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Regulation of Glycolysis: Tissue Differences


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What are the possible fates of glucose enterinng the cell and after being converted to G-P_6?
a) it goes down the glycolytic pathway, b) it is shunted to the pentose phosphate pathway, c) it goes to G-P-1 and becomes either stored as glycogen, or d) complex carbohydrates
What is the purpose of the pentose pathway?
a) It produces reducing equivalents (NADPH) b) pentose sugars for RNA and DNA and c)
What two things is pyruvate a precusor for?
fatty acids and alanine
What prevents glucose from leaving the cell?
What is the only organ that can dephosporylate glucsose? Why?
the liver, so it can export the sugar
Why is it necessary to convert pyruvate into lactate?
It utilizes the reducing equivalents and recycles NAD+ in an anerobic scenario
Which two rxns in glycolysis require ATP?
Glucose to G-6-P and F-6-P to F-1,6-BP (PFK-1)
Which two rxns in glycolysis produce ATP?
1,3-BPG to 3-Phosphoglycerate and phosphophenol pyruvate to pyruvate
What is the significance of glycolysis being -22 kcal/mol?
It is irreversible
What enzyme converts pyruvate to lactate?
It is converted to lactate via lactate dehydrogenase
Describe the malate-aspartate NADH shuttle.
Oxaloacetate converts to Malate by oxidizing 2 NADH > malate enters the matrix > malate is converted back to oxaloacetate and reduces NAD+ to NADH > Oxaloacetate is converted to aspartate, which crosses into the cytosol.
Describe the G-3-P pathway for NADH shuttle.
Dihydroxyacetone converts to G-3-P by oxidizing NADH > G-3-P enters the inner membrane space, FAD is reduced to FADH2
What advantage does allosteric enzymatic regulation have over hormonal regulation?
allosteric regulation is faster⬦ greater concentration = association⬦ lesser concentration = dissociation
Define and give an example of a "maintainer organ" and a "consumer organ".
A maintainer organ maintains homeostasis (liver) and a consumer organ converts chemical energy inot mechanical energy (muscles)
In which organ is glucokinase found, what is its Km (high or low), what stimulates its production, and what does it do?
a) liver b) high c) insulin d) converts glucose to G-6-P
What does PFK-1 do, what inhibits it, what stimulates it?
a) converts F-6-P to F-1,6-P b) ATP and citrate d) AMP and F-2,6-P
What does Pyruvate kinase do, what inhibits it, what stimulates it?
a) converts phosphophenol pyruvate to pyruvate b) phosphorylation (cAMP dependent) and alanine c) F-1,6-P
What implications do a high Km for glucokinase have?
glucose will only be taken up when serum glucose levels are high
Where would you find glucose 6-phosphatase and what does it do?
a) in the liver b) it converts G-6-P to glucose
What two pathways require glucose 6-phosphatase?
glycogenolysis and gluconeogenesis
With respect to the insulin and glucagon ratio, which positively regulates PFK-1 and PK?
High insulin⬦ low glucagon
What effect does insulin have on glucokinase?
it induces synthesis
What effect does product (G-6-P) have on hexokinase in muscles?
Product Inhibition (MAJOR)
What effect does ATP, citrate, alanine, and phosphorylation of pyruvate kinase have on the glycolysis pathway of the liver?
What effect does AMP, F-2,6-P, and F-1,6,-P have on the glycolysis pathway of the liver?
Which steps are majorly regulated in liver glycolysis?
a) glucose to G-6-P, b) F-6-P to F-1,6-P, c) phosphophenol pyrvate to pyruvate
Which steps are majorly regulated in muscle glycolysis?
a) glucose to G-6-P, b) F-6-P to F-1,6 Bis P
What effects do AMP, F-2,6-P, ATP and Citrate have on the F-6-P to F-1,6-P PFK catalyzed reaction?
a) AMP & F-2,6-P induce the reaction b) ATP and citrate inhibite the reaction
Which has a lower Km, hexokinase or glucokinase?
What does it mean that hexokinase has a lower Km?
It will have great affinity at low concentrations of sugar.
How do you calculate the Km given the 1/2 Vmax
Km is at the insect of 1/2 Vmax with the curve
Based on the shape of its curve, how is glucokinase regulated?
What are the implication for glucokinase being allosterically regulated?
the enzyme can increase its affinity lowering its Km and thus moving its curve to the left (it can also change when the ligand is removed)
What is the relationship between glucokinase and glucose 6-phosphatase?
antagonistic, where glucokinase breaks down glucose and glucose 6-phosphatase produces glucose
What type of regulation does PFK-1 undergo?
allosteric by AMP or F-2,6-bis P
What are the implication for PFK-1 being allosterically regulated?
