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1Biochemistry department GluconeogenesisDr. Sooad Al-DaihanBiochemistry department
2IntroductionSome tissues, such as the brain, and red blood cells require a continuous supply of glucose as a metabolic fuel.During a prolonged fast, hepatic glycogen stores are depleted, and glucose is formed from precursors such as lactate, pyruvate, glycerol, and α-ketoacids by a special pathway, gluconeogenesis, that requires both mitochondrial and cytosolic enzymes.
4Gluconeogenesis occurs mainly in liver. It also occurs to a more limited extent in kidney & small intestine under some conditions. Synthesis of glucose from pyruvate utilizes many of the same enzymes as Glycolysis.Almost reverse of glycolysis except for 3 reactions ,which are essentially irreversible.Hexokinase (or Glucokinase)PhosphofructokinasePyruvate Kinase.These steps must be bypassed in Gluconeogenesis.
5Four enzymes are needed to reverse the 3 irreversible steps of glycolysis: Mitochondrial ‐ Pyruvate Carboxylase (liver, kidney but not in muscle)Cytoplasmic ‐ Phosphoenolpyruvate (PEP) CarboxykinaseCytoplasmic ‐Fructose‐1,6,‐BisphosphataseCytoplasmic ‐Glucose 6‐Phosphatase
61-Bypass of Pyruvate Kinase: In gluconeogenesis PK is bypassed by 2 enzyme catalyzed reactions:1- Pyruvate Carboxylase :Pyruvate is carboxylated to oxaloacetate in the mitochondria .pyruvate + HCO3- + ATP oxaloacetate + ADP + Pi2- PEP Carboxykinase :Oxaloacetate is decarboxylated and phosphorylated to yield PEP in the cytosol .oxaloacetate + GTP PEP + GDP + CO2
8fructose‐1,6‐bisP + H2O fructose‐6‐P + Pi 2- Bypass of Phosphofructokinase:In gluconeogenesis PFK bypassed by Fructose 1,6 ‐ bisphosphatase reaction (Removes phosphate group)fructose‐1,6‐bisP + H2O fructose‐6‐P + Pi3- Bypass of Hexokinase (or Glucokinase)In gluconeogenesis this reaction bypassed by glucose 6‐phosphatase reaction (Removes phosphate group) :Glucose-6‐P + H2O Glucose+ PiFree glucose is formed by the action of glucose‐6‐ phosphatase in liver and kidney while it is absent in muscles and adipose tissuesGlucose can not be formed by these organs
9Total Energy Cost 6 high energy bonds used per glucose synthesized 4 are needed to convert pyruvate to PEP2ATP are utilized by pyruvate carboxylase2GTP are utilized by PEP carboxyKinase2 are utilized for reversal of phsphoglycerate kinase
10Precursors for Gluconeogenesis i- Cori CycleLactate released by active skeletal muscle or red blood cells is carried to the liver where it is converted to glucose by gluconeogenic pathway (Cori cycle) and released for reuptake by skeletal muscleii- Glucose-Alanine CycleProtein broken down in skeletal muscle during exerciseAmino acids converted to alanine and released by skeletal muscleTaken up by liver and converted to glucose and released for reuptake by skeletal muscle
11iii- GlycerolGlycerol released from adipocytes and skeletal muscle during lipolysis. Glycerol enters gluconeogenic pathway as dihydroxyacetone phosphate “active form of glycerol”. 2 glycerol required to make one glucose in liver and kidney in fasting or low CHO diet .Glycerol cannot be utilized in adipose tissue due to the lack of glycerol kinase in the adipose tissue.
12iv- Propionate:Propionyl‐CoA is converted to the TCA intermediate, succinylCoA.This conversion is carried out by the ATP‐requiring enzyme, propionyl‐CoA carboxylase then methylmalonyl‐CoA epimerase and finally the vitamin B12 requiring enzyme, methylmalonyl‐CoA mutaseThe utilization of propionate in gluconeogenesis only has quantitative significance in ruminants.
13Regulation of Gluconeogenesis Control of glycolysis and gluconeogenesis is reciprocalGluconeogenesis and Glycolysis are regulated by similar effector molecules but in the opposite directionWhen one pathway is activated , the other is inhibitedGluconeogenesis is subject to both:- Hormonal control by Glucagon, Cortisol, Adrenaline and Insulin- Allosteric regulation of gluconeogenic enzymes
14Hormonal Regulation Glucagon, Cortisol, Adrenaline Are secreted during fasting, stress and sever muscular exerciseInduce gluconeogenic enzymesRepress glycolytic enzymesInsulinSecreted after CHO mealInduce glycolytic enzymesRepress gluconeogenic enzymes
16Biochemistry department Uronic Acid PathwayDr. Sooad Al-DaihanBiochemistry department
17OverviewIt is an alternative oxidative pathway for glucose that doesn’t lead to ATP generation.It includes oxidation of glucose toGlucuronic acidAscorbic acidIt occurs mainly in the liver cytoplasm.
18Metabolic reactionsGlucose 6-phosphate is isomerized to glucose 1-phosphateGlucose 1-phosphate reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyrophosphorylaseUDPGlc is oxidized at carbon 6 by NAD-dependent UDPGlc dehydrogenase in a two-step reaction to yield UDP-glucuronate123
19UDP Glucuronic acid (active form) is needed in: Conjugation to less polar compounds as bilirubin, steroids and some drugs making them more water soluble (detoxicated) .Synthesis of glycosaminoglycans (mucopolysaccharide) as heparin, hyaluronic acid.In plants and some animals (not Human) glucuronic acid serves as a precursor of L-ascorbic acid.The uronic acid pathway also provides a mechanism by which dietary D-xylulose enter the central pathway.