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Gluconeogenesis and CHO Regulation.

Gluconeogenesis and CHO Regulation.

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Week 7 Lecture Part IIBiochemistry of Nutrition 560BDr. Charles SaladinoGluconeogenesis (the formation of glucose)At this point, first look at your text or the internet to find and learn the structures of lactate and pyruvate for the next exam.
You will note that lactate with an OH groupon the number 2 carbon has an OH group and is the reduced form of pyruvate (which hasa carbonyl group on that same carbon). You will also note from your text that thereaction is catalyzed by lactate dehydrogenase; and you need to understand that theenzyme is bidirectional in its function.When conditions favor anaerobic metabolism (such as in heavilty exercised muscle withan oxygen deficit), pyruvate to lactate conversion is favored, which in fact is partlyresponsible for heavily-exercised-muscle cramps, where the pH drops due to increasedlevels of lactate. (In contrast, aerobic conditions favor pyruvate to acetyl CoAconversion for the Kreb’s cycle.)About the most important factor that determines the shift of the equilibrium of the inter-conversion of lactate and pyruvate is the NADH/NAD
+
ratio. When this ratio is low, then pyruvate formation from lactate is favored, as in the conditions which favor gluconeogenesis, the formation of glucose from amino acids, or pyruvate, or lactate or glycerol, etc. Also, and specifically, alanine is easily converted into pyruvate by atransamination reaction (which we discussed earlier in the semester) when conditionsrequire an amino acid for gluconeogenesis.As we begin to discuss the steps of gluconeogenesis, we can use the simple logic that if glycolysis yields some ATP, then gluconeogenesis overall will cost us ATP. The firststep is to take pyruvate (from whatever source) and transport it into the mitochondria.The reason why we do not just reverse pyruvate into phosphoenolpyruvate (PEP) (at thelast step in glycolysis) is for the simple reason that the pyruvate kinase of glycolysis isnot reversible, and no enzyme exists in the cytosol for that reversal process. However,within the mitochondrial matrix is the enzyme pyruvate carboxylase, which adds CO
2
tothe three-carbon pyruvate to form the four carbon oxaloacetate (OAA). That is the sameOAA that is part of the Kreb’s cycle. This costs an ATP, and the enzyme requires thevitamin derivative biotin as a coenzyme.
Your text on pages 621 and 624 diagramthe overall gluconeogenic process, although it shows no structural detail.
Once OAA is formed it can be converted to PEP by the enzyme phosphoenolpyruvatecarboxy kinase (PEPCK), which decarboxylates OAA. This step requires energy in thethe form of GTP hydrolysis to GDP. The OAA can not cross the mitochondrialmembrane to gain access to the cytotosol. Hence, we have the need for OAA conversionto PEP within the mitochondria. The PEP can then leave the mitochondria. However,also shown in the figure is an alternate gluconeogenic route. That is, OAA within the
 
mitochondria can form malate (same as the malate of the Kreb’s cycle), which can leavethat organelle and enter the cytosol, where it is converted to OAA by a cytosolicisoenzyme of PEPCK. Further, OAA can be converted to the amino acid aspartate,which can leave the mitochondria, be reconverted to OAA, and then to PEP by acytosolic PEPCK. Why all this conversion from and back to OAA? There are twoanswers. First there is backup….more than one way to produce PEP, a critical precursor for gluconeogenesis. Second, OAA can obviously not cross the mitochondrialmembranes, in or out.By whatever route PEP is formed, it can be converted into 2-phosphoglycerate in thecytosol. From that point on, gluconeogenesis is essentially a reversal of glycolysis. Your logic would tell you that wherever a phosphate was added by a kinase enzyme to asubstrate in glycolysis, a phosphatase enzyme would remove that phosphate by a phosphatase enzyme in the gluconeogenic pathway.The ATP’s that are required for gluconeogensis will be supplied mostly by fatty acidoxidation (which is the subject of a coming lecture). This would make sense to use lipidsfor fuel, when mandatory gluconeogenesis is telling us that carbohydrate availability isinsufficient to supply adequate amounts of glucose.In the gluconeogenic process, when we reach fructose-6-P generated by the enzymaticaction of fructose-1,6-bisphosphatase, that fructose-6-P is easily converted into glucose-6-P. However, in most tissues, that is the end point of gluconeogenesis. Free glucose isnot generated, but rather glucose-6-P is the product. Here I make an interestingdistinction. Glucose-6-phosphatase (catalyzing the conversion of glucose-6-phosphate toglucose is only present in tissues whose metabolic role is to maintain homeostasis – inother words, tissues that release glucose into the blood. That means the liver, and to asmaller extent, the kidney, so that glucose can be supplied to the brain, as well as tomuscle, the red blood cells, etc. By contradistinction, muscle contains no glucose-6- phosphatase, and thus can not be converted to glucose for export. Rather, the glucose-6-P is converted to glucose-1-P for storage as glycogen use and eventually retrieved as anenergy sourse for muscle use only.In addition, tissues like muscle and the red blood cells, lactate from the muscle andalanine from both the muscle and red cells can be sent back to the liver, having beenformed anaerobically from pyruvate. There, they are routinely used as gluconeogenic precursors. Then the glucose formed from gluconeogenesis can leave the liver and besent back to those tissues in a cycle. These are referred to respectively as the Cori cycleand the alanine cycle.Finally, when muscle is heavily exercised, and lactate builds up, that this sugar does not build up to the point of dangerously lowering the pH in muscle is assured by the export of the lactate as a gluconeogenic precursor for the liver, as mentioned in the above paragraph.
Regulation of Carbohydrate Metabolism (Topic covered here instead of next week).
 
