MOLECULES IN METABOLISM

1. MOLECULES IN METABOLISM

2. Metabolic Chemistry Related to Overweight Reactions and molecules in the digestive process

3. THE FATE OF FOOD • Food is digested to produce molecules that are used to support life • In the context of body weight the fate of three classes of food are central • Carbohydrates (sugars) • Lipids (fats) • Amino acids (from proteins) • The metabolisms of all three overlap

4. METABOLIC CHEMISTRY • Catabolism and Anabolism • Molecular constituents of food are broken down into smaller molecules (catabolism) • for reassembly into larger molecules (anabolism) such as fats or proteins • for oxidation to CO2 and H2O and energy • A balance is required to maintain a stable organism - homeostasis

5. ENERGY STORAGE • Energy produced in metabolism is stored in an energy-rich molecule ATP • Adenosine triphosphate ATP – the battery of life • Biological processes requiring energy use ATP • The accessible energy in ATP lies in the triphosphate link • Removing one phosphate gives adenosine diphosphate (ADP) plus energy.

6. ADENOSINE TRIPHOSPHATE, ATP energy-storage bond triphosphate adenosine

7. ENERGY STORAGE IN ATP Adenosine triphosphate (ATP) - H2O - - - energy released H3PO4 - energy stored H2O - - H3PO4 The human body produces and consumes its own mass in ATP each day Adenosine diphosphate (ADP)

8. ENERGY PRODUCTION IN THE CELL • Energy is produced by oxidation of molecular fuels - small molecules derived from carbohydrates, lipids, proteins • The oxidation uses oxidised forms of coenzymes ultimately producing CO2, H2O and stored energy • Energy is stored directly as ATP or as reduced forms of coenzymes that ultimately reduce oxygen to H2O • Reduction of oxygen to H2O yields more ATP and oxidised form of coenzymes

9. MOLECULES IN METABOLISM • Organic molecules from metabolised nutrients often enter metabolic pathway reactions bound to a coenzyme. • Coenzyme A is an important coenzyme • Phosphate is often bound to organic molecules • Oxidation/reduction (electron transport) reactions use NADH NAD+

10. COENZYME A Usually written as HS-CoA HS-CoA activates organic molecules for metabolic reactions by binding through HS-group to give reactive “–CoA” species Acetyl-CoA is an important example

11. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) 1 phosphate nicotinamide phosphate adenine Important in oxidation/reduction reactions

12. NAD+ AS AN OXIDISING AGENT • NAD+ is the main coenzyme for oxidation reactions of metabolic fuels for energy • NAD+ oxidises other molecules forming NADH and H+ • NADH is oxidised back to NAD+ indirectly by oxygen to give H2O (the electron transport chain) • For each molecule of NADH reoxidised 2.5 molecules of ATP are produced from ADP • So energy from oxidising metabolic fuels is stored as ATP

13. ACETYL CoA – THE CROSSROADS carbohydrates glycogen glucose fats glycolysis proteins pyruvate fatty acids oxidation amino acids fatty acid oxidation acetyl-CoA fatty acid synthesis citric acid cycle CO2 + energy Glucose in excess of metabolic needs results in fat deposition

14. SOURCES OF ACETYL CoA • Three metabolic reactions of food components produce are linked • Glycolysis of glucose • Oxidation of fatty acids • Amino acid deamination • Each can act as a source of Acetyl-CoA • Acetyl-CoA is oxidised in the citric acid (Krebs) cycle producing energy

15. THE CITRIC ACID CYCLE • All air-breathing organisms use the citric acid cycle to generate energy • Several metabolic pathways deliver acetyl-CoA and other intermediates for the cycle: • Glycolysis of glucose via pyuvate to acetyl-CoA • Fatty acid oxidation via acetyl-CoA • Amino acid deamination via α-ketoacids

16. THE CITRIC ACID CYCLE CH3 C=O CO2- acetyl CoA SCoA C=O CH2 CO2- CO2- CO2- CO2 CH2 CH2 H - C HO-C - CO2- - CO2- HO-CH CH2 CO2- CO2- CO2- oxaloacetate citrate isocitrate CH2 Two carbon atoms enter as acetyl-CoA and are ejected as to CO2 CH2 CO2- C=O HOCH CO2- CO2- CO2- a-ketoglutarate CH2 CH2 CO2- CH CO2- CH2 CH2 malate CH C=O CH2 CO2- SCoA CO2- CO2 fumarate succinylCoA succinate

