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BC 2- > Regulation of glycolysis and gluconeogenesis > Flashcards

Regulation of glycolysis and gluconeogenesis Flashcards

1
Q

__ is regulated to maintain constant ATP levels

A

Glycolysis is regulated to maintain constant ATP levels

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2
Q

Glycolysis occurs if __ is high and __ is low

Gluconeogenesis occurs if __ is low

A

Glycolysis occurs if AMP is high and ATP is low.

Gluconeogenesis occurs if AMP is low

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3
Q

Which hormones regulate expression/function

of glycolytic enzymes

A

Glucagon, epinephrine and insulin

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4
Q

What are the isoforms of hexokinase

A

1, 2, 3 and 4

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5
Q

Where are hexokinase I &II found? What is their affinity for glucose ?

A
  • Predominantly expressed in muscle

- High affinity for glucose (activity reaches maximum quickly)

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6
Q

Where is hexokinase IV found? What is it’s affinity for glucose

A
  • Predominant in liver

- Lower affinity for glucose

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7
Q

What inhibits hexokinase IV

A

Inhibited by a regulatory protein (liver specific; GKRP

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8
Q

How’s hexokinase IV and glucose concentration related?

A
  • Activity increases at high glucose concn
  • Glu escapes glycolysis at low concn
    High glucose concentration is required for max activity
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9
Q

Are hexokinase I, II and IV inhibited by

A

Hexokinase IV is not inhibited by G-6-P
Hexokinase II and III are allosterically inhibited by G-6-P, which is the product of hexokinase I and II (negative feedback_

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10
Q

How is hexokinase IV inhibited by GKRP?

A

GKRP (Glucokinase regulatory protein ) can take hexokinase away from the site of glycolysis (cytoplasm) into the nucleus. Occurs in the liver only
This translocation of Hex IV from cytoplasm to nucleus is stimulated by fructose 6-phsophate- downstream product of hexokinase IV->
If there’s a lot of glucose Hex IV will be drawn back to cytoplasm

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11
Q

What happens when blood glucose level raises?

A

when the blood glucose level rises, insulin acts in muscle to

(1) increase glucose transport into cells by conveying GLUT4 to the plasma membrane
(2) induce the synthesis of hexokinase, and
(3) activates glycogen synthase by covalent alteration

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12
Q

In which cells does glycolysis and gluconeogenesis occurs?

A

Glycolysis takes place in any cell.

Only few cells can do gluconeogenesis- hepatocytes, kidneys, intestinal epithelium

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13
Q

Which enzymes are used in liver when:
Blood glucose is low
Blood glucose is high

A
  • High blood glucose – Hexokinase IV

- Low blood glucose – Glu-6-phosphatase

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14
Q 
PFK-1
- Function 
Regulation: 
- Inhibitors
- Stimulators
A

PFK-1 (Phosphofructokinase-1) converts phospho-6-fructose to fructose 1,6-bisphosphate

  • High ATP allosterically inhibits PFK-1 (No ATP is needed = no need to break down glucose)
  • High citrate increases ATP-inhibition
  • High AMP or ADP relieve ATP-inhibition
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15
Q

FBPase-1
- Function
Regulation:
- Inhibitors

A

FBPase-1 (Fructose 1,6-Bisphosphatase) converts fructose 1,6-bisphosphate to fructose 6-phosphate
- High AMP allosterically inhibits FBPase-1 (Low energy inhibits FBPase as glucose doesn’t need to be made- it needs to be used )

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16
Q

What is an enzymes in gluconeogenesis that replaces PFK-1 in glycolysis?

A

FBPase-1

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17
Q

How are PFK-1 and FBPase-1 enzymes regulated?

