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BIOC/DENT/PHCY 230 LECTURE 2

BIOC/DENT/PHCY 230 LECTURE 2. Lactate dehydrogenase. pyruvate + NADH lactate + NAD +. M and H subunits: 5 isozymes M subunit has a lower affinity for pyruvate i.e. a higher K M M-type predominates in anaerobic tissues. M 4 predominates in muscle and liver

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BIOC/DENT/PHCY 230 LECTURE 2

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  1. BIOC/DENT/PHCY 230 LECTURE 2

  2. Lactate dehydrogenase pyruvate + NADH lactate + NAD+ M and H subunits: 5 isozymes M subunit has a lower affinity for pyruvate i.e. a higher KM M-type predominates in anaerobic tissues

  3. M4 predominates in muscle and liver This isozyme can tolerate high concentrations of lactate Can either: continue to convert pyruvate to lactate under anaerobic conditions OR recycle lactate to pyruvate

  4. Cori Cycle Lactate produced in skeletal muscle can be recycled in the liver

  5. H4 predominates in heart (aerobic tissue) H4 favours lactate to pyruvate Cardiac cells are permeable to lactate This isozyme: has a low KM for pyruvate and lactate AND is allosterically inhibited by high concentrations of pyruvate This prevents intracellular pH dropping to levels which may affect cellular function

  6. Regulation of glycolysis In general: Inhibited by: ATP, pyruvate, fatty acids, ketone bodies, citrate. Co-ordinately regulated with: glycogen metabolism, gluconeogenesis, pentose phosphate pathway, CAC.

  7. O2 glucose consumption Pasteur effect: no O2 anaerobic yeast Increase in G-6-P and F-6-P Decrease in all intermediates from F-1,6-BP

  8. Oscillations in glycolytic intermediates NADH ATP ADP NAD+ AMP lactate Start with aerobic yeast culture NAD+ NADH

  9. hexokinase phosphofructokinase (PFK) pyruvate kinase Regulatory steps of glycolysis: 3 key control points

  10. Glucose glucose-6-phosphate - increased levels of G-6-P signal high levels of ATP and glycolytic intermediates Hexokinase:

  11. phosphoenolpyruvate pyruvate + ATP Pyruvate kinase: Four subunit enzyme 3 isozymes (L, M, A) Inhibited by: ATP, acetyl-CoA, alanine, glucagon Activated by: fructose-1,6-bisphosphate

  12. pyruvate kinase +

  13. Key regulatory enzyme of glycolysis Homotetramer: Mr = 360,000 reversibly dissociates to dimer (active form) Inhibited by: ATP, citrate pH Phosphofructokinase

  14. ATP inhibition: Allosteric inhibition: increases KM @ low [ATP] PFK in R-state @ high [ATP] PFK in T-state R T

  15. Citrate inhibition: Citrate enhances allosteric PFK ATP binding High levels of citrate indicate sufficient CAC intermediates \ no need to metabolise (waste) glucose

  16. NAD+ lactate pH inhibition: Intracellular pH drops under anaerobic conditions Caused by a build up of lactate Low pH decreases PFK activity

  17. PFK activation Activated by: AMP, ADP, F-2,6-BP [AMP] and [ADP] signal low energy state Fructose-2,6-bisphosphate is an alternative product of F-6-P metabolism Low concentrations of F-2,6-BP activate PFK [F-2,6-BP] increases the affinity of PFK for F-6-P - acts through decreasing ATP inhibition of PFK

  18. PFK-1 PFK-2 P [F-2,6-BP] increases as [F-6-P] increases

  19. Why is this important? - + Fructose-2,6-BP Glucose hexokinase Glucose-6-P Fructose-6-P PFK Fructose-1,6-BP

  20. The take home message: Lactate can be recycled as a fuel LDH isoenzymes influence how lactate is processed by different tissues Glycolysis is tightly regulated in accordance with environmental and intracellular conditions There are three key enzymatic reactions involved in the regulation of glycolysis

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