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Roth Lecture 1
Gluconeogenesis and Glycogen Metabolism
44
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Graduate
07/31/2008

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Term
Generation of metabolic energy by oxidation of glucose.

Maintenance of blood glucose level by glucose synthesis from non-carbohydrate sources and by mobilization of stored carbohydrate.

Provision of specialized monosaccharides as biosynthetic precursors.

Utilization of dietary sugars other than glucose.

These actions are the role of ???
Definition
Carbohydrate Metabolism
Term
Gluconeogenesis is essentially the reverse of glycolysis. The synthesis of 1 mole of glucose from 2 moles of pyruvate requires energy equivalent to about 6 moles of ATP. Gluconeogenesis provides glucose in absence of dietary carbohydrate (glucose is the primary energy sourcefor CNS tissues and RBCs).
Primary site for gluconeogenesis is the ???, which regulates blood glucose by releasing glucose to the blood stream.
Definition
Liver
Term
True or False: The gluconeogenesis pathway is the exact reverse of glycolysis.
Definition
FALSE


EXCEPT for those steps necessary to bypass the three (3) irreversible steps of glycolysis.
Term
What are the three gluconeogenesis enzymes that catalyze the regulatory steps in glycolysis (hexokinase, PFK1, Pyruvate Kinase)?
Definition
Glucose-6-phosphatase, Fructose-1,6 bisphosphatase, Pyruvate carboxylase and PEP carboxykinase
Term
True or False: All the gluconeogenesis enzymes that catalyze the regulatory steps of glycolysis are expressed in the cytosol.
Definition
FALSE

Pyruvate carboxylase (mitochondrial)
Term
(2) Enzyme Contains biotin, uses CO2 from bicarbonate, and requires K+, Mg2+, also ATP.Activated in the presence of Acetyl CoA in a bypass of gluconeogenesis

- if [ATP]/[ADP] is high, oxaloacetate is used for gluconeogenesis

- if [ATP]/[ADP] is lower, oxaloacetate is provided for TCA cycle

Oxaloacetate exits the mitochondrion via the malate-aspartate shuttle

(2) This enzyme uses GTP, requires K+, Mn2+ to catalyze the second step of this glucogenisis bypass

What is the substrate, intermediate, product?
Definition
Pyruvate carboxylase, PEP carboxykinase (PEPCK)

Pyruvate --> oxaloacetate --> PEP
Term
What enzyme catalyzes the following?

Reverses action of PFK-1, releases inorganic phosphate

Allosterically inhibited by AMP, Fructose-2,6-bis-P

Rate-limiting enzyme for gluconeogenesis

What bypass is this in gluconeogenesis?

What is the substrate and what is the product?
Definition
Fructose 1,6-bis-phosphatase, 2nd bypass

Fructose-1,6-bisphosphate --> Fructose-6-phosphate
Term
This enzyme that catalyzes the 3rd bypass of gluconeogenesis is located in the lumen of the endoplasmic reticulum and present in liver, kidney medulla and RER but is absent in other tissues, especially the CNS and erythrocytes, where glucose is the primary fuel. What is the substrate and what is the product?
Definition
Glucose-6-Phosphatase

Glucose-6-Phosphatase --> Glucose
Term
What enzyme in gluconeogenesis is absent in muscle and brain, which exhibit maximal use of glucose as a source of energy?
Definition
Glucose-6-Phosphatase
Term
True or False: Fructose-2,6-bisphosphate and AMP inhibits Fructose-2,6-bisphosphatase, while citrate, glucagon and ATP stimulate the enzyme for gluconeogenesis.
Definition
FALSE

