Energy stores in different organs for a 155 lb male, in Calories

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1 Energy stores in different organs for a 155 lb male, in Calories Organ Glucose/ Glycogen Triacyl Glycerols* Liver Brain Mobile Proteins Muscle 1, ,000 Adipose Tissue , * Fat molecules Fat tissue

2 Pyruvate is a hub. Interconversion of sugars and proteins Glycolysis no O 2 lactate Alanine, { transamination Glucose Pyruvate ATP Glycogen NAD,FAD H 2 O Oxidative Phosphorylation O 2, CO 2 Acetyl Co-A ADP, PO 4 Citric Acid Cycle CO 2 NADH / FADH CO 2

3 Identify the hubs Fig

4 There are relatively few hubs 5

5 Two-way traffic Traffic circles vs. switches Efficiency: intermediates common to both pathways. Gluconeogenesis: 7 of the ten enzymes of glycolysis are used for gluconeogenesis. Others: three glycolytic enzymes are replaced with four specific to gluconeogenesis for the purposes of regulation and energetics (ratchets).

6 Glycolysis vs. gluconeogenesis Of ten reactions in glycolysis, 7 run close to equilibrium, small changes in [S] or [P] can nudge them forward or backward. Exceptions: hexokinase, phosphofructokinase and pyruvate kinase: sites of metabolic regulation. These three reactions are mediated by different enzymes for gluconeogenesis.

7 Metabolic types Correlate w. possession of whole pathways, or not. eg. photosynthesis (we are comfortable with not having that). Glycolysis: and ancient and honourable pathway. Developed under anaerobic conditions and perpetuated in all known later forms of life. (There are a few other founder pathways too). Pathways that never got edged out. Table 17.2.

8 Energetics Glycolysis: C6H12O6 2 H3C-CHOH-COO - + 2H + No redox, net yield in ATP = 2 Energy yield: ΔG = -184 kj/mol total, 60 kj/mol captured as ATP. ATP: energy for stunningly diverse processes

9 NAD(P) Fig NADH vs. NADPH catabolic vs. anabolic and photosynthetic. NADH/NADPH: primarily chemical/electrochemical H - on a handle. Transduction of energy from chemical to electrochemical to H + gradient to mechanical back to chemical (ATP)

10 Pyruvate is a hub, feeding / draining the citric acid cycle. Glucose alanine, lactate ATP pyruvate oxaloacetate : low ATP, low 2C supply CO 2 Acetyl-CoA Citric A. cycle

11 The incentive to use the TCA cycle C 6 H 12 O O 2 -> 6 CO H 2 O Glycolysis + conversion to acetyl Co-A ΔG = kj/mol Glucose + 2 PO4 + 2 ADP + 4 NAD + -> 2 acetate + 2 CO2 + 2 ATP + 4 (3 ATP) 2 Acetyl Co-As through TCA cycle { } 2X 2 H2O + acetate -> 2 CO2 + GTP + 3 (3 ATP) + (2 ATP) 24 ATP from TCA cycle vs. 2 ATP from glycolysis alone, 38 ATP from glucose to CO2 including glycolysis, conversion to acetyl CoA and 12 TCA cycle (some energy lost for transport into mitochondria.)

12 Efficiency of energy capture: each ATP is worth 30.5 kj/mol Glucose + 2 PO ADP + 2 H -> 2 ethanol + 2 CO 2 + 2ATP + 2 H 2 O ΔG = -234 kj/mol, Energy captured in ATP = 61 kj/mol = 26% of possible for this reaction, 2% of glucose CO2 energy. Glucose + 2 PO ADP -> 2 lactate + 2ATP + 2 H 2 O ΔG = -115 kj/mol, Energy captured in ATP = 61 kj/mol = 53% of possible for this reaction, 2% of glucose CO2 energy. Glucose + 2 PO ADP + 4 NAD + -> 2 acetate + 2 CO 2 + 2ATP + 4 NADH + 4H + ΔG = -607 kj/mol, Energy captured in ATP = 427 kj/mol = 70% of possible for this reaction, 15% of glucose CO2 energy. Glucose + 6 O 2 -> 6 CO H 2 O + 4 ADP + 10 NADH +H + + 2FMNH 2 ΔG = kj/mol, Energy captured in ATP = 1159 kj/mol 13 = 41% of possible for this reaction: glucose CO2 energy.

13 BUT... The cost of transport of pyruvate into the mitochondria reduces this yield somewhat. 14

14 Entry into the mitochondrion Pyruvate dehydrogenase, see page 614 pyruvate + CoA + NAD + acetyl-coa + CO2 + NADH + H + Fig

15 Acetyl CoA, another control point pyruvate CO 2 :ATP, Co-A,citrate Ketones (Cholesterol) (acetoacetate, hydroxybutyrate, acetone) Acetyl Co-A Fatty acids, Fat β oxidation oxaloacetate, (via citric acid cycle) Citric Acid Cycle 3NADH + FADH + ATP per acetyl CoA

16 Glycolysis no O 2 { Glucose ATP Glycogen NAD,FAD H 2 O Oxidative Phosphorylation Alanine, lactate Pyruvate O 2, Ketones CO 2 Acetyl Co-A Fat ADP, PO 4 Citric Acid Cycle CO 2 NADH / FADH CO 2

17 Themes : The many many reactions that go on all the time in your cells are orchestrated and regulated by complex intercommunication: Hormonal regulation: insulin vs. glucagon, Feedback inhibition by downstream products, Stimulation by abundant starting materials. Catabolism vs. Anabolism at traffic intersections.

