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carbohydrate metabolism - pentose phosphate pathway, gluconeogenesis II

Carbohydrate metabolism - pentose phosphate pathway, gluconeogenesis II

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Unformatted text preview: Learning Objec-ves Discuss the biological significance of the branched chain structure of glycogen. Compare and contrast the pathways for glycogen synthesis and glycogenolysis. Describe the difference in the physiological roles of liver versus muscle glycogen. Iden=fy the substrates, products and cofactors of glycogen phosphorylase Iden=fy the substrates and products of glycogen synthase. Explain the physiological basis (i.e., ra=onale of the effect) for glucose-6-phosphate allosterically ac=va=ng glycogen synthase Discuss the allosteric regula=on of glycogen phosphorylase. Describe the func=on of phosphorylase kinase in promo=ng mobiliza=on of glycogen rela=ve to phosphoryla=on state of glycogen phosphorylase. Discuss events associated with the reversal of the cyclic AMP-mediated cascade including the roles of inac=va=on of the Gs protein, phosphodiesterase and protein phosphatase-1. Describe the features in the regula=on of glycogen synthase by covalent modifica=on. Describe the regula=on of the ac=vity of protein phosphatase-1 by insulin. Explain (on a biochemical level) how flux through glycolysis, glycogenolysis, gluconeogenesis, and glycogen synthesis contributes to blood sugar control. Reading Chapter 21 Problems: 2, 3, 4, 7, 9, 10, 11 (a, c, d, and e), 12 and Problem set Glycogen provides a source for glucose during fasts and/or =mes when energy is needed quickly. Muscle glycogen provides glucose for oxida=on or fermenta=on within that =ssue, while liver glycogen provides glucose into circula=on for a number of cells and =ssues including muscle, brain, and red blood cells. Glycogen is a branched polysaccharide, present at high levels in hepatocytes (liver cells) and muscle. The branched structure of glycogen allows for more compact storage of glucose than starch. Breakdown of glycogen requires glycogen phosphorylase and debranching enzyme and yields glucose 1-phosphate. Glycogen phosphorylase-catalyzed Breakdown of glycogen Glycogen phosphorylase catalyzes the glycogen breakdown un#l it reaches a point 4 glucose monomer units away from a branchpoint. At this point two enzymes- transferase and - 1, 6-glucosidase (aka debranching enzyme) catalyze the remodeling of glycogen so breakdown can con=nue. Breakdown of glycogen occurs through phosphorylysis instead of hydrolysis to release glucose-1-phosphate, which is subsequently converted to glucose-6- phosphate through phosphoglucomutase. Glycogen Degrada-on: Glycogenn+1 + Pi -> Glycogenn + glucose 1-phosphate Important bookkeeping note: Glucose entering glycolysis from glycogen u=lizes one less ATP than glucose entering from outside the cell. That ATP was invested to make glycogen. Glycogen Synthesis First step is glycogen synthesis is to transfer the phosphate from the C6 posi=on of glucose 6- phosphate to the C1 posi=on to create glucose-1-phosphate (G1P). This is the reverse of what happens in glycogenolysis. G1P is then "ac=vated" by becoming aZached to another phosphate group to form UDP-glucose. Hydrolysis of two phosphoanhydride bonds makes this reac=on spontaneous. One phosphate bond is recouped during glycogen breakdown (glycogenn to glycogenn-1 and G1P). Note the use of UTP as the phosphoryl group carrier- how does this affect the total "cost" in terms of ATP for glycogen synthesis? Glycogen synthase catalyzes the transfer of one glucose molecule from UDP- glucose to the nonreducing end of glycogen, elonga=ng the chain. Glycogen branching enzyme catalyzes the forma=on of branches (-1,6 linkages) enabling the forma=on of glycogen granules. Glycogen Metabolism Differs Depending on the Tissue Liver glycogen is used as a short term energy source for the organism by providing a means to store and release glucose in response to blood glucose levels; liver cells do not use this glucose for their own energy needs. Muscle glycogen provides a readily available source of glucose during exercise to support anaerobic and aerobic energy conversion pathways within muscle cells; muscle cells lack the enzyme glucose-6- phosphatase and therefore cannot release glucose into the blood. Courtesy of Dr. R.L. Miesfeld There are many different types of glycogen storage diseases We will fill these in together! Why are there so many diseases that map to defects in these two pathways? Regula=on of glycogen metabolism Glycogen phosphorylase and glycogen synthase have opposing effects on glycogen metabolism, therefore the two enzymes are ac=ve under different metabolic condi=ons What is the metabolic logic of glucose inhibi-on of glycogen phosphorylase ac-vity and ac-va-on of glycogen synthase? Serine phosphoryla-on of glycogen phosphorylase favors the R state (phosphorylase a) Glycogen phosphorylase is controlled by covalent modifica=on that is the final step in the epinephrine and/or glucagon pathways. Does this Look Familiar? Regula=on of Glycogen Phosphorylase Ac=vity The enzyme responsible for phosphoryla=ng glycogen phosphorylase b to ac=vate it, is phosphorylase kinase Courtesy of Dr. R.L. Miesfeld Tissue-specific isozymes of glycogen phosphorylase The ac=vity of glycogen phosphorylase can also be controlled by allosteric regulators, which binds to the T state and shies the equilibrium to the R state. Liver and muscle isozymes of glycogen phosphorylase are allosterically-regulated in different ways, which reflects the unique func=ons glycogen in these two =ssues. Courtesy of Dr. R.L. Miesfeld Tissue-specific isozymes of glycogen phosphorylase Liver glycogen phosphorylase a, but not muscle glycogen phosphorylase a is subject to allosteric inhibi=on by glucose binding which shies the equilibrium from the R to T state. When liver glycogen phosphorylase a (phosphorylated form) is shieed to the T state, it is a beZer substrate for dephosphoryla=on by PP-1 than is the R state. Why does it make sense that muscle glycogen phosphorylase b, but not liver glycogen phosphorylase b, would be allosterically ac-vated by AMP in the absence of hormone signaling? Hint: what does the liver do with the glucose-6P that is produced? Courtesy of Dr. R.L. Miesfeld Glycogen Synthase is also regulated by covalent modifica=on by glycogen synthase kinase 3 (GSK3) Regula=on of Glycogen Synthase Ac=vity Hormone ac=va=on of glycogen synthase ac=vity is mediated by insulin, which promotes the ac=va=on of glycogen synthase by s=mula=ng PP-1 ac-vity. Epinephrine and glucagon signaling leads to inac=va=on of glycogen synthase. Courtesy of Dr. R.L. Miesfeld Mechanisms by which insulin facilitates the ac-va-on of glycogen synthase to promote glycogen storage 1. Protein phosphatase-1 removes the phosphate from phosphorylase kinase so that it cannot phosphorylate glycogen synthase 2. Phosphodiesterase degrades cyclic AMP so PKA becomes inac-ve and unable to phosphorylate glycogen synthase 3. Insulin promotes dephosphoryla-on (ac-va-on) of glycogen synthase through ac-va-on of protein phosphatase-1 4. Insulin prevents phosphoryla-on of glycogen synthase inac-va-ng glycogen synthase kinase-3 Note the mul-ple steps required to reverse the effects of glucagon/epinephrine signaling Courtesy of Dr. M. Tischler Hormones regulate blood glucose levels by driving changes in glycolysis, gluconeogenesis, and glycogen metabolism in a coordinated fashion As you study this diagram, think about the enzymes that are being ac=vated and inhibited in the various pathways and how this contributes to flux through the various pathways and ul=mately to maintaining blood sugar levels. ...
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