Biochemistry 9 Carbohydrate Metabolism I – Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Pathway

Biochemistry 9: Carbohydrate Metabolism I – Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Pathwa Glucose Transport GLUT-2 Found in liver (for glucose storage) and pancreatic b-islet cells (as part of the glucose sensor). Has "Km GLUT-4 Found in adipose tissue and muscle. Stimulated by insulin. Has ¯Km Glycogenesis and Glycogenolysis * See appendix for full diagram Glycogenesis: The production of glycogen using two main enzymes: Glycogen Synthase, and Branching Enzyme. Occurs in the liver and muscle cells. Glycogen is stored in liver. Glycogen Synthase: Creates a-1,4 glycosidic bonds between glucose. Branching Enzyme: Creates branches with a-1,6 glycosidic bonds. Glycogenolysis: The breakdown of glycogen using two main enzymes: Glycogen Phosphorylase, and Debranching Enzyme. Glycolysis * See appendix for full diagram Glucose + 2NAD+ + 2ADP + 2P ® 2Pyruvate + 2ATP + 2NADH + 2H+ Important enzymes: Glucokinase: Converts glucose to glucose 6-phosphate in the (irreversible) pancreatic b-islet cells as part of the glucose sensor. Hexokinase: Converts glucose to glucose 6-phosphate in in (irreversible) peripheral tissues. Inhibited by its product G 6-P. Phosphofructokinase-1: PFK-1. Phosphorylates fructose 6-phospate to (irreversible) fructose 1,6-bisphosphate in the rate-limiting step. Activated by AMP and fructose 2,6bisphosphate. Inhibited by ATP and citrate. Phosphofructokinase-2: PFK-2. Produces fructose 2,6-bisphosphate that activates PFK-1. It is activated by insulin; inhibited by glucagon. Glyceraldehyde-3-phosphate dehydrogenase: Produces NADH, which can feed into the electron transport chain. Pyruvate Kinase: Perform substrate-level phosphorylation, placing (irreversible) an inorganic phosphate onto ADP to form ATP. The NADH produced in glycolysis is oxidized by the mitochondrial electron transport chain when O2 is present. If O2 or mitochondria are absent, the NADH produced in glycolysis is oxidized by cytoplasmic lactate dehydrogenase. Examples include RBCs and skeletal muscle. Pyruvate Dehydrogenase A complex of enzymes that convert pyruvate to Acetyl-CoA right before the citric acid cycle. It is stimulated by insulin and inhibited by acetyl-CoA. Glycogen Removes single glucose 1-phosphate molecules by Phosphorylase: breaking a-1,4 glycosidic bonds. In the liver, it is activated by glucagon to prevent low blood sugar. In exercising skeletal muscle, it is activated by epinephrine and AMP to provide glucose for the muscle itself. Debranching Moves a block of oligoglucose from the branch and Enzyme: connects it to the chain using an a-1,4 glycosidic bond. It also removes the branchpoint, which is connected via an a-1,6 glycosidic bond, releasing a free glucose molecule. Gluconeogenesis * See appendix for full diagram Occurs in both the cytoplasm and mitochondria, predominantly in the liver with a small contribution from the kidneys. Most gluconeogenesis is simply the reverse of glycolysis, using the same enzymes. The 3 irreversible steps of glycolysis must be bypassed by different enzymes. Pyruvate Converts pyruvate to oxaloacetate, which is converted to Carboxylase: PEP by PEPCK. Together, these two enzymes bypass pyruvate kinase. Pyruvate carboxylase is activated by Acetyl-CoA. PEPCK is activated by glucagon and cortisol. Fructose-1,6- Converts fructose 1,6-bisphosphate to fructose 6bisphosphatase: phosphate, bypassing phosphofructokinase-1. This is the rate-limiting step of gluconeogenesis. It is activated by ATP and glucagon. Inhibited by AMP and insulin. The Pentose Phosphate Pathway Also known as the hexose monophosphate (HMP) shunt, it occurs in the cytoplasm of most cells. Glucose 6-Phosphate enters the pathway and the products are NADPH, sugars for biosynthesis, and glycolysis intermediates. Rate-Limiting Glucose-6-phosphate dehydrogenase (G6PD), which is Enzyme: activated by NADP+ and insulin and inhibited by NADPH. Other Monosaccharides Galactose: Comes from lactose in milk. Trapped in the cell by galactokinase, and converted to 1-phosphate via galactose-1phosphate uridyltransferase and an epimerase. Fructose: Comes from honey, fruit, and sucrose. Trapped in the cell by fructokinase, then cleaved by aldolase B to form glyceraldehyde and DHAP.