All metabolism is regulated to do one thing – maintain the brain!

1. Regulation of Metabolism All metabolism is regulated to do one thing – maintain the brain! What are we trying to regulate by altering the flux of fuels through these pathways? Why do you think these pathways are regulated at these points? What kind of regulation might be taking place? • Fuel supplies (blood glucose in particular) • Free energy • Big losses of free energy at these steps • Branch points in the pathway • Regulation of enzymes through • Allosteric regulation • Covalent modification (phosphorylation)

2. If you want to slow glucose utilization which enzymes are likely to be highly regulated? 1 2 • Free Energy Changes • Rxn# Enzyme DG°'(kJ/mol) • Hexokinase -16.7 • Phosphogluco-isomerase +1.7 • Phosphofructokinase -14.2 • 4 Aldolase +23.9 • Triose phos. Isomerase +7.6 • 6 G-3-PDH +12.6 • 7 Phosphoglycerate kinase -37.6 • 8 Phosphoglycerate mutase +8.8 • 9 Enolase +3.4 • 10 Pyruvate kinase -62.8 3 4 5 6 7 8 9 10

3. If you need glucose for the blood, which metabolic pathways are likely to be activated?

4. The means for regulating what goes on in the cell requires communication between different parts of the body. How will the cell know what to do unless it has information about other processes taking place? The main mechanisms for cell-to-cell communication are: the nervous system, the endocrine system, and local cell communication.

5. Endocrine regulation of metabolism Blood glucose is regulated by controlling enzymes that either help use glucose when energy is needed, or enzymes that help store glucose when it is in excess. This is typically done via hormonal control. Hormone = • Types: • peptide or protein = at least 3 amino acids • steroid = derived from cholesterol • amine = derived from single amino acids (tryptophan, tyrosine)

6. Peptide Hormones Synthesis/transport/half-life = Storage? Multiple processing patterns for protein hormones

7. Because peptides are impermeable, they must use membrane receptors and second messenger signal transduction mechanisms to produce the desired effects. Most use g-protein coupled receptors, but some use tyrosine kinase type receptors (i.e. insulin)

8. Steroid Hormones

9. Steroid hormone synthesis/storage/half-life Mechanism of cellular activation?

10. Amine hormones

11. Two Alternatives for Glucose Metabolism (and indirectly fat and protein metabolism): • Lots of glucose – indicates need for storage, energy for anabolic reactions (building proteins, fats, other tissues) is present. Principal hormone involved – insulin. • Low glucose – indicates stress conditions, low energy, anabolic reactions should wait, alternative fuels should be used to replace or make glucose. Principal hormones involved – glucagon, cortisol, epinephrine.

12. After a meal blood glucose is high • Cells in the pancreas sense [glucose] and release the peptide hormone insulin • Insulin circulates in the blood and attaches to receptors on target cells • Receptors translate insulin binding into an appropriate cellular response (lower blood glucose) via a second messenger signaling pathway. • In the case of insulin, the response is to insert glucose transporter proteins into the cell membrane so that glucose can enter the cell. Overall, the response helps to stop the initial signal. In this case, by moving glucose out of the blood, it stops the release of insulin from the pancreas.

13. When enzymes need to be regulated (i.e. when we need more energy to run away from a bear or to store excess glucose), a signal transduction cascade is activated by a hormone. • The hormone that signals storage of glucose is insulin. The enzymes that help regulate glucose storage (i.e. glycogen synthesis) or fat production (if you are really in excess) are in the “on” mode when insulin is present. • The hormones that signal low blood glucose are glucagon, cortisol, and epinephrine. • Most of these hormones (notcortisol) work on cells via second messenger signaling cascades called G-protein linked cAMP cascades. Regulation of Metabolic Enzymes

14. Cyclic AMP (cAMP) is made from ATP by the enzyme adenylyl cyclase. • In the cAMP signal transduction cascade, as long as the signaling hormone is bound to the receptor, adenylyl cyclase will continue to make cAMP. Generally, ONE molecule of hormone binding can result in hundreds of cAMP molecules being produced inside the cell. This is called AMPLIFICATION. • When the hormone is removed from the receptor, another enzyme, phosphodiesterase, converts cAMP back to AMP. This turns off the signal transduction when it isn’t needed.

16. In the case of glucagon, and epinephrine, most cells with receptors respond to hormonal activation by phosphorylating (activating) target enzymes. In the case of glucagon, the enzymes are involved in fat and protein catabolism, and gluconeogenesis. Epinephrine enhances these effects but also targets key enzymes in glycolysis, producing a quick burst of energy (to run away from the bear). Phosphorylation of target proteins

17. Cortisol is a steroid hormone that targets gene transcription. • One of its main functions with regard to glucose metabolism is to cause cells to make more of the enzymes involved with the catabolism of protein. • Those break down proteins into amino acids, which feed in to gluconeogenesis or provide ketones for alternative fuel source.

18. Tissues can be targeted by multiple hormones. How is this possible? Hormones can act synergistically, permissively, or antagonistically Synergistic effects of hormones on blood glucose concentration