9. Gluconeogenesis, PPP

Question 1

Five characteristics of the pentose phosphate pathway (PPP)?

Answer 1

 This pathway obtains pentoses (C5): building blocks RNA + DNA
 Provides 50% of NADPH, needed for fatty acid synthesis. Highly expressed at sites for fatty acid synthesis (liver, mammary gland, adipose)
- Only source of NADP for red blood cells
 Connects Ch metabolism with lipid metabolism
- substrate is glucose

Question 2

NAD and NADP: conversible?

Answer 2

NAD vs NADP: cannot simply exchange these two or convert them to one another. NADP really needs to be synthesized by PPP

Question 3

NADP has a ..

Answer 3

NADP: phosphorylated OH group

Question 4

Look at the metabolic map. How many gl-6-p are needed for the PPP ? How many riboses are obtained?

Answer 4

3 mol, 3 mol

Question 5

Explain the pathway using the map.

Answer 5

You need to start with three mol glucose.
Then, you get three mol g-6-p, to obtain three riboses (which is the natural pathway: 3x)
Then, you get the intermediate gl-3-p. Detour to the riboses. Release 3 x 2 NADPH and 3x CO2. Then two intermediates of glycolysis released: one glyceraldehyde-3-p and two fr-6-p. Can be used for ATP production following glycolysis.

Question 6

After ribulose-5-p, there are C’s exchanges. Explain this process.

Answer 6

• 2 glucoses yield 2 ribuloses (C5).
• They start to exchange C’s: one converts in C7 and the other in C3.
• Exchange again until one has C4 and one has C6.
• First product yield: (C6) fr-6-p
• Another glucose is used, another C5 is created
• Interacts with C4: yield one C6 and one C3.
  Second products yielded: (C6) fr-6-p and (C3) gl-3-ph

Question 7

Now, what is yielded in total by PPP?

Answer 7

1x C3
2x C6
3x 2= 6 NADPH
3x CO2

Question 8

PPP vs glycolysis: ATP yield.
PPP yields 1x C3 (Ga-3-p) and 2x C6 (fr-6-p). = 6 NADPH
Glycolysis: to reach the same metabolites

Answer 8

Yield: 2x C6 (fr-6-p) = 0 ATP
Yield: 2x ga-3-p with one mol of glucose = -1 ATP
Therefore, one can be used in oxidation.
Oxidation of one ga-3-p = 16 ATP.
Total = 16-1 = 15 ATP.

Question 9

Choosing whether to make 6 NADPH or 15 ATP is dependent on..

Answer 9

e.g. amount of glucose in the cells.
If there is a peak, either glycogen will be stored or NADPH will be produced.

Question 10

What are neutral energetics vs substrate cycle?

Answer 10

Neutral energetics (mass driven, equilibrium)
= Energy invested in the forward reaction is released in the backward reaction. Net result = 0
Substrate cycle (tourniquet principle: go in ‘pay’/go out ‘free’)
= Energy invested in the forward reaction is not released in the backwards reaction

Question 11

Glycolysis:
1 m Glucose -> 2 m pyruvate

So, gluconeogenesis = ..

Answer 11

2 m pyruvate -> 1 m glucose

Question 12

What are the neutral reactions in glycolysis and gluconeogenesis?

Answer 12

ga-3-p > 1,3bip > 3-phosphoglycerate

Question 13

Energy loss of glucose -> 2 pyruvate -> glucose (glucose substrate cycling)?

Answer 13

-6 ATP

(down: +5 ATP)
(up: -11 ATP)

Question 14

Pyruvate can go a lot of directions, namely..
For what?

Answer 14

1. Acetly-CoA: glycolysis
2. Lactate: anaerobic oxidation
3. OAA: gluconeogenesis

Question 15

Gluconeogenesis: starts from pyruvate:
Cells have to switch:
Pyruvate -> acetyl-CoA
or:
Pyruvate -> oxaloacetate

What does this depend on?

Answer 15

 High acetyl-CoA = change to oxaloacetate
 High AMP (signaling low energy) = low ATP = stimulation citric acid cycle = condensation oxaloacetate + Acetyl-CoA
 Low AMP = high ATP = stimulation of gluconeogenesis, oxaloacetate is converted to PEP; inhibition glycolysis

Question 16

Pasteur effect: 15x more glucose needed in anaerobic oxid. to obtain same amount of ATP when finishing TCA cycle.

Why do cells switch to lactate glycolysis when in need? Under which conditoins was it used again?

Answer 16

it is very very fast.

• No oxygen
• No mitochondria

Question 17

What type of NADH does lactate pathway use? What happens to the NAD+?

Answer 17

Cytosolic.
use it in conversion pyruvate to lactate and NAD+ is reused upstream. So you can immediately cycle NADHc to release lactate, which is shuttled out of the muscle cell

Question 18

How much ATP is produced / glucose with pyruvate?

Answer 18

2 ATP

Question 19

How much NADH is USED when converting pyruvate to lactate if the pyruvate is coming from a glucose molecule?
What happens with the NAD+?

When the lactate then enters the liver, ..

Answer 19

• 2 NADHc, because you get 2 lactate per 2 pyruvate per 1 glucose.
• NAD+ is reused in converting glucose to pyruvate, which yields 2 NADHc
• When the lactate then enters the liver, it is converted to pyruvate again releasing 2 NADHc
• 2 NADHc is used in gluconeogenesis

Question 20

Where does lactate go?

Answer 20

It then goes into the liver, where lactate is used to recycle it into glucose, which can be released into circulation.

Question 21

What is the Cori cycle?

Answer 21

Recycling of lactate

1. glycolysis in muscle (1 glucose -> 2 pyruvate -> 2 lactate)
2. Gluconeogenesis in the liver (2 lactate -> 2 pyruvate -> 1 glucose)

Then glucose will go to muscle again … creating a cycle
p.94

Question 22

Cycling of lactate: ATP in muscle vs liver?

Answer 22

Muscle: glucose -> 2 ATP + lactate
Liver: 2 lactate + 8 ATP -> glucose

Extra costs: 6 ATP
Energy goes into heat

Question 23

Some tissues better adapt to anaerobic conditions. Examples?

Answer 23

• RBCs do not contain mitochondria and only use the lactic acid pathway.
• Occurs in skeletal muscles and heart when ratio of oxygen supply to oxygen need falls below critical level.

Question 24

What happens when cardiac muscle expires anaerobically?

Answer 24

Cardiac muscle normally respires aerobically:
– Myocardial ischemia occurs under anaerobic conditions.

Question 25

Ratio ATP yield in ATP of aerobic and anaerobic breakdown of glucose?

Answer 25

30/2 = 15x

Question 26

After 5 days high fat vs low fat diet in mice they saw..

Answer 26

Change in certain genes: 5 days diet have huge effect on metabolism at tissue level

Question 27

How many Cs does propionic acid have?

Answer 27

C3

Question 28

Direct oxidation of propionic acid (C3 -> C4 acetyl-CoA so apparently now you need 2x propionic acid).

How much ATP?

Answer 28

2 x 13.5 = 27 ATP
Direct = convert to PEP -> acetyl- CoA -> TCA cycle

Question 29

How much ATP with propionic acid if you use indirect oxidation via glucose-6-p? Or glucose? Or glycogen?

Answer 29

Gl-6-p = 26 ATP
glucose = 25 ATP
Glycogen = 25 ATP