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?
- phosphorylation
- 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?
- inhibition
- What effect does AMP, F-2,6-P, and F-1,6,-P have on the glycolysis pathway of the liver?
- induces
- 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?
- Hexokinase
- 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?
- allosterically
- 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?
- No
- 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?
- Acetaldehyde
- 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+
- both
- 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