1. CHAPTER 15 Metabolism: Basic Concepts and Design

2. Chapter 15 – An overview of Metabolism Metabolism is the sum of cellular reactions -Metabolism – the entire network of chemical reactions carried out by living cells -Metabolites – small molecule intermediates in degradation and synthesis of polymers -Catabolic reactions – degrade molecules to create smaller molecules – produces energy -Anabolic reactions – synthesize molecules for cell maintenance, growth and reproduction – requires energy.

3. Figure 15.1-glucose metabolism The eventual fate of glucose is to convert it to CO 2 and H 2 O w/ the generation of ATP. The aerobic fate of pyruvate is to produce 3 CO 2 molecules

4. Figure 15.2: Many metabolic pathways are linked together

5. Key to all catabolic and anabolic reactions is that energetically unfavorable reactions can be driven by favorable reactions. Enzymes are good at coupling reactions when needed: unfavorable favorable The coupled reaction is favorable.

6. The Free Energy of ATP -Energy from oxidation of metabolic fuels is largely recovered recovered in the form of ATP Glucose + O 2  CO 2 + H 2 O and electron transport together makes ~ 32 ATPs per cycle ATP contains 2 phosphoanhydride bonds

7. ATP is an “energy-rich” compound It has lots of “stored energy” -A large amount of energy is released in the hydrolysis of the phosphoanhydride bonds of ATP (and GTP, UTP, CTP) -All nucleoside phosphates have nearly equal standard free energies (  G’s) of hydrolysis.

8. Why does ATP have so much stored energy?? 1. Electrostatic repulsion among negatively charged oxygens of phosphoanhydrides of ATP 2. Solvation of products (ADP and P i ) or AMP and PP i ) are better solvated by water than that of ATP 3. Resonance Stabilization of P i- Phosphates are particularly stable

9. Free energy (-45.6 kJ/mol) that can be coupled to unfavorable reactions Free energy (-30.5 kJ/mol) that can be coupled to unfavorable reactions The hydrolysis of ATP H2OH2O + PiPi H2OH2O + PP i (pyrophosphate)

10. Figure 15.6- ATP is centrally located in the phosphoryl-transfer reactions Notice the 1,3-BPG and PEP are more negative in  G o ’ these two will essentially drive the production of ATP in glycolysis. Excellent for Quick bursts of energy Clinical Insights

11. Figure 15.9 The ATP-ADP Cycle The oxidation of carbon fuels to generate reduced cofactors The oxidation of carbon fuels is linked with reduction

12. Reduced Coenzymes Conserve Energy from Biological Oxidation -Amino acids, monosaccharides and lipids are oxidized in the catabolic pathways - Oxidizing agents – accept electrons and is reduced - Reducing agents – lose electrons and is oxidized -Oxidation of one molecule must be coupled with the reduction of another molecule

13. Fuels that are highly reduced can be oxidized for energy Highly reduced carbon Highly oxidized carbon Electrons must be transferred but to what????? vs More reduced

14. Compound with high energetic phosphoryl groups attached can couple with carbon oxidation and electron transfer Other reactions are coupled to this oxidation reaction. However this reaction does not occur in one step as shown.

15. Electrons are transferred to a oxidizing agent (NAD + ) Oxidized Reduced

16. High energy 1,3-BPG can be used to drive the formation of ATP Very high energy phosphoryl compound

17. The electron carrier Nicotinamide adenine dinucleotide (NAD + ) Figure 15.12 Transfer of a hydride (H - ) Common redox reaction

18. The electron carrier Flavin adenine dinucleotide (FAD) Figure 15.13

19. Figure 15.16: the carriers of two carbon units (acetyl groups) Coenzyme A(CoA)

20. Coenzymes are derived from most vitamin supplements

22. Figure 15.19: Energy Charge Regulates Metabolism All ATP All AMP EC range is usually 0.80 to 0.95. EC range is usually 0.80 to 0.95.

23. Metabolic Pathways are Regulated -Biosythesis and degradation pathways have reactions in common. -Metabolism is highly regulated to permit organisms to respond to changing conditions -Most pathways contain one or more steps that are irreversible -These regulated, irreversible reactions are always distinct from within different pathways. -Flux – flow of material through a metabolic pathway Flux depends upon: - Supply of substrates - Removal of products - Properties of enzymes

24. Regulated pathway through a Allosteric Inhibition Flux through the pathway is regulated depending on the concentration of P -Product of a pathway controls the rate of its own synthesis by inhibiting an early step (usually the first “committed” step (unique to the pathway).

25. -Metabolite early in the pathway activates an enzyme further down the pathway B is an allosteric activator Regulated pathway through a Allosteric Activation

26. - Interconvertible enzymes can be rapidly and reversibly altered by covalent modification. - The addition/removal of phosphoryl groups is one example Kinases vs. Phosphatases

27. Assignment Read Chapter 15 Read Chapter 16