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Where can we get glucose?
- from the liver
- portal vein enter the liver: low glucose concentration
- hepatic vein leaves the liver: high glucose concentraiton
- the process by which intermediates of carbohydrate metabolism & non-carbohydrate substrates are converted to glucose
- functions to maintain blood glucose levels after glycogen stores have been depleted
90% of gluconeogenesis occurs in the ____ and 10% percent in the ______
- 90% occurs in the liver
- 10% occurs in the kindey
- some possibly occurs in the intestine
What are the three main substrates for gluconeogenesis?
- Lactate: formed in the liver or coming to it from glycolysis in the erythrocytes or exercising muscle
- Amino acids: come from breakdown of endogenous or dietary protein
- Glycerol: derived from lipid backbones
How do lactate, amino acids, and glycerol first enter gluconeogenesis?
- lactate --> pyruvate
- amino acids --> pyruvate, TCA intermediates
- glycerol --> DHAP, then moves backwards through glycolysis
What does the liver use to synthesize glucose? Why does it use two sources?
- Glycogen: starch-like polymer
- Gluconeogenesis: new synthesis from small molecule precursors
- there are two sources because glycogen only sustains blood glucose for a few hours after a meal, however gluconeogenesis sustains blood glucose for MANY DAYS in the absence of carbohydrate intake
What are the two major end products of gluconeogenesis?
glucose and glucose-6-phosphate
What is the overall reaction of gluconeogenesis FROM pyruvate?
2 Pyruvate + 4ATP + 2GTP + 2NADH + 6H2O --> Glucose + 4ADP + 2GDP + 6Pi + 2NAD+ + 2H+
While most gluconeogenic enzymes are the same as the glycolytic enzymes, what four enzymes are specific to gluconeogenesis?
- 1) pyruvate carboxlyase
- 2) phosphoenolpyruvate carboxykinase
- 3) fructose-1,6-bisphosphatase
- 4) glucose-6-phosphatase
enyzme that converts pyruvate into oxaloacetate via carboxylation in the mitochondria
Describe the conversion of pyruvate into phosphoenolpyruvate
- 1) pyruvate is transported into the mitochondria
- 2) in the mitochondria pyruvate carboxlyase carboxylates pyruvate, turning it into oxaloacetate
- 3) the next step is converting oxaloacetate into phosphoenolpyruvate in the CYTOPLASM
- 4) unfortunately, oxaloacetate cannot cross the mitochondrial membrane
- 5) oxaloacetate is converted into malate or aspartate
- 6) malate or aspartate cross the mitochondrial membrane
- 7) malate or aspartate are turned back into oxaloacetate
- 8) phosphoenolpyruvate carboxykinase converts oxaloacetate into phosphoenolpyruvate
In order to convert pyruvate into phosphoenolpyruvate, a pair of electrons are required, however where they come from depends on whether the gluconeogenic substrate is derived from alanine or lactate:
- electrons come from within the mitochondria
- electrons are generated in the cytoplasm at the outset when lactate is oxidized to pyruvate
How is oxaloacetate converted to aspartate in the mitochondria?
by transamination from glutamate
- converts aspartate to oxaloacetate when the gluconeogenic substrate is derived from lactate
- lactate --> pyruvate --> oxaloacetate --> aspartate --> oxaloacetate --> PEP
What likely determines whether the lactate or alanine --> pyruvate pathway is used?
probably the cytoplasmic NADH/NAD+ ratio that determines which pathway is used
phosphoenolpyruvate carboxykinase (PEPCK)
converts oxaloacetate --> phosphoenolpyruvate (PEP) in the cytoplasm
What are the cofactors for pyruvate carboxylase?
- Biotin, magnesium, & manganous ions
- all carboxylyases require biotin as a cofactor
What is the activator pyruvate carboxylyase requires for enzymatic activity?
carboxylase cofactor that covalently binds to the enzymes and serves as a carrier of activated carbon dioxide that's added to a carboxylase substrate
- enzyme that cleaves the bond between biotin and a protein to regenerate free biotin so it can bind to another protein
- a deficiency in the enzyme means biotin can't be cleaved from proteins being degraded and reused in other carboxylases; clinically evident in infants through seizures, other neurological signs, skin rash, & hair loss
How may habitually eating raw egg whites cause biotin deficiency?
egg whites contain a protein called AVIDIN that strongly binds to biotin, and in very rare cases essentially remove it from solution
phosphoenolpyruvate carboxykinase (PEPCK)
- enzyme found in the cytoplasm that decarboxylates oxaloacetate and transfers a phosphate group from GTP forming phosphoenolpyruvate (PEP)
- Oxaloacetate + GTP --> PEP + GDP + CO2
Mice genetically engineered to over-express which enzyme exhibit "mighty mouse-like" treadmill running abilities?
