolysis Carbohydrate metabolic diseases Examples Diabetes mellitus Type I DM Type II DM  Examples Lactose intolerance Low level of lactase due to genetic deficiency or intestinal injury Unbroken lactose à cause conversion to lactic acid, methane gas, H2 gas à nausea, flatulence, diarrhea Glucose-6-phosphate dehydrogenase (G6PD) deficiency Absence of G6PD cause lacking of NADPH Lack protection against oxidative damage References & Extra readings Nelson, D & Cox, M., Lehninger Principles of Biochemistry, 4th Ed. Peet. A., Lieberman, M. A. & Marks, A. 2012. Marks’ Basic Medical Biochemistry: A Clinical Approach. Philadelphia: Lippincott Williams & Wilkins Aerobic Glycolysis Anaerobic Glycolysis Gluconeogenesis Glycogenesis, Glycogenolysis, Gluconeogenesis Glycogenesis Energy Metabolism In The Liver Tutorial task Understanding THE BIG PICTURE 1. Compare and contrast Type I & II DM. Your answer must include pathophysiology, how does it affecting glucose metabolism and symptoms.