I have already mentioned the importance of the NADH/NAD
+
ratio
 
in determining thedirection of equilibrium between lactate and pyruvate. In our discussion of glycogenformation and breakdown, I have also asked you to refer to the information in your textregarding the regulation of glycogen phosphorylase. You can safely assume that thosefactors that favor activation of this enzyme inhibit – directly or indirectly – the action of glycogen synthase.
Please read and understand the main points of metabolicregulation discussed on pages 852-862 in your Devlin text for the next exam.
Themain take home message that I want you to understand regarding hormones is thatconcerning insulin and glucagon.
(You are not responsible for all the details of enzyme regulation by hormones, and allosteric regulators etc, but you need to knowthe main points. I leave that to your judgement.)
We must, however, understand thatinsulin levels normally rise in the blood in response to a meal with carbohydrates.Glucagon levels concomitantly fall. Common sense would tell us then that increasedinsulin levels would not favor high glucose production from gluconeogenesis or fromglycogen breakdown. Rather, glycolysis would be favored, as would the Kreb’s cycle.However, after a point where ATP levels were high, the pyruvate dehydrogenase enzyme(that forms acetyl CoA from pyruvate) would be deactivated by abundant ATP. Thiswould necessitate a shift toward triglyceride formation – the subject of the future lipidlecture material. Indeed, insulin favors triglyceride formation in the adipose tissue,especially when carbohydrate intake is excessive beyond need. Obviously, what I justnoted about the effects of increased insulin levels would be generally antagonized byhigh glucagon levels. For example, insulin simulates glucose transporters in manytissues, whereas glucagon does not. Also, two important enzymes that help driveglycolysis are glucokinase (step # 1) and pyruvate kinase (where pyruvate is formed fromPEP). Both enzymes are activated by way of the action of insulin. Glucagon has theopposite effect upon their activity.
Some further points on the reciprocity of gluconeogenesis and glycolysis
 
and TheirInter-related Control Systems
These two pathways are coordinated so that they roughly reciprocally active. Now with both pathways balancing out regarding energy usage vs. energy given off (ex two ATP produced in glycolysis), there is no thermodynamic impediment to then not going on afull speed simultaneously. In fact, both are exergonic. However, the amounts and theactivities of the enzymes of both pathways are so controlled that they do not activate fullyat the ame time. Remember, the rate of glycolysis is also controlled by the amount of glucose and the rate of gluconeogenesis by the amount of its available precursors, such aslactate.We have not discussed in lecture how stringently controlled the conversion of fructose-1-P to fructose-1,6-bisphosphate (F-1,6-BP) is during glycolysis. Whereas AMPstimulates phosphofructokinase (the enzyme that puts the second phosphate on fructoseduring glycolysis), ATP and citrate inhibit it. For example, high AMP levels indicate thatenergy levels are low, and that there is need for ATP production from glycolysis. Theconverse is also true for high levels of ATP and citrate.

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