17. ENERGY FROM GLUCOSE OXIDATION • Three processes are involved • Glycolysis of glucose to two pyruvate molecules • Pyruvate oxidation to acetyl-CoA • Oxidation of acetyl-CoA to CO2in the citric acid cycle • Energy stored from oxidation of one molecule of glucose = 36 ATP after all reduced coenzymes are reoxidised

18. GLYCOLYSIS OF GLUCOSE TO PYRUVATE HC=O HC=O CH2O-P CH2OH CH2OH CH3 CH2O-P CH2O-P CH2 HC-OH HC-OH C=O C=O HC-OH HC-O-P C=O C=O C-O-P HO-CH HO-CH HO-CH HO-CH CH2O-P CH2OH CO2- HC-OH HC-OH HC-OH HC-OH HC-OH HC-OH HC-OH HC-OH CH2O-P CH2O-P CH2OH CH2O-P CH2O-P HC-OH HC=O glucose glucose 6-phosphate fructose 6-phosphate fructose 1,6-bisphosphate CO2- CO2- CH2O-P 2 2 2 2 HC-OH 2 CO2- pyruvate 2-phosphoglycerate bisphosphoglycerate phosphoenolpyruvate 3-phosphoglycerate Glycolysis of glucose yields 2 pyruvate + 2 ATP + 2 NADH

19. CONVERSION OF PYRUVATE TO ACETYL CoA CH3 HSCoA + NAD+ CO2 + NADH C=O CO2- CH3 acetyl CoA C=O SCoA

20. ACETYL CoA FROM OXIDATION OF FATTY ACIDS n n - 2 CH3 CH3 CH3 CH3 (CH2)n (CH2)n (CH2)n (CH2)n CH3 CH HC-OH C=O CH2 (CH2)n CH CH2 CH2 CH2 C=O C=O C=O C=O C=O SCoA SCoA SCoA SCoA SCoA CH3 acetyl CoA C=O SCoA

21. ACETYL CoA FROM GLUCOSE FOR FATTY ACID SYNTHESIS glycolysis pyruvate (cytosol) pyruvate (mitochondria) acetyl CoA (mitochondria) glucose in cytosol oxaloacetate CO2 citrate (mitochondria) acetyl CoA in cytosol malate (cytosol) oxaloacetate (cytosoL) citrate (cytosol) CO2 Fatty acid synthesis from acetyl CoA takes place in the cytosol

22. ACETYL CoA FROM GLUCOSE FOR FATTY ACID SYNTHESIS CH3 CH3 C=O C=O SCoA CO2- acetyl CoA C=O CH2 glycolysis pyruvate (mitochondria) glucose CO2- (cytosol) CO2- pyruvate (cytosol) (mitochondria) oxaloacetate oxaloacetate (cytosol) CO2- CO2 CH2 CO2- HO-C-CO2- HO-CH2 CH3 CH2 acetyl CoA in cytosol CH2 C=O CO2- CO2 CO2- SCoA citrate (cytosol) citrate (mitochondria) malate (cytosol)

23. AMINO ACID METABOLISM • Amino acids, from protein hydrolysis, can be deaminated to form α-ketoacids • Some α-ketoacids can be converted to pyruvate or to other intermediates in the citric acid cycle for glucose synthesis • Others are converted into acetyl-CoA, used in fatty acid synthesis

24. LIPID (FAT) SYNTHESIS • Lipids (fats) are fatty acid esters of glycerol • Fatty acids are synthesised by sequential addition of two-carbon units to acetyl-CoA • Acetyl CoA is derived from several sources, egglycolysis of glucose, from dietary carbohydrates • Acetyl CoA is produced in the mitochondria but fatty acid synthesis takes place in the cytosol • Lipids are synthesised from fatty acids in adipose tissue and in the liver • Fatty acids for lipid synthesis can also arise from dietary fats

25. FATTY ACID SYNTHESIS FROM ACETYL CoA growing fatty acid chain C=O SACP C=O CO2- CO2- R R R R R SCoA HC CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 malonylCoA CH3 acetyl CoA C=O SCoA HC HC-OH CH2 C=O C=O C=O C=O C=O C=O SACP SACP SACP SACP SACP malonyl ACP

26. CHEMICAL CONTROLS • Hormones are chemicals messengers released by a cell or a gland in one part of the body that transmit messages that affect cells in other parts of the organism. • Important hormones in human metabolism include: • Ghrelin- the hunger-stimulating hormone • Leptin-the satiety (full-feeling) hormone • Glucagon - the stored glucose releasing hormone • Insulin - stimulates the formation of stored fat from glucose • Insulin and glucagon are part of a feedback system to regulate blood glucose levels • Leptin production is suppressed by abdominal fat.