18 Brain Glucose is the preferred fuel for the brain Brain uses some 420 Cal/day 60% of resting state glucose consumption (Not stimulated during mental activity) Brain can t use fat, because it doesn t cross blood-brain barrier. Ketones are the brain s emergency fuel (liver supplies glucose and ketones).

19 Muscle Maintains a glycogen reserve, glucose is the preferred fuel for bursts of activity. During intense activity, when O 2 is depleted, does glycolysis. Pyruvate is converted to lactate or alanine, which are converted back to pyruvate for complete consumption, by liver (this borrows time). Muscle also transaminates amino acids to make them usable as fuels in the citric acid cycle. Resting muscle derives 85% of its energy from fatty acids. Heart muscle does not readily resort to glycolysis, and does not maintain glycogen reserves. Citric acid cycle activity is crucial. Fatty acids are the major fuel (ketones in a pinch).

20 Fat Tissue (Adipose tissue) Contains huge reservoir of fuel: fat. The triacyl glycerols need to be broken into fatty acids plus the glycerol backbone first. When triacyl glycerol is to be consumed, removal of the first fatty acid is rate limiting. This step is under hormonal regulation: stimulated by adrenalin (epinephrine). Fatty acids are synthesized in liver and assembled into triacyl glycerols in fat cells. An intermediate of glycolysis, DHA, is needed. If lots of glucose is available (and therefore lots of DHA) triacylglycerol is reformed. Otherwise the fatty acids are released into blood for use by other tissues.

21 To burn or to store? Unneeded Acetyl-CoA fatty acyl-coas = R-CoA, R = fatty acid. Glycolysis DHAP glycerol. 3 R-CoA + glycerol triacyl glycerol (a fat molecule). Liver cells lipoprotein triacyl glycerol 3 R-CoA + glycerol ( consumption) Blood R-CoA β oxidation in muscle/liver. R-CoA Fat cells : insulin? +glycerol? glycerol fat : adrenalin, glucagon

22 Liver A metabolic hub. (Be nice to your liver). Removes all sugars other than glucose from blood. Makes reserves of glycogen (up to 400 Cal worth). Leaves some glucose for other tissues. (which ones?) Excess glucose acetyl CoA fatty acids. When glucose runs short, makes it from lactate, alanine (muscle), glycerol (fat). When fuel is very scarce, uses fatty acids as fuel (β oxidation and ketone production). This is regulated in oppositely to fatty acid synthesis. When amino acids must be burned, the liver does this too, after removal of N and excretion as urea ( CO(NH 2 ) 2 ). The C skeletons (α keto acids) are used to make glucose or fatty acids. Liver uses α keto acids as fuel, NOT glucose, which it sends back into blood for the brain and muscle.

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24 Job One: Glucose Homeostasis (maintenance of a constant status). Brought to you by... The Liver.

25 Just after a meal Insulin rises, glucagon drops, in response to elevated blood glucose. Insulin stimulates glycolysis in liver, to make DHA fat. Insulin stimulates glycogen formation in muscle and liver, supresses gluconeogenesis in liver. Glucose itself inhibits glycogen degradation. Insulin stimulates uptake of amino acids by muscle too, and inhibits protein degradation.

26 Many hours after a meal (after the surge) Insulin levels drop again, glucagon is secreted as the glucose level drops. Lower insulin less uptake of glucose into muscle and fat. Glucagon acts at the liver to stimulate mobilization of glycogen. Also release of fatty acids from fat cells. It also inhibits glycogen formation and fatty acid synthesis. Muscle and liver use fatty acids as fuel, not glucose. Once glycogen is exhausted, glycerol from fat is used to make glucose for export to brain. Also, amino acids from protein.

27 Fasting Although a well-fed (healthy) adult carries reserves for 2-3 mo. Most of this is fat. Carbohydrate reserves are exhausted after 1 day. Blood glucose must be maintained for the sake of the brain. Fatty acids can t be made into glucose, only the glycerol. Proteins must be used, with loss of function. Instead, our organs undergo a metabolic shift, from glucose to fatty acids (liver) and ketones (brain). Muscles switch from glucose use (inhib. by low insulin) to fatty acids (β oxidation). Acetyl CoA and citrate rise and shut down glycolysis at point of production of acetyl CoA. Instead, pyruvate, alanine and lactate are used to make glucose (for brain).

28 Prolonged fasting (three days) Liver begins producing ketones and the brain increasingly uses these (acetoacetonate) instead of glucose. Ketones can be made from fatty acids, whose oxidation via the citric acid cycle is not possible any more now that oxaloacetate is depleted by gluconeogenesis. About a third of brain activity is now supported by ketones, and the heart begins to use these too. Several weeks into a fast Ketones become the major fuel for the brain (they can pass through the blood-brain barrier. Only 40 g glucose needed per day vs. 120 g on first fasting day. Fat is used instead of muscle (20 g/day vs. 75 g/day early on.) When fat runs out, you use protein, from muscle, heart, liver, kidney (and die).

29 Zubay, Figure

30 Zubay, Figure

31 Zubay, Figure

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