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Carbohydrate anabolism

Carbohydrate anabolism. We have covered some aspects of carbohydrate catabolism: glycolysis, PPP, citric acid cycle, etc. and now we turn to carbohydrate anabolic pathways that utilize ATP and reducing power for biosynthesis (ATP used to make favorable reactions)

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Carbohydrate anabolism

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  1. Carbohydrate anabolism • We have covered some aspects of carbohydrate catabolism: glycolysis, PPP, citric acid cycle, etc. and now we turn to carbohydrate anabolic pathways that utilize ATP and reducing power for biosynthesis (ATP used to make favorable reactions) • Anabolic pathways are generally reductive rather than oxidative • We will use this tact in the future to cover the metabolism of amino acids, lipids, etc.

  2. Which way am I going? • It’s easiest to consider metabolic pathways as simple linear processes where A leads to B, B to C, etc. • BUT, anabolic and catabolic pathways proceed simultaneously (albeit at different rates) producing a dynamic steady state

  3. Levels of organization • Although they may share many reactions, biomolecules are synthesized and degraded via different pathways. • Each catabolic and anabolic pathways has at least one unique enzymatic reaction that is essentially irreversible • If not for this, flux through metabolic pathways would solely be due to mass action

  4. Unique reactions are points of control • Like other pathways, a biosynthetic pathway is usually regulated at an early step that commits intermediates to that pathway • Opposing (catabolic and anabolic) pathways are regulated in coordinated reciprocal manners

  5. Citric acid cycle and glyoxylate cycle • Isocitrate conversion is the point of control between these two pathways • Accumulation of citric acid cycle intermediates activate isocitrate dehydrogenase • Accumulation of citric acid cycle intermediates inhibits isocitrate lyase

  6. Carbohydrate biosynthesis

  7. Gluconeogenesis • A seemingly universal pathway • “reverse” glycolysis; Pyruvate  glucose • Seven of the ten reactions of gluconeogenesis are the reverse of glycolytic pathways • Three glycolytic steps are essentially irreversible under cellular conditions • Hexokinase, PFK-1, pyruvate kinase

  8. These three reactions are “bypassed” • Pyruvate  PEP • Fructose 1,6 bisphosphate  Fructose 6-phosphate • Glucose 6-phosphate  glucose

  9. First “by-pass” involves two steps • Instead of pyruvate kinase, phosphorylation of pyruvate is accomplished by through intermediate stages involving oxaloacetate and malate • Pyruvate is transported from cytosol to mitochondria (or generated from alanine within mitochondria via transamination)

  10. Pyruvate carboxylase is the first regulated step in gluconeogenesis • This biotin-containing enzyme was introduced via anaplerotic reactions • Pyruvate carboxylase requires acetyl-CoA as a positive effector • Oxaloacetate is formed through this reaction, which is subsequently reduced to malate via malate dehydrogenase and NADH

  11. Malate serves as a shuttle for oxaloacetate • The resulting malate is transported to the cytosol via the malate – a-KG transporter (from aspartate-malate shuttle) • In the cytosol, malate is re-oxidized to OAA by cytosolic MDH • OAA is converted to PEP by phosphoenolpyruvate carboxykinase

  12. From pyruvate to PEP

  13. Note the investment in activation of intermediates through this reaction • One ATP and one GTP used, contrasting the single ATP used to make PEP in glycolysis • The CO2 added in the first reaction is released in the second

  14. Why go thru the mitochondria? • The [NADH]/[NAD] ratio in the cytosol is ~105 times lower than in mitochondria, gluconeogenesis relies on NADH • Transport of malate (reduced form of OAA) facilitates transport of reducing power from mitochondria to cytosol (subsequent generation of NADH by MDH) to aid in gluconeogenesis

  15. A second PEP biosynthetic pathway • Lactate, instead of pyruvate, serves as a starting substrate in some situations (anaerobic muscle or erythrocytes) • Conversion of lactate to pyruvate generates NADH obviating the need to export reducing power from mitochondria • As a result, the PEP is generated within the mitochondria

  16. The second and third “by-pass” are similar • Fructose 1,6-bisphosphate is converted to fructose 6-P by fructose 1,6-bisphosphatase • Glucose –6-phosphate is converted to glucose by glucose 6-phosphatase • These reactions do NOT result in ATP formation, instead the irreversible hydrolysis forming inorganic phosphate

  17. The cost of gluconeogenesis

  18. Many molecules can feed into gluconeogenesis • This is of importance when we get to amino acid biosynthesis

  19. Reciprocity of glycolysis and gluconeogenesis • Simultaneous operation of both glycolytic and gluconeogenic reactions would be wasteful if both reactions proceed at high rates in cells (The “simultaneous” operation of anabolic and catabolic pathways is a regulated process) • Futile cycles can be engaged for physiological purposes such as heat energy

  20. Reciprocal regulation • The first control point for regulating flux between these pathways is pyruvate • Pyruvate can be converted to acetyl-CoA (pyruvate dehydrogenase) or to OAA (pyruvate carboxylase) • Acetyl-CoA is a positive allosteric effector of pyruvate carboxylase and a negative modulator of pyruvate dehydrogenase

  21. Effects of acetyl-CoA

  22. A regulatory example • When cells have enough energy, oxidative phosphorylation slows, NADH accumulates, inhibits the citric acid cycle and acetyl-CoA accumulates. • This directs pyruvate to gluconeogenesis

  23. A second control point • Fructose 1,6-bisphosphatase is strongly inhibited by AMP, while PFK-1 is activated by AMP and ADP, but inhibited by citrate and ATP • Again, these opposing steps are regulated in coordinated and reciprocal fashion • Also, hormonal regulation in the liver

  24. Hormonal regulation is mediated by fructose 2,6 bisphosphate • fructose 2,6 bisphosphate is an allosteric effort for PFK-1 and fructose 1,6-bisphosphatase • fructose 2,6 bisphosphate binds and increases PFK-1 affinity for fructose 6-phosphate, and reduces it’s affinity for ATP and citrate – stimulating glycolysis • fructose 2,6 bisphosphate inhibits fructose 1,6-bisphosphatase

  25. Fructose 2,6-bisphosphateregulation

  26. Fructose 2,6-bisphosphate formation regulation • Fructose 2,6 bisphosphate is generated by PFK-2 and broken down by fructose 2,6 bisphosphatase (single polypeptide) – note this compound is not a metabolic intermediate, but a regulatory compound

  27. Glucagon lowers the cellular level of fructose 2,6-bisphosphate • Inhibits glycolysis, but stimulates gluconeogenesis • Process occurs via a signal transduction pathway, which results in alteration of PFK-2/FBPase-2 polypeptide

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