Fructose-1,6-bisphosphate
Term
True or False: Acetyl CoA and glucagon stimulates pyruvate carboxylase while ADP inhibits PEP carboxykinase in gluconeogenesis.
Definition
True
Term
What is the committed step (rate-limiting enzyme) of gluconeogenesis?
Definition
Fructose-1,6-bisphosphatase
Term
Gluconeogenesis is energetically expesive and synthesis of 1 molecule of glucose from 2 molecules of pyruvate utilizes 6 ATP equivalents + 2 NADH. What enzymes are involved in these energy steps?
Definition
Pyruvate carboxylase (2 ATP)
PEP carboxykinase (2 GTP)
Phosphoglycerate kinase (2 ATP)
Glyceraldehyde 3-phosphate DH (2 NADH)
Term
The energy for gluconeogenesis comes from fatty acid oxidation conducted where?
Definition
Liver
Term
What metabolites supply carbon for gluconeogenesis?
Definition
Glucogenic metabolites
Term
Fatty acids are degraded, yielding acetate and propionate, and one of them is partially glucogenic. Which one?
Definition
Propionate
Term
True or False: Fatty acid degraded into acetate is glucogenic.
Definition
FALSE
Term
There is no net yield of glucose from acetate or Acetyl CoA, however, acetyl CoA does act as an allosteric stimulator ofp pyruvate carboxylase, thereby stimulating ???
Definition
Gluconeogenesis
Term
True or False: Propionyl CoA generated during b-oxidation of odd-numbered fatty acids is glucogenic, when metabolized to yield Succinyl CoA
Definition
True
Term
Triglycerides can be metabolized to:

- Glycerol (glucogenic)
- Fatty acids (propionate from odd numbered f.a. is glucogenic)

Therefore, oxidation of lipids can provide some precursors for gluconeogenesis, and provides what necessary element for gluconeogenesis to occur?
Definition
Energy (ATP)
Term
The Cori cycle between erythrocytes and the liver involves the transfer of what substance from the RBC to the liver for gluconeogenesis.

Hint: Anything that inhibits gluconeogenesis at this site, would lead to decrease in pH
Definition
Lactate
Term
True or False: Glucagon stimulates PKA when blood glucose is scarce. Fructose-2,6-bisphosphate is activated, glycolysis is inhibited, and gluconeogenesis is stimulated.
Definition
True
Term
True or False: High levels of fructose-6-phosphate stimulates phosphoprotein phosphatase. PFK2 is activated, glycolysis is stimulated and gluconeogenesis is inhibited.
Definition
True
Term
Ethanol is oxidized to acetate primarily in the ???
Definition
Liver
Term
Ethanol + NAD ----> Acetaldehyde + NADH + H+
- is catalyzed by what enzyme in the cytosol of hepatocytes?
Definition
Alcohol Dehydrogenase (ADH)
Term
Acetaldehyde + NAD+ -----> Acetate (CH3-COO-) + NADH + H+
- is catalyzed by what enzyme in the mitochondrial matrix?
Definition
Aldehyde dehydrogenase
Term
Effects of ethanol metabolism on liver metabolism result primarily from accumulation of NADH within hepatocytes. Decreased liver NAD+ inhibits both gluconeogenesis from lactate, and fatty acid oxidation (both require NAD+ and produce NADH). What are some effects of this?
Definition
Reactions using NAD+ as cofactor are affected
Result is increased ratio of lactate/pyruvate (shifted to lactic acidosis)
Also decreased malate/oxaloacetate ratio (TCA cycle inhibited)
Because fatty acid oxidation is inhibited, triglyceride accumulation in liver is increased (fatty liver)
Term
Interruption of mitochondrial ATP synthesis results in increased production of lactate. Accumulation of lactate, usually in response to decreased availability of oxygen leads to what disease?
Definition
Lactate Acidosis
Term
True or False: Failure of gluconeogensis for whatever reason can result to lactate acidosis.
Definition
True
Term
This glucose polymer is osmotically stable and allows glucose to be mobilized quickly when blood glucose is low.Can be used for energy generation even in the absence of oxygen. These are all advantages of ???
Definition
Storing Glucose as Glycogen
Term
Glycogen synthesis begins with addition of the reducing end of a glucose molecule (from UDP-glucose) to what carrier protein using a glucose transferase enzyme?

