Energy Metabolism Note PDF

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07.ENERGY METABOLISM OF CARBOHYDRATESAND LIPID1. GLYCOLYSIS: AN OVERVIEW2. GLYCOLYSIS – PART 1, THE ENERGY INVESTMENT PHASE3. GLYCOLYSIS – PART 2, THE ENERGY GENERATION PHASE4. GLYCOLYSIS: TEN-STEP PATHWAYA. Conversion of glucose to glucose-6-phosphate B. Conversion of gluccose-6-phosphate to fructo...

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07.02.2019

ENERGY METABOLISM OF CARBOHYDRATES AND LIPID 1. GLYCOLYSIS: AN OVERVIEW

2. GLYCOLYSIS – PART 1, THE ENERGY INVESTMENT PHASE

3. GLYCOLYSIS – PART 2, THE ENERGY GENERATION PHASE

4. GLYCOLYSIS: TEN-STEP PATHWAY A. Conversion of glucose to glucose-6-phosphate B. Conversion of gluccose-6-phosphate to fructose-6-phosphate C. Conversion of fructose-6-phosphate to fructose-1,6-bisphosphate D. Conversion fructose-1,6-bisphosphate to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate E. Conversion of dihydroxyacetone phosphate to glyceraldehyde-3-phosphate F.

Conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphate

G. Conversion of 1,3-bisphosphate to 3-phosphoglycerate H. Conversion of 3-phosphoglycerate to 2-phosphoglycerate I.

Conversion of 2-phosphoglycerate to phosphoenolpyruvate

J.

Conversion of phosphoenolpyruvate to pyruvate

5. STAGES OF CELLULAR RESPIRATION A. Stage 1: Generation of Acetyl CoA B. Stage 2: Citric Acid Cycle C. Stage 3: Oxidative Phosphorylation

6. FORMATION OF ACETYL COA A. Stage 1: Generation of Acetyl CoA i.

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Stage 1: The generation of an activated 2-carbon fragment: acetyl-CoA a cell can use different fuels other than glucose (via glycolysis) to generate acetyl-

CoA. It can also use amino acids and fatty acids – so carbohydrate, fat and protein all feed into the citric acid cycle.

7. OXIDATION OF PYRUVATE TO GENERATE ACETYL COA A. Pyruvate oxidation first involves its movement across the mitochondrial membrane by the pyruvate carrier

8. OVERVIEW OF LIPID METABOLISM A. Minimal digestion by lipases in saliva B. Stomach stores and emulsifies fatty food. Gradually transferred to duodenum. C. Small intestine: Lipases break fat into free fatty acids that are absorbed by the gut epithelial cells where they are resynthesized into triglycerol.

9. FAT DIGESTION AND ABSORPTION A. Bile salts: detergent substances- emulsify fat, allowing access of enzymes to digest fat. B. Lipids complex with protein to become soluble aggregates: lipoproteins C. Products of lipid digestion: Glycerol, free fatty acids, monoacylglycerols, diacylglycerols

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LIPID DIGESTION A. Lipases in the saliva and in the small intestine break triacylglycerol into glycerol and 3 free fatty acids. B. Short chain fatty acids are absorbed directly into the blood stream from the gut epithelial cells and transported to the liver attached to albumin C. Longer chain fatty acids and those still attached to glycerol (monoglycerides) are taken up into the ER of the gut epithelial cells and converted back to triacylglycerol for transportation.

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PRODUCTION OF ACETYL COA FROM FATTY ACIDS

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B-OXIDATION OF FATTY ACIDS

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B-OXIDATION IN THE MITOCHONDRIAL MATRIX

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B-OXIDATION OF FATTY ACIDS WITH AN ODD NUMBER OF CARBONS A. carboxylation – absolute requirement of biotin as co-enzyme B. Conversion of D-isomer to L-isomer C. Synthesis of succinyl CoA D. Succinyl CoA enters citric acid cycle directly

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ENTRY OF SUCCINYL COA FROM B-OXIDATION OF ODD NUMBERED FATTY ACIDS

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STAGE 2 OF CELLULAR RESPIRATION A. Stage 2: The oxidation of the 2 carbons in acetyl-CoA in the citric acid cycle to form 1 x GTP/ATP, 2 x CO2 and 4 pairs of electrons

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THE CITRIC ACID CYCLE A. Citrate synthase B. Aconitase C. Isocitrate dehydrogenase D. α-ketoglutarate dehydrogenase complex E. Succinate thiokinase F.