A

They are regulated in the liver by enzymes FBPase-2 and PFK-2
PFK-2 uses ATP to add a phosphate group to fructose 6-phosphate making fructose 2,6-bisphosphate.
Fructose 2,6-bisphosphate is not a glycolytic intermediate- not used in glycolysis due to its asymmetry and is produced mainly in the liver. It is a allosteric activator of PFK-1 and inhibitor of FBPase-1
FBPase-2 removes a phosphate group from fructose 2,6-bisphosphate, turning it back into fructose 6-phosphate

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18
Q

PFK-1 and FBPase-1 vs PFK-2 and FBPase-2

A
  • PFK-1 and FBPase-1 are encoded by two genes, PFKM and FBP1

- PFK-2/FBPase-2 is a bifunctional enzyme, expressed from single gene, PFKFB1

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19
Q

How is PFK-2/FBPase-2 regulated?

A

PFK-2/FBPase-2 is regulated by phosphorylation
Unphosphorylated-> PFK-2 activity -> increase in Fructose 2,6-bisphosphate
Phosphorylated-> FBP-2ase activity-> Fructose 2,6-bisphosphate is converted to Fructose 6-phosphate

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20
Q

How is phosphorylation of PFK-2/FBPase-2 regulated?

A

Insulin/ Xylulose 5-phosphate stimulates phospho-protein phosphatase which removes phosphate group and converting it to PFK-2
Glucagon/cAMP activates cAMP-dependent protein kinase that comes from GPCR- glucagon receptor. It phosphorylates the enzyme and induces FBP-2ase activity

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21
Q

What does high concentration of F26BP stimulates and inhibits?

A

High concentration of F26BP stimulates glycolysis and inhibits gluconeogenesis

22
Q

Why does Xylulose 5-phosphate stimulates PFK-2 activity?

A

Xylulose 5-phosphate comes from phosphate pathway-> no more glucose is required for pentose phosphate pathway
Thus PFK-2 will stimulate the production of fructose 2,6-bisphosphate which activates PFK-1 and leads to glycolysis, breaking down glucose that is no longer needed

23
Q

Does phosphorylation of pyruvate kinase activate or deactivate it

A

Deactivates

24
Q

How’s pyruvate kinases regulated in the liver?

A

Glucagon activates cAMP-dependent protein kinase, which phosphorylates the pyruvate kinase L isozyme, inactivating it.
When the glucagon level drops, a protein phosphatase (PP) dephosphorylates pyruvate kinase, activating

25
Q

What inhibits pyruvate kinase in all glycosidic cell, including liver?

A

Pyruvate kinase is allosterically inhibited by ATP, acetyl-CoA, and long-chain fatty acids.
Accumulation of alanine, which can be synthesized from pyruvate in one step, allosterically inhibits pyruvate kinase

26
Q

What activates pyruvate kinase in all glycosidic cell, including liver?

A

Accumulation of fructose 1,6-bisphosphate triggers its activation.

27
Q

Which step of glycolysis involves pyruvate kinase

A

The last step

28
Q

Why should liver isoform of pyruvate kinase be regulated?

A

his mechanism prevents the liver from consuming glucose by glycolysis when blood glucose is low; instead, the liver exports glucose.

29
Q

Are liver and muscle pyruvate kinases regulated hormonally and by phsophorylation?

A

The liver isozyme (L form) is regulated hormonally and is subject to further regulation by phosphorylation
The muscle isozyme (M form) is not affected by phosphorylation mechanism- muscles do not express glucagon receptor

30
Q

What activates pyruvate kinase in all glycosidic cell, including liver?

A

High concentration of precursor/ substrates (e.g. glucose-6-phosphate and F16BP)

31
Q

What are the 2 fates of pyruvate?

A

Acetyl CoA-> Citric acid cycle-> energy

Oxaloacetate-> gluconeogenesis -> glucose

32
Q

What are the 2 ways of production of AcetylCoA?

A

acetyl-CoA can be produced either by fatty acid oxidation or by the pyruvate dehydrogenase complex from pyruvate

33
Q

What is the effect of acetyl CoA on pyruvate carboxylase and pyruvate dehydrogenase?

A

Acetyl CoA stimulates pyruvate carboxylase and inhibits pyruvate dehydrogenase.

