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Recall that there are 2 G3P per glucose.. Exergonic oxidation of the aldehyde in glyceraldehyde-3- phosphate, to a carboxylic acid, drives formation of.

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Presentation on theme: "Recall that there are 2 G3P per glucose.. Exergonic oxidation of the aldehyde in glyceraldehyde-3- phosphate, to a carboxylic acid, drives formation of."— Presentation transcript:

1 Recall that there are 2 G3P per glucose.

2 Exergonic oxidation of the aldehyde in glyceraldehyde-3- phosphate, to a carboxylic acid, drives formation of an acyl phosphate, a "high energy" bond (~P). This is the only step in Glycolysis in which NAD + is reduced to NADH.

3 7. Phosphorylation by Phosphoglycerate Kinase: 1,3-bisphosphoglycerate + ADP  3-phosphoglycerate + ATP The enzyme undergoes substrate-induced conformational change similar to that of Hexokinase. (hinge) Pi is transferred from substrate to ATP

4 1, 3 BPG has higher phosphoryl potential that ATP such that Pi can be transferred to ATP. This is called substrate level phosphorylation: since Pi donor is a substrate with high phosphoryl potential. (differs from ETC making ATP.)

5 8. Isomerization by Phosphoglycerate Mutase: 3-phosphoglycerate  2-phosphoglycerate Phosphate is shifted from the OH on C3 to the OH on C2.

6 isomerase enzyme that catalyzes the structural rearrangement of isomers. Mutase: enzyme that catalyzes the shifting of a functional group from one position to another within the same molecule EC 5 Isomerases EC 5.4 Intramolecular transferases EC 5.4.2 Phosphomutases that transfer phospho groups EC 5.4.2.1 D-phosphoglycerate 2,3-phosphomutase

7 An active site histidine side-chain participates in P i transfer, by donating & accepting phosphate. The process involves a 2,3bisphosphate intermediate. Enz-His-Pi + 3PG <  Enz-His + 2,3BPG Enz-His + 2,3BPG <  Enz-His-Pi + 2PG 2, 3 BPG Pi donor and regenerated

8 9. Dehydration by Enolase: 2-phosphoglycerate  phosphoenolpyruvate + H 2 O This dehydration reaction is Mg ++ -dependent. 2 Mg ++ ions interact with oxygen atoms of the substrate carboxyl group at the active site. The Mg ++ ions help to stabilize the enolate anion intermediate that forms when a Lys extracts H + from C #2.

9 9. Dehydration by Enolase: 2-phosphoglycerate  phosphoenolpyruvate + H 2 O enolate anion

10 http://www.biochem.wisc.edu/faculty/rayment/lab/gallery_jpgs/enolase.jpg

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12 10. Phosphorylation by Pyruvate Kinase: phosphoenolpyruvate + ADP  pyruvate + ATP Again a substrate-level phosphorylation with PEP have a high phosphoryl potential.

13 10. Phosphorylation by Pyruvate Kinase: phosphoenolpyruvate + ADP  pyruvate + ATP Pyruvate Kinase is highly regulated also! Allosterically regulated by ATP, if there is enough then we don’t need to go through glycolysis to make more! BUT it is also regulated by.. Alanine

14 Pyruvate Kinase it is also regulated by.. Alanine So if there is a lot of alanine in the cell, it tells the cell that there is a lot of pyruvate, therefore enough ATP!!!! transaminase

15 High [glucose] within liver cells causes a transcription factor to activate transcription of the gene for Pyruvate Kinase. This facilitates converting excess glucose to pyruvate, which is metabolized to acetyl-CoA, the main precursor for synthesis of fatty acids, for long term energy storage. Pyruvate Kinase, the last step Glycolysis, is controlled in liver partly by modulation of the amount of enzyme.

16 Pyruvate kinase Pyruvate kinase has at least three isozymes and one of them is liver-specific. The liver pyruvate kinase is being regulated differently than other tissue type.

17 Pyruvate Kinase 3 isozymes ATP, AcSCoA, long chain fatty acids inhibit all isozymes L inhibited by phosphorylation by glucagon –activated cAMP-dependent protein kinase (low blood sugar  cAMP) M activated by cAMP in response to epinephrine (G- protein system)

18 Regulation of pyruvate kinase cAMP dependent

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20 Flux through the Glycolysis pathway is regulated by control of 3 enzymes that catalyze spontaneous reactions: Hexokinase, Phosphofructokinase & Pyruvate Kinase. Local control of metabolism involves regulatory effects of varied concentrations of pathway substrates or intermediates, to benefit the cell. Global control is for the benefit of the whole organism, & often involves hormone-activated signal cascades. Liver cells have major roles in metabolism, including maintaining blood levels various of nutrients such as glucose. Thus global control especially involves liver.

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23 Recall that there are 2 G3P per glucose.

