S81, S82: Integration of Intermediary Metabolism!Learning Objectives 1) Appreciate the differences between the major metabolic tissues in their fuel utilization. 2) Understand how these differences in fuel utilization reflect the unique roles of metabolic tissues in overall energy homeostasis. 3) Review some of the imp. catabolic and anabolic pathways and their major points of regulation. 4) Understand what limits anaerobic and aerobic exercise. 1) Appreciate the differences between the major metabolic tissues in their fuel utilization. - Brain - Neurons= most abundant cells in brain, produce neurotransmitters, specialized for conducting electrical signals along axons and dendrites!- major users of E and req. a steady supply of fuel to replenish their ATP pools!- use large amts of ATP to maintain ion gradients critical for conduction of nerve signals!- constantly making neurotrans for synaptic signaling!- glial cells= support neurons, supply nutrients to neurons, make myelin sheath!- Brain accounts for 20% of total O2 consumption and 25% of total body glucose utilization!- Most of E comes thru glycolysis, TCA cycle, and oxidative phosphorylation!- brain cells express low Km (high affinity) forms of glucose transport (GLUT1/GLUT3) and hexokinase --> rapid uptake and metabolism of glucose!- glucose metab in brain is NOT reg. by insulin, glugacon, others!- Metabolism!- Has very little glycogen stores, glucose can fall (<3mM) --> coma, seizures!- Long term fasting/starvation: brain can switch to ketone bodies for E (ex. acetoacetic acid and B-hydroxybutyric acid)!- Ketone bodies --> convert to acetyl CoA --> TCA cycle to support oxidative phosphory.!- Sphingolipids!- Brain is enriched in sphingolipids and glycolipids, they form components of neuronal membranes and myelin sheaths (ex. sphingomyelin, ganglioside)!- Blood- Brain Barrier= separates circulation in the brain from the rest of the body, brain has a privelaged circulation= cerebral spinal fluid (CSF)!- protects brain, selectively transports specific metabolites/nutrients!- has a low Km transport for glucose --> uptake even at low plasma levels!- has specific transporters for ketone bodies (for starvation)!- DOES NOT effectively take up non-essential fatty acids --> brain doesn't effectively use fatty acids for E.!- specialized transporters for uptake of essential fatty acids --> brain makes many complex lipids for special membranes!- Contains an active P450-drug metabolizing system sim. to liver --> forms an enzymatic barrier against harmful substances= Brain's detoxifying system!!- Neurotransmitters - Many neurotrans used in synaptic transmission are aa's (glycine, glutamate) or are directly syn. from aa's (tyrosine, glutamate...)!- Uptake of certain aa's across bbb is restricted so that they don't interfere w/highly reg. production of neurotrans!- ex. Glutamate (critical neurotrans) must be syn. in brain from 1 of these rxns:!- glutamate dehydrogenase!- transamination of a-ketoglutarate!- Erythrocytes= RBCs!- Highly spec. cells, use hemoglobin to carry O2!- Lack internal organelles (incl. mitochondria), have limited metabolic functions!- Completely dependent on glycolysis and substrate-level phosphorylation for meeting their E needs.!- To keep glycolysis running, they need to regen. NAD+ for glyceraldehyde-3-phosphate dehydrogenase rxn --> they do this thru lactate dehydrogenase!- Lactate formed is transported to liver to be used to make more glucose thru gluconeogenesis (Cori cycle) !- Glycolysis in RBCs makes substrate for formation of 2,3- BPG= an allosteric effector of O2 binding to hemoglobin!- 2,3-BPG made to Hg and decreases affinity for O2 --> facilitates the unloading of O2 in tissues!- 5-10% of glucose metab. by them used to make NADPH by pentose phosphate pathways !- use NADPH to maintain glutathione (GSH) in reduced state to protect against damage to proteins and lipids caused by ROS!- people can have genetic def. in glucose-6-phosphate dehydrogenase --> reduced ability to form NADPH --> anemia!- Have to RECHARGE the glutathione w/NADPH!- Insufficient levels of RBCs/hemoglobin --> anemia!- Iron def. anemia- most common form worldwide --> microcytic hypochromic anemia (small cells, decreased [ ] of hemoglobin)!- Def. in folate or vit B12 --> megaloblastic anemia (large, multinucleated immature RBCs due to decreased production of dNTPs to support DNA syn.)!- The Heart!- Works at constant rate of moderate work 100% of the time (unlike skeletal m.)!--> Can metabolize wide variety of fuel (fatty acids, glucose, lactate)!- Major fuel source for heart= fatty acid B-oxidation (70% of its E needs)!- lipoprotein lipase found in heart= highly eff. are harvesting fa's from triglys of chylomicrons or VLDLs!- has a lot of mitochondria to support B-oxidation, TCA cycle, oxidative phosphorylation!- can use ketone bodies, but prefers fa's (spares ketone bodies for brain)!- Contains a diff. isozyme of the bifunctional enzyme!- in liver: 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase reg. balance btween glycolysis and gluconeogenesis!- P-ed in response to glucagon --| inhibits it kinase activity --| flux thru glycolysis --> increase gluconeogenesis!- in heart: isozyme is P-ed in response to epinephrine --| biphosphatase activity --> promote formation of fructose-2,6-bisphosphate --> INCREASING glycolysis as an E source !- Skeletal Muscle--Controller of Work Functions!- Main fuels: glucose from diet or muscle glycogen and fatty acids!- Post meal --> resting m. syn. glycogen from circulating glucose for E store!- Long exercise --> m. switches to B-oxidation for most of its E!- Long fasting/starvation --> m. can use fatty acids and ketone bodies for fuel, m. protein catabolized (broken down) to provide gluconeogenic precursors to liver (use C skeleton to make glucose from protein in m.)!- Eat glucose --> goes to blood --> most goes to m. cells --> (insulin) can store it as glycogen! 2) Understand how these differences in fuel utilization reflect the unique roles of metabolic tissues in overall energy homeostasis. - See above 3) Review some of the imp. catabolic and anabolic pathways and their major points of regulation. 4) Understand what limits anaerobic and aerobic exercise. - Exercise Biochemistry - E Sources Change as Intensity Increases - Faster you run --> the more E comes from CHOs !!!!!!!!!!!!- Anaerobic Exercise!- During short, intense exercise: skeletal m. relies on anaerobic glycolysis fueled by
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