34
Q

Reaction of pyruvate to acetyl CoA

A

By pyruvate dehydrogenase complex

Pyruvate-> Acetyl CoA + CO2

35
Q

Reaction of pyruvate to oxaloacetate

A

By pyruvate carboxylase

Pyruvate-> Oxaloacetate

36
Q

When is Acetyl CoA concentration is high

A

When liver has sufficient FA for β-oxidation- fatty acids are being oxidized in high amounts

37
Q

Insulin __ expression of enzymes involved in glycolysis

Insulin __ expression of enzymes involved in gluconeogenesis

Effect of glucagon is the __

A

Insulin increases expression of enzymes involved in glycolysis

Insulin decreases expression of enzymes involved in gluconeogenesis

Effect of glucagon is the opposite

38
Q 
What are the roles of the following enzymes? What is the effect of insulin on these enzymes? 
Hexokinase II
Hexokinase IV
Phosphofructokinase-1 (PFK-1)
PFK-2/FBPase-2
Pyruvate kinase
A

Essential for glycolysis, which consumes
glucose for energy
Insulin increases their expression

39
Q

What are the roles of the following enzymes? What is the effect of insulin on these enzymes?
Glucose 6-phosphate dehydrogenase
6-Phosphogluconate dehydrogenase
Malic enzyme

A

Produce NADPH, which is essential for conversion of glucose to lipids. Involved in glycolysis
Insulin increases their expression

40
Q

What are the roles of the following enzymes? What is the effect of insulin on these enzymes?
PEP carboxykinase
Glucose 6-phosphatase (catalytic subunit)

A

Essential for glucose production by gluconeogenesis

Insulin decreases their expression

41
Q

What’s ChREBP?

What is it’s role

A

ChREBP (carbohydrate response element binding protein) is a transcription. It serves to coordinate the synthesis of enzymes needed for carbohydrate and fat synthesis
It serves to coordinate the synthesis of enzymes needed for carbohydrate and fat synthesis.

42
Q

Where’s ChREBP expressed?

A

It is expressed primarily in liver, adipose tissue, and kidney.

43
Q

What is the inactive state of ChREBP and where is it found?

A

ChREBP in its inactive state is phosphorylated, and is located in the cytosol.

44
Q

Describe how does ChREBP regulate

A

When ChREBP in the cytosol of a hepatocyte is phosphorylated on a Ser and a Thr residue, it cannot enter the nucleus.
Dephosphorylation of p-Ser of ChREBP by protein phosphatase PP2A allows ChREBP to enter the nucleus, where a second dephosphorylation of P –Thr by nuclear PP2A activates ChREBP so that it can associate with its partner protein, Mlx.
ChREBP-Mlx now binds to the carbohydrate response element (ChoRE) in the promoter and stimulates transcription.

45
Q

What does protein phosphatase PP2A do?

A

Dephosphorylates p-Ser of ChREBP, allowing it to enter the nucleus

46
Q

What activates PP2A?

A

PP2A is allosterically activated by xylulose 5-phosphate, an intermediate in the pentose phosphate pathway.

47
Q

What is the role of FOXO?

A

FOXO1 (forkhead box other) stimulates the synthesis of gluconeogenic enzymes and suppresses the synthesis of the enzymes of glycolysis, the pentose phosphate pathway, and triacylglycerol synthesis. Induces expression of PEP carboxykinase and Glucose 6-phosphatase

48
Q

Describe functioning of FOXO1

A

Insulin activates the signaling cascade, leading to activation of protein kinase B (PKB).
FOXO1 in the cytosol is phosphorylated by PKB, and the phosphorylated transcription factor is tagged by the attachment of ubiquitin for degradation by proteasomes.
FOXO1 that remains unphosphorylated or is dephosphorylated can enter the nucleus, bind to a response element, and trigger transcription of the associated genes.
Insulin therefore has the effect of turning off the expression of these genes, which include PEP carboxykinase and glucose 6-phosphatase.

49
Q

What does FOXO1 suppress?

A

Transcription of enzymes of glycolysis, pentose phosphate pathway and FA synthesis

50
Q

What’s the effect of insulin on gluconegenisis enzymes?

A

Insulin activates a signaling cascade that degrades FOXOQ and therefore has the effect of turning off the expression of these genes, which include PEP carboxykinase and glucose 6-phosphatase.

BC 2- (19 decks)

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