Succinate dehydrogenase

G. Fumarate hydratase 6

H.

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Malate dehydrogenase

i.

The 2 carbon atoms from the Acetyl CoA are released from the cycle as carbon dioxide.

ii.

Oxidation of NADH in the electron transport chain produces 3 ATP molecules. Oxidation of FADH 2 produces 2 ATP.

iii.

In total the citric acid cycle produces 12 ATP molecules for each molecule of acetyl CoA.

STAGE 3 OF CELLULAR RESPIRATION A. Stage 3: The electron transport chain. i.

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During this the reduced electron carrier get re-oxidised and ATP is synthesised. This process is catalysed by membrane bound enzymes in the inner mitochondrial membrane. The inner membrane is extensively stacked and folded into projections called cristae which greatly expand its surface area.

THE ELECTRON TRANSPORT CHAIN 7

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STORAGE OF EXCESS GLUCOSE A. Excess glucose is stored as glycogen (secondary energy store)

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i.

Glycogen is stored mainly in the liver where it is a source of glucose for all other organs.

ii.

Glycogen synthesis requires energy

DE NOVO FATTY ACID SYNTHESIS AND STORAGE Storage of Fatty Acids as Triacylglycerols (TAGs) A. The fatty acids are usually not the same type within a triacylglycerol molecule B. Glycerol 3-phosphate (to from glycerol) is produced by liver and adipocytes C. TAG only slightly water soluble – stored as oily droplets in WHITE adipocytes D. TAG stored in brown adipocytes serve as a source of heat through non-shivering thermogenesis. E. Liver exports TAGs packaged with other lipid and apolipoproteins to form very low-density lipoproteins (VLDLs)

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FAT AS AN ENERGY RESERVE A. More energy release than carbohydrates B. Denser than carbohydrates C. Insolubility of fat does not affect intracellular osmotic pressure. D. 70kg human = 500,000 kJ fuel reserves in body fat, 100,000 kJ in protein, 6800 kJ in glycogen, 300 kJ in free glucose E. Most of the energy in fat released as oxidation of fatty acids for many tissues (except brain)

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MOBILISATION: RELEASE OF FATTY ACIDS FROM TAGS A. ‘Lipolysis’ – achieved by lipases i.

Adipose triglyceride lipase

ii.

Hormone-sensitive lipase

iii.

Monoacylglycerol lipase

B. Fate of glycerol: transported through blood to liver, phosphorylated to glycerol-3-phosphate to form new TAGs C. Fate of fatty acids: bind to albumin, transported to tissues / cells, activated into CoA derivatives, oxidised in mitochondria.

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METABOLIC ENZYMES AND DISEASE – CASE STUDY A. A 34-year-old African-American man presented with fever and shortness of breath. Shortly afterwards, he developed pancreatitis and was treated with clindamycin (an antibiotic) and primaquine (an anti-malarial). B. Four days onto therapy haematuria was noted C. The patient’s haemoglobin fell from 11g/dL to 7.4g/dL, total bilirubin increased from 1.2 mg/dL to 4.3 mg/dL, and lactate dehydrogenase (LDH) increased from 248 IU/L to 612 IU/L.

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METABOLIC ENZYMES AND DISEASE – CASE STUDY ANSWER A. The patient is most likely suffering from glucose-6-phosphate dehydrogenase (G6PD) deficiency. B. G6PD is an enzyme involved in the pentose-phosphate pathway that is important for redox metabolism for our cells. It is especially true in erythrocytes, as it is the only source of NADPH. C. G6PD maintains NADPH levels, which in turn protects cells against oxidative stress. D. The haemolysis is due to primaquine, as it is an oxidant drug. E. A contraindication for primaquine is G6PD deficiency, as it has a risk of haemolytic anaemia – which we have seen here with our patient.

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PRINCIPLES OF GENE AND PROTEIN ANALYTICAL TECHNIQUES If you suspect an issue with a gene or protein, there are multiple techniques you can use to analyse these. A summary is below: A. PCR: Polymerase Chain Reaction i.

Amplifies DNA

ii.

Several varieties including semi-quantitative and quantitative

B.

Protein Analysis i.

Protein Extraction

ii.

Protein Quantification

iii.

Western blotting vs ELISA

C.

Co-Immunoprecipitation (Co-IP) i.

D.

Chromatin Immunoprecipitation (ChIP) i.

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Detects physical protein-protein interactions

Detects binding of protein to DNA...