In the presence of AMP or F-2,6-bis P, the enzyme will increase in affinity lowering its Km and thus moving its curve to the left
How do PFK-1 and PK respond to a high insulin to glucagon ratio?
The are positively regulated
How does PFK-1 respond to high [ATP] or low [AMP]?
[High] ATP = inhibited and [High] AMP = positively regulated
Which substituent has a greater effect on the positive regulation of PFK-1
F-2,6-Bis P
Why does an AMP change result in a greater influence on PFK-1 than ATP
ATP doesn't change that much, but AMP, which generally has a low concentration can increase very quickly, since adenylate kinase converts ADP to AMP.
Given that AMP concentration can serve as an important signal amplification, where does AMP play an important role in regulation? (~300% ∆)
muscle (2 ADP <-> AMP + ATP)
Is F-2,6-BP a glycolysis intermediate?
a) What does F-2,6-BP regulate? b) And in what tissues? c) why in these tissue?
a) PFK-1 of glycolysis b) Liver and and adipose tissue c) why? because glycolysis supplies carbon for TAGs synthesis.
What happens to the [F-2,6-BP] when the insulin to glucagon ratio increases?
it increases
What is the role of PFK-2?
it is a bifunctional enzyme that can convert F-6-P to F-2,6-P and then back again.
How is the action of PFK-2 regulated in the liver?
Controlled by PKA (protein kinase A)⬦ Phosphorylation increases phosphatase activity and inhibits kinase activity
With respect to PFK-1 and PFK-2, what happens after a high carb meal? Note that [insulin] is up and [glucagon] is low.
PFK-2 is dephosphorylated (active) > Levels of F-2,6-BP increase > PFK-1 is activated > Glycolysis is stimulate > glucose is converted to TAGs
Is PFK-2 dephosphorylated during fasting state? And what are the effects of this?
a) no⬦ thus PFK-2 is now producing b) PFK-2 will produce F-6-P
What happens when the insulin to glucagon ratio is low? (give mechanism)
Glucagon bind cell receptor > G-protein is now active with GTP > Adenylate cyclase convert ATP to cAMP > cAMP increases > PKA is active > PFK-2 is phosphorylated by PKA > PFK-2 produces F-6-P > PFK-1 activity decreases > less glycolysis in liver
When PKA is present what effect does it have on PFK-2
PFK-2 goes from kinase activity to phosphatase activity (favoring F-6-P production)
With respect to PFK-2, what does phosphatase activity favor and what does kinase activity favor?
a) Kinase = F-2,6-BP (which is a positive allosteric regulator of PFK-1) > PFK-1 activity > glycolysis in liver b) Phosphatase = F-6-P > less glycolysis in liver
Could glucagon effect PFK-2 in muscles?
No, there are no glucagon receptor in muscle
What effect does epinephrine have on PFK-2 in the liver?
epi causes increase in cAMP which leads to the phosphorylation the kinase domain of PFK-2, which favors phosphatase activity = F-6-P > no glycolysis
What effect does epinephrine have on PFK-2 in cardiac muscle?
epi causes phosphorylation the phosphatase domain of PFK-2, which favors kinase activity = F-2,6-BP > glycolysis
With respect to the liver, what is the mechanism for deactivating PK in the liver?
Same as the others⬦ glucagon binds receptor > G-protein > adenylate cyclase > cAMP > PKA > phosphatase activity > no glycolysis
What are the products of ethanol metabolism in the liver?
13 ATP/molecule, acetaldehyde, acetate, and acetyl CoA, NADH and H+ (in the form of lactic acid)
What can acetyl CoA be used for?
TCA cycle or fatty acid synthesis
Of the products produced by the metabolism of ethanol, which is toxic?
What nutritional considerations are there in chronic alcoholism?
decreased absorption of B1 and B12
What are the two key enzymes in alcohol metabolism and what rxns do they catalyze and where are they located in the cell?
a) alcohol dehydrogenase (ethanol ->acealdehyde⬦ in cytosol) b) aldehyde dehydrogenase (acetaldehyde -> acetate⬦ in mitochondria)
Which of the alcohol metabolism reactions produce NADH + H+
What is the relevance of isozymes as they relate to alcohol clearance?
If the alcohol dehydrogenase has a high affinity when compared to aldehyde dehydrogenase due to differences in the AA difference this has an impact on degree of inebriation, liver disease, alcoholism, etc.
What is the effect of excess production of NADH in alcohol consumption?
Inhibition of the TCA cycle, production of ketone bodies and fatty acids, stimulation of lactic acid production,
What positive effects does a high Km for aldehyde dehydrognease have?
decreased alcoholism

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