Sugar Metabolism Pathways Lecture Notes PDF

Pathways of Sugar Metabolism: Pentose Phosphate Pathway, Fructose & Galactose Metabolism Diet consists of fructose, glucose and galactose Glucose used in glycolysis Problem: How to metabolize other sugars in our diet Sol...

Pathways of Sugar Metabolism: Pentose Phosphate Pathway, Fructose & Galactose Metabolism Diet consists of fructose, glucose and galactose Glucose used in glycolysis Problem: How to metabolize other sugars in our diet Solution: Other pathways  Fructose sucrose Fructose found in diet in free form or as sucrose (also a product of the polyol pathway in eyes) Fructose forms into a glycolytic intermediate for generation of ATP (will discuss later) Liver most important organ *May account for 30-60% of dietary carbohydrate The Polyol Pathway Polyol pathway produces fructose from unused glucose in 2 steps 1. Aldolase reductase (glucose->sorbitol) 2. sorbitol dehydrogenase (sorbitol- >fructose) Net: C=O group shifted, NADPH oxidized and NAD+ reduced *polyol pathway contributes to cataracts, particularly in diabetics, due to the high concentrations of glucose and accumulation of sorbitol Fructose Metabolism Fructose metabolized in 3 unique steps (strategy to enter glycolysis): 1. F->F-1-P by fructokinase (costs ATP) 2. F-1-P->glyceraldehyde + DHAP (DHAP to glycolysis) by aldolase B 3. glyceraldehye->glyceraldehyde-3-P (costs ATP, to glycolysis) by triose kinase *In the liver, aldolase B has a dual functions with different substrates (F16P for glycolysis and F1P for fructose metabolism) Metabolism of Galactose Galactose metabolized in 2 steps (galactose primarily from lactose in milk) 1. Galactose->Galactose-1-P by galactokinase (costs ATP) 2. Galactose-1-P + UDP-Glucose->UDP- Galactose + Glucose-1-P by galactose- 1-P uridyltransferase (G1P then converted to G6P to enter glycolysis or be excreted as glucose by phosphomutase of glycogen pathway) Epimerase converts UDP-Galactose back to UDP-Glucose Galactosemia: accumulation of galactose due to deficiency of 1st or 2nd enzyme Overview of the Pentose Phosphate Pathway (a detour of glycolysis) G6P is substrate for pentose phosphate pathway (also glycolysis & glycogen formation) Oxidative & non-oxidative parts Oxidative part generates NADPH (i.e. reducing equivalents) NADPH used in other pathways In non-oxidative part, 5 carbon sugars converted to glycolysis intermediates (F6P and G3P) or used in nucleotide synthesis =>Bypass of glycolysis to generate NADPH and 5C sugars Oxidative Part of the Pentose Phosphate Pathway 3 steps in oxidative pathway 1. glucose 6-phosphate dehydrogenase (G6P->6-Phosphoglucono-d-lactone, generates a NADPH) 2. gluconolactonase (OH added to C5) 3. 6-phosphogluconate dehydrogenase (NADPH generated, C6->C5) *2 NADPH produced and product enters non-oxidative part  Epimerization Step Ribulose 5-phosphate forms xylulose 5- phosphate via epimerase (changes stereochemical position of OH) Products will be used to form glycolysis intermediates or nucleotides  Transketolase Transketolase converts 2XC5-> C3 + C7 *thiamine pyrophosphate coenzyme => We have G3P, a glycolytic intermediate, but what to do with sedoheptulose 7-phosphate? Answer: add another reaction step  Transaldolase Transaldolase converts C3 + C7 -> C4 + C6  Net Reactions of Pentose Phosphate Pathway 3 G6P produce 6 NADPH, 3 CO2, 2 fructose 6-P, glyceraldehyde 3-P (reducing equivalents and glycolysis intermediates) => 3 X C6 -> 3 X C5 + 3 X CO2-> -> 2 X C6 + C3 *no oxidation/reduction reactions occur in the “non-oxidative” part  Pathways That Require NADPH Pentose Pathway Generates NADPH for other Pathways: Detoxification (e.g. reduction of oxidized glutathione) Reductive synthesis (e.g. FA synthesis)  Hemolysis (Loss of RBC Membrane Integrity) Loss of pentose phosphate pathway leads to lack of NADPH Lack of NADPH leads to lack of reduced glutathione Lack of reduced glutathione leads to high levels of peroxide and oxygen stress, which cause hemolysis *Heinz bodies, cross-linked Hb, also lead to mechanical stress and hemolysis  Control of the Pentose Phosphate Pathway Cellular Needs =>