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MET1 > Glycolysis and Glucose Oxidation > Flashcards

Glycolysis and Glucose Oxidation Flashcards

1
Q

What is involved in glucose uptake?

A
  • Before anything, glucose needs to be taken up into the cells
  • Issue: glucose is a charged (polar) molecule and cell membrane is hydrophobic.
  • Need specialized glucose transporters: GLUTs
    o facilitate transport across a concentration gradient (no ATP needed!)
  • 14 different isoforms of GLUT – expressed in different tissues
  • Important GLUTs:
    o GLUT1: expressed in all cells (low Km)
    o GLUT2: expressed in liver and pancreas (high Km) – acts as a glucose sensor
    o GLUT 4: expressed in muscle and adipose cells (low Km) – controlled by insulin
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2
Q

Which GLUTs are insulin independent and which are insulin dependent?

A

Insulin independent:
GLUT1 (low Km)
GLUT2 (high Km, low affinity)
GLUT3 (low Km, high affinity)

Insulin dependent:
GLUT4 (low Km)

Low Km = fast
High Km = slow (acts as sensor)

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3
Q

How is GLUT4 controlled hormonally?

A
  • In skeletal muscles, most GLUT4 transporters are bound to vesicles inside the cell, so glucose cannot move inside.
  • Upon insulin signalling, these vesicle merge with the cell membrane, exposing the GLUT4 transporters and allowing glucose uptake.
  • Exercise also promotes this action (why exercise is good for diabetics)
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4
Q

What is glycolysis? How many steps are there? What is required and what is generated?

A
  • Simply: process which converts glucose to pyruvate.
  • 10 step process
    o First 5 steps require energy (2 ATP) “investment”
    o Last 5 steps (“payback”) generate:
     4 ATP
     2 NADH (energy rich molecule)
     2 pyruvate molecules (used in Krebs cycle to generate much more ATP)
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5
Q

What happens in step 1 of glycolysis?

A

Step 1: Phosphorylation of Glucose
- First step is to add a phosphate group to glucose, forming glucose -6 – phosphate (G6P).
o Requires one ATP (energy draining step)
o This is required to prevent glucose from leaving the cell
- Catalysed by the enzyme hexokinase
o Can phosphorylate any 6 ringed carbohydrates
o Expressed in mostly all cells
o Sensitive to negative feedback from G6P.
 Knock on effect on glucose uptake by GLUT (by blocking GLUT to prevent uptake).

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6
Q

What is an alternative step 1 for glycolysis?

A

Step 1 Alternative: Glucokinase
- Only found in liver and pancreas
- Catalyses only glucose. Why?
o Responds quicker to changes in glucose levels (acts as glucose sensor)
- High Km
- No feedback inhibition – it will keep working even in high glucose environments (and will work more quickly in high glucose to keep glucose constant)
- Acts as a sensor for glucose levels in β-cells of the pancreas to regulate insulin/glucagon production/secretion
- Activity is regulated by localisation by binding it to the protein glucokinase – regulatory protein (GKRP).

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7
Q

What is step 2 of glycolysis?

A

Step 2: Isomerisation

  • Changing G6P into one of its isomers: fructose-6-phosphate
  • Makes later chemical reactions more energetically favourable
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8
Q

What is step 3 of glycolysis and why is it important?

A

Step 3: Phosphorylation of Fructose 6-Phosphate

  • Important step: rate-limiting step by regulating the function of the enzyme phosphofructokinase 1 (first step that is specific to glycolysis)
  • Adds another phosphate group (uses another ATP - down 2 ATPs)
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9
Q

How can phosphofructokinase 1 be controlled?

A

Control of Phosphofructokinase 1
- Phosphofructokinase 1 (PFK1) enzyme can be regulated by a number of molecules which will determine whether glycolysis moves forward, stops or backwards.
- PFK1 is allosterically activated by:
o High AMP levels (cell needs energy/ATP)
o Fructose-2,6-bisphosphate (F2,6P) produced from fructose 6-phosphate by an isoform of PFK1, called PFK2, an enzyme which is hormonally regulated.
- PK1 is inhibited by products of glycolysis and the Krebs cycle:
o High ATP levels
o Citrate (a by-product of the Krebs cycle)

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10
Q

What is phosphofructokinase 2 and what does it do? How is it stimulated? What is step 5 and why does it occur?

A
  • Phosphofructokinase-2 is a bifunctional enzyme – it has kinase and phosphatase activities.
  • Insulin stimulates the kinase activity leading to fructose-2, 6-bisphosphate (which in turn stimulates PFK-1).
  • Glucagon stimulates the phosphatase activity and gluconeogenesis
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11
Q

What is step 4 of glycolysis? What are the products and which enzymes are involved?

A

Step 4: Breakdown of 6-Carbon Ring to Two 3-Carbon Chains
- F1,6-bisP is broken down the middle to give two 3 carbon chains, both carrying one phosphate group but with different structures:
o One is an aldehyde – glyceraldehyde-3-phosphate
o Other is an acetone – dihydroxyacetone phosphate
- Catalysed by the enzyme aldolase.
- The acetone can be converted to the aldehyde through an isomerisation reaction (step 5), since only the aldehyde can be used for glycolysis.
- So now we have two glyceraldehyde – 3 – phosphate molecules from one glucose.
- How many ATP’s are we at now? (+ or -)

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12
Q

What is step 6 of glycolysis?

A
  • Prior to generating our first ATP, we need to add a phosphate group from the cytosol (rather than from ATP as was happening before)
  • The dehydrogenase enzyme catalyses the addition of a free phosphate to the glyceraldehyde producing a 3 carbon chain carrying 2 phosphate groups (a high energy molecule)
  • As a by-product of this reaction, NAD+ is reduced to NADH plus a free proton (H+).
  • NADH is used later in the KREB’s cycle and electron transport chain to regenerate NAD+ which is needed to keep glycolysis going.
  • NAD+ can also be regenerated by lactic acid produced from anaerobic breakdown of glucose.
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13
Q

What is step 7 of glycolysis?