PEPCK phosphoenolpyruvate carboxykinase
- irreversibly changes fructose-1,6-bisphosphate into fructose-6-phosphate
- enzyme unique to gluconeogenesis
- [in glycolysis, PFK 1 catalyzes fructose-6-phosphate --> fructose-1,6-bisphosphate]
What is the OVERALL reaction catalyzed by fructose-1,6-bisphosphatase?
fructose-1,6-bisphosphate + H2O --> fructose-6-phosphate + Pi
What enzyme hydrolyzes glucose-6-phosphate to yield glucose?
- unique to gluconeogenesis; is a hydrolysis reaction
- overall rxn: G-6-P + H2O --> glucose + Pi
- [in glycolysis, hexokinase catalyzes glucose --> glucose-6-phosphate]
What are the only three types of cells that can hydrolyze glucose-6-phosphate?
- liver, intestine & kidneys; G-6-P is only found in these cells
- they return glucose to the circulation after its absorption
Why is hydrolysis of glucose-6-phosphate into glucose by glucose-6-phosphatase necessary for liver, intestine & kidney cells to return it into the blood stream?
because the highly charged phosphorylated sugar cannot pass through the cell membrane; free glucose is not charged and can pass through the membrane and be released to the circulation
True or False: high levels of glucose-6-phosphate increase the activity of glucose-6-phosphatase?
True; G-6-phosphatase acts to dephosphorylate (that's what a phosphatase does) G-6-P so glucose can be deposited in the blood stream
What are the 3 different proteins that make up glucose-6-phosphatase and where is the enzyme found?
- one phosphatase and two translocases
- T1: transports glucose-6-phosphate from the cytoplasm to the opposite side of the ER membrane
- phosphatase: attached to the side of the membrane that isn't in direct contact with the cytoplasm
- T2: mediates transport of Pi back to the cytosol
In which cellular compartment is glucose-6-phosphatase found?
the endoplasmic reticulum
True or False: both pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK) use ATP?
- pyruvate carboxylase uses ATP
- phosphoenolpyruvate carboxykinase uses GTP
How many moles of pyruvate and ATP equivalents are required to synthesize ONE mole of glucose via gluconeogenesis?
2 moles of pyruvate and 6 moles of ATP equivalents are required to synthesize one mole of glucose
What are the four points in gluconeogenesis where metabolite regulation occurs?
- 1. pyruvate can be converted to either oxaloacetate OR acetyl-CoA
- 2. two different outcomes for PEP
- 3. synthesis/degradation of F-1,6-bisP
- 4. hydrolysis of G-6-P
What are the two things pyruvate can be converted to once it enters liver mitochondria?
- pyruvate --> oxaloacetate (by pyruvate carboxylase) for gluconeogenesis
- pyruvate --> acetyl-CoA (by pyruvate dehydrogenase) for a) fatty acid synthesis OR b) TCA cycle oxidation
True or False: high levels of pyruvate and acetyl-CoA favor pyruvate carboxylase activity over pyruvate dehydrogenase
- True: pyruvate carboxylase turns pyruvate into oxaloacetate for gluconeogenesis
- pyruvate dehydrogenase turns pyruvate into more acetyl-CoA which clearly we don't need based on the question stem
How is pyruvate dehydrogenase regulated?
- inhibited by certain serine phosphorylation --> promotes gluconeogenesis because it can't make acetyl-CoA from pyruvate when inhibited(no fatty acid synthesis or TCA cycle oxidation)
- activated: dephosphorylation of that certain serine (and enzyme ACTIVATION) is stimulated by insulin in fat cells
What stimulates the phosphorylation of pyruvate dehydrogenase (inactivation of the enzyme)?
an increase in mitochondrial NADH & acetyl-CoA
Phosphoenolpyruvate (PEP) can be a substrate for which two enzymes?
- 1. enolase: converts it to 2-phosphoglycerate for gluconeogenesis
- 2. pyruvate kinase for energy production
What are two important inhibitors of pyruvate kinase?
ATP (product) & alanine (which is not only a substrate for gluconeogenesis but also inhibits a competing reaction!)
What activates pyruvate kinase?
- fructose-1,6-bis-phosphate (F-1,6-bisP)
- this activation is an example of forward stimulation in which an intermediate of a pathway (glycolysis) accelerates a reaction further along the pathway
_____________________ is the most potent regulator at the key steps of formation and hydrolysis of fructose-1,6-bisphosphate by fructose-1,6-bisphosphatase and phosphofructokinase 1, which catalyzes the reverse reaction (F-6-P to F-1,6-bisP)
Which enzyme is the main regulator involved in balancing glycolysis vs. gluconeogenesis?