Hint: This molecule appears to catalyze the addition of three to eight additional glucose units to the growing polymer.
Definition
Glycogenin
Term
Enzyme that takes glucose ---> glucose-6-P in glycogen synthesis?
Definition
Hexokinase
Term
Enzyme that takes glucose-6-P ---> glucose-1-P in glycogen synthesis?
Definition
Phosphoglucomutase
Term
Glucose residues are added by the enzyme ??? to the reducing end (C1) of UDP-glucose. UDP-glucose reacts with C4 of glucose on the end of the polymer,forming a a-1,4-glycosidic linkage, therefore, each glycogen molecule has only ONE reducing end.

Note: (reducing end is at C1 of glucose)
Definition
Glycogen synthase
Term
When the a-1,4-glycoside (amylose) chain reaches 10-11 residues, it becomes a substrate for the ???, which can remove a block of six or seven glucose residues and transfer them to a neighboring amylose chain, forming a a-1,6-glycosidic linkage.
Definition
Branching enzyme
Term
In regulation of glycogen synthesis,glucose-6-phosphate is an ??? of glycogen synthase?
Definition
Allosteric Activator
Term
During regulation of glycogen synthesis covalent modification (phosphorylation) is more important than allosteric activation. Which of the two forms shown below is NOT sensitive to stimulation by glucose-6-P?
- phosphorylated form (synthase b) is inactive
- dephospho form (synthase a) is fully active
Definition
Dephospho form is NOT sensitive to stimulation by glucose-6-P.

Remember that glycogen is usually found in the liver and muscle, therefore they must have a way to react without stimulation. POSSIBLE TEST QUESTION
Term
True or False: Glycogen synthase is phosphorylated by several kinases, which are stimulated by several ‘second messenger molecules: cyclic AMP, calcium, diacylglycerol
Definition
True
Term
Glucose is mobilized from glycogen stores by phosphorolysis. What enzyme catalyzes this reaction?


Note:
in muscle – glucose for immediate local use in ATP generation
in liver – functions to release glucose into the bloodstream
Definition
Glycogen phosphorylase
Term
True or False: Glycogen phosphorylase
- activated by phosphorylation by phosphorylase kinase
- phosphorylated form, phosphorylase a = active.
- dephospho- form, phosphorylase b = inactive
- glucose is allosteric inhibitor of glycogen phosphorylase
- reaction is activated allosterically by AMP and inhibited by glucose and ATP
Definition
True
Term
True or False: Insulin inhibits glycogen synthesis.
Definition
False
Term
True or False:
- glucagon and epinephrine, which raise the level of cyclic AMP, promote glycogenolysis
- insulin stimulates protein phosphatase, lowers cAMP level, inhibits glycogen phosphorylase
Definition
True
Term
Clinical Correlation: Glycogen storage diseases

Disruptions in liver and muscle glycogen metabolism are caused by enzyme deficiency
- Type I (Van Gierke’s) glucose-6-phosphatase (liver, kidney)
- Type II (Pompe’s) lysosomal acid maltase (all tissues)
- Type III (Cori’s) debranching enzyme ( muscle, liver)
- Type IV (Andersen's disease) branching enzyme (liver, spleen)
- Type V (McArdle's disease) phosphorylase (muscle)
- Type VI (Hers' disease) phosphorylase (liver)

The variety of pathologies proves both synthesis and degradation of glycogen are necessary for glucose homeostasis
Definition
Term
WHAT IS THE NAME OF THE PROFESSOR THAT TEACHES THIS STUFF???

(A) Dr. Jackie Roth
(B) Dr. Daniel Roth
(C) The Rothmeister
(D) Roooooooooottttttttthhhhhhhh
Definition
PUSH IT TO THE LIMIT.

DONT FORGET THE HIGHLIGHTS AND LARIIIIAT STRUCTURE!!!
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