A

Step 7: First ATP Produced

  • The high energy molecule 1,3-bisphosphoglycerate gives one of its phosphates to generate one ATP.
  • Catalysed by phosphoglycerate kinase.
  • Substrate level phosphorylation: means that we are just shifting phosphate groups around to create ATP (different from how ATP is generated later in the electron transport chain)
  • So what is our ATP count at this step?
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14
Q

What is step 8 of glycolysis?

A

Step 8: Shifting the Phosphate

- Phosphate group shifted from one carbon to the middle carbon – catalysed by phosphoglyceromutase.

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15
Q

What is step 9 of glycolysis?

A

Step 9: Dehydration
- Removal of a water molecule produces PEP
- PEP is an important intermediary since it can also be produced by gluconeogenesis.
- Enzyme is enolase
(can be inhibited by fluoride ions)

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16
Q

What is step 10 of glycolysis?

A

Step 10: Another ATP is produced!

  • The last step of glycolysis produces the last ATP from PEP by the enzyme pyruvate kinase.
  • The production of pyruvate is also important since it feeds into the next energy producing cycle – the Kreb’s cycle. (or can take sideways step to produce lactate: anaerobic respiration)
  • This also is a substrate level phosphorylation of ATP from ADP.
  • So what is the NET production or loss of energy of glycolysis?
17
Q

Summarise the key points of glycolysis.

A
  • Key points to remember:
    o 1st 5 steps are energy depleting
    o 2nd 5 steps are energy generating
    o In all 2 ATPS are consumed and 4 generated
    o 2 pyruvate molecules are also generated per glucose
    o And 2 NADH molecules
    o Most important step is regulation is step 3, catalysed by phosphofructokinase enzyme – a rate limiting reaction.
18
Q

What happens to pyruvate after glycolysis?

A
  • Aerobic versus anaerobic
  • If oxygen is present, pyruvate is catalysed to acetyl CoA by pyruvate dehydrogenase
  • Acetyl CoA then reacts with oxaloacetate in the Krebs cycle
  • If oxygen is scarce, glycolysis could stop if NAD+ is not regenerated from NADH
  • At this point, pyruvate can act as the electron acceptor and be reduced to lactate, and NADH is re-oxidised to NAD+
19
Q

How does glycerol interact with glycolysis?

A
  • Only the liver has the enzymes that can convert glycerol into dihydroxyacetone phosphate (DHAP) which can feed into glycolysis at step 4.
  • Glycerol is converted to glycerol -3-phosphate by glycerol kinase (mainly in liver), which in turn is oxidised to DHAP, releasing another NADH.
20
Q

How does glycolysis interact with fructose metabolism?

A
  • Fructose, like glucose, is a 6-carbon hexose carbohydrate
  • Very common in the diet (common sugar)
  • Can be metabolised by hexokinase to fructose – phosphate and joins glycolysis at step 3 (occurs in all cells)
  • Alternatively, liver produces fructokinase (kinase that acts only on fructose) to produce fructose-1-phosphate. This can be converted immediately to dihydroxyacetone phosphate and glyceraldehyde by the enzyme aldolase B to join glycolysis at step 5.
21
Q

What is essential hepatic fructosuria? What causes hereditary fructose intolerance?

A
  • Essential hepatic fructosuria:
    o Autosomal recessive genetic condition caused by mutations in KHK gene (ketohexokinase gene).
    o Causes deficiency in fructokinase enzyme leading to patients being unable to process fructose.
    o Can be controlled by avoiding sugary foods.
  • Hereditary fructose intolerance is caused by a deficiency in aldolase B enzyme
22
Q

How does glycolysis interact with the pentose phosphate pathway?

A
  • An important pathway for the production of 5-carbon sugars (pentoses) used in nucleic acids (that make up DNA and RNA) and NADPH needed for steroid hormones and fatty acids synthesis.
  • Important in liver and red blood cells.
  • Important products of pentose pathway:
    o Ribose 5 phosphate
    o NADPH (different from NADH)
  • Pentose pathway also produces glyceraldehyde-3-phosphate and fructose-6-phosphate, both of which can feed into glycolysis.
23
Q

How many ATPs are needed in glycolysis and how many are produced?

A

2 ATPs needed in the “investment” phase and 4 are produced in the ”pay back“ phase

24
Q

Why is NAD important and how is it produced when oxygen is scarce?

A

NAD is needed to oxidise glyceraldehyde-3-phosphate to glyceraldehyde 1,3 bisphosphate via glyceraldehyde-3-phosphate dehydrogenase. NAD is reduced to NADH in this step. Without NAD, this step can’t take place and glycolysis stops. Pyruvate steps in as the electron acceptor from NADH and forms lactate and NAD when oxygen is low.

25
Q

Why is PKF1 important and how is it regulated?

A
  1. PFK1 is the committed step in glycolysis. It senses the energy charge in the cell. It is regulated by ATP.ADP and AMP. It is inhibited by ATP, but upregulated by ADP, AMP and fructose-2,6-bisphosphate which is produced by PFK2 from fructose-6-phosphate.
26
Q

How are triglycerides linked to glycolysis?

A
  1. Glycerol is produced from the degradation of triglycerides. Glycerol is fed into glycolysis via glycerol-3-phosphate (via glycerol kinase) and then dihydroxyacetone-phosphate which is produced via glycerol-3-phosphate dehydrogenase and NAD

MET1 (16 decks)

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