- phosphofructokinase 2 (PFK2)/fructose-2,6-phosphatase
- it's a single enzyme with two activities
- when phosphorylated --> there's more phosphatase activity that produces F-6-P --> favors gluconeogenesis
- when DEphosphorylated --> there's more kinase activity that produces F-2,6-bisP --> activates/favors glycolysis
- dephosphorylated state, + kinase activity
- phosphorylated state, + phosphatase activity)
In what state would PFK2 be activated?
- in a well-fed state when blood glucose is high
- as a result, insulin is released which triggers PFK2 to catalyze this reaction:
- F-6-P --> F-2,6-bisP (fructose-2,6-bisPhosphate)
- an ATP is used to turn the 6 into 2,6
What are the two functions of F-2,6-bisP?
- it activates PFK1 to INCREASE glycolysis and control blood glucose concentration
- F-2,6-bisP ALSO inhibits gluconeogenesis by inhibiting fructose-1,6-bisphosphatase
What two gluconeogenic enzymes does insulin inhibit?
- PEPCK & fructose-1,6-bisphosphatase
- those are two gluconeogenic enzymes, so clearly insulin is PRO glycolysis
In what state would glucagon be released?
- in an energy POOR state glucagon will be released to help increase blood glucose concentrations
- it''ll activate fructose-1,6-bisphosphatase to help drive gluconeogenesis to make glucose
- glucagon will also decrease the activity of PFK2 lowering the amount of F-2,6-bisP that promotes glycolysis
The glycolysis enzyme PFK 1 is inhibited by ___ and this inhibition is relieved by ___. In contrast, the gluconeogenesis enzyme fructose-1,6-bisphosphatase is activated by ___ and inhibited by both ___ and __________________
- PFK 1: F-6-P --> F-1,6-bisP
- inhibited by ATP, activated by AMP
- fructose-1,6-bisphosphatase: F-1,6-bisP --> F-6-P
- inhibited by AMP and F-2,6-bisP, activated by ATP
- promotes gluconeogenesis
- glucagon causes the liver to convert stored glycogen into glucose which is released into the bloodstream and raises blood glucose levels
- it also targets adipose tissue and is a signal of fasting
- it's active in carbohydrate and lipid metabolism
How does glucagon affect muscle?
it doesn't - muscle cells have NO glucagon receptors
- responds to elevated blood sugar to promote glycolysis
- causes liver, skeletal muscles, & fat tissue to absorb glucose from the blood and store it as glycogen or triglycerides in fat tissue
- it's a signal of feeding
- it's active in carbohydrate, lipid, & protein metabolism
An increased concentration of glucose-6-phosphate favors the __________ activity over that of ________
- more G-6-P --> hydrolytic glucose-6-phosphatase activity
- more glucose --> glucokinase activity to MAKE G-6-P
What happens after a meal when insulin is being secreted?
- PFK2 is dephosphorylated, exhibits kinase activity, & therefore produces F-2,6-bisP activating glycolysis
- gluconeogenesis is INHIBITED
What are the three ways by which glucagon stimulates gluconeogenesis?
- It stimulates:
- the phosphorylation of pyruvate kinase (no pyruvate made from PEP; PEP can be used for gluconeogenesis)
- the phosphorylation of phosphofructokinase
- increases gene transcription and synthesis of other gluconeogenic enzymes
In diabetes the activity of which hormone is relatively unopposed?
the gluconeogenic activity of glucagon is relatively unopposed because there's insufficient insulin function
How do glucocorticoids (adrenal cortical steroid hormones) and pituitary growth hormones stimulate gluconeogenesis? (2)
- 1. they promote the synthesis of enzymes that convert amino acids to substrates for gluconeogenesis
- 2. they increase synthesis of phosphoenolpyruvate carboxykinase (PEPCK) & glucose-6-phosphatase
Why is muscle unable to synthesize glucose via gluconeogenesis?
- neither pyruvate carboxylase nor glucose-6-phosphatase are expressed in muscle
- muscle either consumes glucose or stores it as glycogen for its own later use
- (lactate formed by erythrocytes is also transported to the liver for glucose synthesis)
- the pathway by which muscle produces LACTATE during a state of energy depletion (exercise) and exports it to the liver where it can be converted back to glucose
- the glucose will then get sent back to muscle to generate energy
- (Lactate has a C; C for cori cycle)
- the pathway by which muscle produces ALANINE from pyruvate during a state of energy depletion and sends it to the liver where it can be converted back to glucose
- the glucose will then get sent back to muscle to generate energy
- (Cahill has an A; A for alanine)
What are common symptoms of gluconeogenic enzyme deficiencies?
- Hypoglycemia (low blood glucose) between meals
- Acidosis: mostly caused by accumulation of lactate
Production of NADH ________ gluconeogenesis:
high levels of NADH INHIBITS gluconegenesis