Gluconeogenesis - Lecture notes 1 PDF

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Gluconeogenesis Lecture...

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Gluconeogenesis        

Glucose formation from non-carbohydrate precursors Carbohydrates are important molecules in biological systems Synthesis of carbohydrate containing biological molecules relies on a source of activated monosaccharides These activated molecules can be derived from non-carbohydrate precursors e.g. seedlings, bacteria, starving mammals Major site of Gluconeogenesis is the liver – little takes place in muscle or brain Helps maintain blood glucose levels so brain and muscle can extract it Converts pyruvate into glucose – not the reverse of glycolysis Precursors first converted to pyruvate or enter pathway further along (at Oxaloacetate or DHAP)

Glucose    

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Primary fuel for the brain normally glucose Only fuel for Red Blood Cells is glucose Daily requirement for glucose 160g (Brain 120g) Readily available glucose (sufficient for 1 day) - 20g Body fluids - 190g Glycogen What about longer periods of starvation or prolonged exercise?

Major Precursors   

Lactate – Skeletal muscle when glycolysis exceeds oxidative metabolism Amino acids – Diet or during starvation (Muscle breakdown) not leucine or lysine Glycerol – Hydrolysis of TAG yields glycerol and fatty acids

Gluconeogenesis Vs Glycolysis   

Equilibrium of glycolysis lies far in the direction of Pyruvate production Mostly due to the three irreversible reactions (Hexokinase, PFK and Pyruvate Kinase) These reactions must be bypassed during Gluconeogenesis

Irreversible Steps in Glycolysis    

Glucose +ATP  Glucose 6-Phosphate +ADP Fructose 6-Phosphate +ATP  Fructose 1,6-bisphosphate+ADP Phosphoenolpyruvate +ADP  Pyruvate +ATP These steps must be bypassed in gluconeogenesis

Bypass 1: Pyruvate to PEP  Two step process 1. Carboxylation of pyruvate to oxaloacetate by Pyruvate Carboxylase - Anaplerotic Reaction (“Fill Up”) 2. Step 2: Decarboxylation and phosphorylation of oxaloacetate by Phosphoenolpyruvate Carboxykinase - GTP required (donates the phosphate group) - Enzyme located both in cytosol and mitochondria - Mitochondrial Phosphoenolpyruvate Carboxykinase used if lactate is glucogenic precursor (Lactate to Pyruvate yields NADH) - Cytosolic Phosphoenolpyruvate Carboxykinase used if pyruvate is glucogenic precursor (Used if reducing equivalents low i.e. NADH needed) Oxaloacetate Shuttle    

Cytosolic Phosphoenolpyruvate Carboxykinase used if pyruvate is glucogenic precursor. (Used if reducing equivalents low i.e. NADH needed) Oxaloacetate cannot directly diffuse out Converted to Malate which leaves via specific transporter Malate converted back to Oxaloacetate with concomitant production of NADH (required later)

Mitochondrial Phosphoenolpyruvate Carboxykinase  

Mitochondrial Phosphoenolpyruvate Carboxykinase used if lactate is glucogenic precursor (Lactate to Pyruvate yields NADH) The NADH generated in the cytosol is used for the conversion of 1, 3 bisPglycerate to glyceraldehyde 3 phosphate by the enzyme Glyceraldehyde 3-phospahte dehydrogenase further up the pathway

Bypass 2: Fructose 1,6-bisP to Fructose 6-P     

PEP is metabolised by the enzymes of glycolysis but in reverse until Fructose 1,6-bisP is formed The reactions are near equilibrium so when conditions favour gluconeogenesis they will be driven in the direction of Fructose 1,6-bisP PFK catalyses an irreversible step likewise Fructose 1,6-bisP to Fructose 6-P is irreversible The enzyme responsible is Fructose 1,6-bisphosphatase which is an allosteric enzyme - Catalyses the hydrolysis of the C1 phosphate group Fructose 1,6-bisphophate + H2O  fructose 6-phosphate + Pi

Bypass 3: Glucose 6-P to Glucose    

In most tissues conversion of Fructose 6-P to Glucose 6-P is the end of Gluconeogenesis However tissues responsible for maintaining blood glucose homeostatis (Liver and Kidney) need to convert glucose 6-P to Glucose Muscle cannot directly increase blood [glucose] Takes place in ER

Gluconeogenesis and Glycolysis are Reciprocally Regulated The Cori Cycle      

Lactate formed by active muscle is converted to glucose by the liver Lactate produce by active muscle and RBC Lactate dead end product of metabolism Well oxygenated cells convert lactate to pyruvate which enters TCA cycle e.g. cardiac muscle Excess lactate enters liver and converted to glucose Maintains blood glucose levels

Lactic acid Production during Anaerobic Activity  

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Vertebrates are mainly aerobic organisms (pyruvate is completely oxidised to CO2 and water) During extreme muscular activity oxygen delivery to muscle is lower than oxygen requirements for oxidation of NADH NADH is oxidised by transfer of electrons to pyruvate to form lactate Lactic acid dissociates to lactate and H+ The pH (-log[H+]) therefore decreases Muscle pain and failure to contract Activity decreases “Oxygen debt” reduced in about 30 mins by conversion of lactic acid to glucose by gluconeogenesis in the liver

Vertebrate Size and Anaerobic Metabolism  

Smaller vertebrates rarely rely on anaerobic metabolism e.g. migrating birds fly large distances without producing an oxygen debt Larger vertebrates are often slow moving and rarely undertake intense muscular activity e.g. elephants and alligators

Glyoxylate Cycle (Not in Exam)     

Pathway by which plants and microorganisms can convert fatty acids (other compounds which yield acetyl CoA) into glucose Acetyl CoA generated by b-oxidation is converted into glucose via glyoxylate cycle and gluconeogenesis Decarboxylation reactions of TCA cycle bypassed so the carbon of acetyl CoA is assimilated Isocitrate cleaved to glyoxylate and succinate (metabolised by TCA enzymes to OA then to glucose by gluconeogenesis) Glyoxylate condenses with another acetyl CoA to generate malate which is oxidised to generate OA for another round of the cycle...