24 Glycolysis Balance sheet for ~P bonds of ATP: How many ATP ~P bonds expended? ________ How many ~P bonds of ATP produced? (Remember there are two 3C fragments from glucose.) ________ Net production of ~P bonds of ATP per glucose: ________ 2 4 2 http://www.youtube.com/watch?v=mmACA_eVLTE

25 Balance sheet for ~P bonds of ATP:  2 ATP expended  4 ATP produced (2 from each of two 3C fragments from glucose)  Net production of 2 ATP per glucose. Glycolysis - total pathway, omitting H + : glucose + 2 NAD + + 2 ADP + 2 P i  2 pyruvate + 2 NADH + 2 ATP In aerobic organisms:  pyruvate produced in Glycolysis is oxidized to CO 2 via Krebs Cycle (can also be stored as fatty acids)  NADH produced in Glycolysis & Krebs Cycle is reoxidized via the respiratory chain, with production of much additional ATP.

26 Glycolysis Enzyme/Reaction  G o ' kJ/mol  G kJ/mol Hexokinase-20.9-27.2 Phosphoglucose Isomerase+2.2-1.4 Phosphofructokinase-17.2-25.9 Aldolase+22.8-5.9 Triosephosphate Isomerase+7.9 negative Glyceraldehyde-3-P Dehydrogenase & Phosphoglycerate Kinase -16.7-1.1 Phosphoglycerate Mutase+4.7-0.6 Enolase-3.2-2.4 Pyruvate Kinase-23.0-13.9 *Values in this table from D. Voet & J. G. Voet (2004) Biochemistry, 3 rd Edition, John Wiley & Sons, New York, p. 613. net -44.2

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28 Other Sugars

29 Other Fates

30 Figure 6.8 Glucose 2 Pyruvic acid

31 Glycolysis, omitting H + : glucose + 2 NAD + + 2 ADP + 2 P i  2 pyruvate + 2 NADH + 2 ATP Fermentation, from glucose to lactate: glucose + 2 ADP + 2 P i  2 lactate + 2 ATP Anaerobic catabolism of glucose yields only 2 “high energy” bonds of ATP.

32 What Are the Metabolic Fates of NADH and Pyruvate Produced in Glycolysis? NADH is energy - two possible fates: If O 2 is available: NADH is re-oxidized in the electron transport pathway, making ATP in oxidative phosphorylation If O 2 is not available (anaerobic conditions): NADH is re-oxidized by lactate dehydrogenase (LDH), providing additional NAD + for more glycolysis

33 What Are the Metabolic Fates of NADH and Pyruvate Produced in Glycolysis? Pyruvate is also energy - two possible fates: If O 2 is available pyruvate enters the mitochondria, where it undergoes further breakdown If O 2 is not available (anaerobic conditions) fermentation occurs and pyruvate undergoes reduction Fermentation is an anaeorbic process and does not require oxygen. In humans, pyruvate is reduced to lactic acid during fermentation.

34 What happens when oxygen is not available? Cells turn to fermentation. During fermentation, pyruvate formed by glycolysis is reduced to lactate. The reduction of pyruvate to lactate regenerates NAD+ from NADH. The NAD+ is free to pick up more electrons during early steps of glycolysis This keeps glycolysis going.

35 Fermentation in Human Muscle Cells Human muscle cells can make ATP with and without oxygen They have enough ATP to support activities such as quick sprinting for about 5 seconds A secondary supply of energy (creatine phosphate) can keep muscle cells going for another 10 seconds To keep running, your muscles must generate ATP by the anaerobic process of fermentation Pyruvate is reduced by NADH, producing NAD+, which keeps glycolysis going In human muscle cells, lactic acid is a by-product

36 Glucose 2 Pyruvate

37 Figure 6.15a 2 ADP+ 2 Glycolysis Glucose 2 NAD  2 Pyruvic acid + 2 H  2 NAD  2 Lactic acid (a) Lactic acid fermentation LDH

38 Skeletal muscles ferment glucose to lactate during exercise. Lactate released to the blood may be taken up by other tissues, or by skeletal muscle after exercise, and converted via Lactate Dehydrogenase back to pyruvate, which may be oxidized in Krebs Cycle or (in liver) converted to back to glucose via gluconeogenesis

39 Lactate serves as a fuel source for cardiac muscle as well as brain neurons. Astrocytes, which surround and protect neurons in the brain, ferment glucose to lactate and release it. Lactate taken up by adjacent neurons is converted to pyruvate that is oxidized via Krebs Cycle.

40 Some anaerobic organisms metabolize pyruvate to ethanol, which is excreted as a waste product. NADH is converted to NAD + in the reaction catalyzed by Alcohol Dehydrogenase.

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42 Advantages and Disadvantages of Fermentation Fermentation can provide a rapid burst of ATP in muscle cells, even when oxygen is in limited supply. Lactate, however, is toxic to cells. Initially, blood carries away lactate as it forms; eventually lactate builds up, lowering cell pH, and causing muscles to fatigue. Oxygen debt occurs, and the liver must reconvert lactate to pyruvate.

43 Efficiency of Fermentation Two ATP produced during fermentation are equivalent to 14.6 kcal. Complete oxidation of glucose to CO 2 and H 2 O represents a yield of 686 kcal per molecule of glucose. Thus, fermentation is only 2.1% efficient compared to cellular respiration. (14.6/686) x 100 = 2.1%


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