Pentose Phosphate Pathway

Question 1

General purpose of the PPP

Answer 1

Provides 5C sugars as precursors to make nucleotides (pentoses or phosphopentoses)

Also produces NADPH = reducing power for biosynthetic pathway…FAs, steroids, and NTs

Also protects membranes and tissues from oxidative damage and detoxifies xenobiotic durgs

Question 2

Where are enzymes for PPP located

Answer 2

Cytosol

Question 3

What do the following tissues use the PPP mainly for?

1. Adrenal gland
2. Liver
3. Testes
4. Adipose tissue
5. Ovary
6. Mammary gland
7. RBCs

Answer 3

1. Steroid syn
2. FA and cholesterol syn
3. Steroid syn
4. FA syn
5. Steroid syn
6. FAS
7. Maintenance of reduced glutathione

Question 4

NADH vs. NADPH

Answer 4

NADH = donates electrons to the ETC, generating ATP by oxidative phosphorylation

NADPH = reducing power for biosynthetic pathways

Question 5

Oxidative vs. nonoxidative PPP pathways

General

Answer 5

Oxidative = generates NADPH for biosynthetic pathways, and to counter the damaging effect of ROSs

Non-ox = recycles the pentose phosphate back to useful glycolytic intermediates…which are further metabolized

Question 6

How many molecules of NADPH produced for every glucose molecule (actually G6P) to enter PPP

Answer 6

2 NADPH

Question 7

Glucose 6P dehydrogenase (PPP)

Answer 7

Oxidative phase (reaction 1)

G6P —> 6-phosphoglucono-delta-lacton

NADPH is produced

‘Commitment step’

Under allosteric regulation by NADPH

Reversible

G6P comes from hexokinase reaction in glycolysis (glucokinase in liver)

Question 8

Lactonase (PPP)

Answer 8

Oxidative phase / reaction 2

6-phosphoglucono-delta-lactone —> 6-phosphogluconate

Ring structure —> linear chain form

Irreversible

Question 9

6-phosphogluconate dehydrogenase (PPP)

Answer 9

Oxidative phase / reaction 3

6-phosphogluconate —> D-ribulose-5P

Oxidative carboxylation (NADPH + CO2 produced)

Irreversible

Question 10

Phosphopentose isomerase (PPP)

Answer 10

Oxidative / reaction 4

Ribulose-5P —> ribose-5P

Keto-sugar —> aldo-sugar

As needed ribose-5P = nucleotide precursor’

Reversible

Question 11

Overall results of PPP

Answer 11

Glucose-6P —> ribose-5P

2 NADPH

1 CO2

Question 12

Cell requirements that would dictate the need for the non-oxidative phase of PPP

Answer 12

Amount of NADPH required is much greater than the need for ribose-5P

Takes ribose-5P and makes useful intermediates for glycolysis or run through PPP again

The case for RBCs…since no nucleus

Question 13

Epimerase (PPP)

Answer 13

Non-oxidative / reaction 1

Ribose-5P —> xylulose-5P

Aldose —> ketose sugar

X5P = regulatory molecule in carb and lipid metabolism

Question 14

Transketolase (PPP)

Answer 14

Non-oxidative / reactions 2 and 4

Reaction 2:

Removes 2C from ribose-5P —> xylulose-5P

Result: 2 5C sugars —> 3C and 7C sugars

REQUIRES THIAMINE PYROPHOSPHATE (TPP, VITAMIN B1) as a cofactor

Reaction 4:

Removes 2C from ribose-5P (again) —> the 4C product from step #3

Results: 5C —> 3C (glyceraldehyde-3P)

4C —> 6C (fructose-6P)…which can be converted to G6P

Question 15

Transaldolase (PPP)

Answer 15

Non-oxidative / reaction 3

Removes 3C from the 7C sugar and adds to the 3C sugar (both from step 2)

7C —> 4C (gets 2C in step 4)

3C —> 6C (F6P)

Does NOT need TPP as cofactor like transketolase

Question 16

Allosteric regulation by NADPH on PPP

Answer 16

High NADPH inhibits glucose-6P dehydrogenase

First step in oxidative phase (commitment step)

Question 17

If cell needs only steady supply of ribose-5P and no NADPH…

Answer 17

Oxidative phase is shut off

Instead the non-ox phase is run in the reverse direction using both F6P and glyceraldehyde3P to generate the phosphopentose

Question 18

Role of xylulose-5P in control of carb and fat metabolism

Answer 18

After a high carb meal…

Levels of X5P rise via epimerase reaction in oxidative phase

Activates phosphoprotein phosphatase (PP2A)

Which dephosphorylates the PFK-2/FBPase-2 enzyme

Activates PFK-2 activity

Increases fructose-2,6-BP

Activates glycolysis…while inhibiting gluconeogenesis

….

Also boosts production of acetyl-CoA…the synthesis of NADPH (PPP) and Acetyl-Coa (PDH complex/glycolysis) both stimulate synthesis of FAs

Question 19

NADPH requirement to reduce glutathione

Answer 19

RBCs need alot of NADPH for this purpose…to protect it from ROS

Glutathione exists in 2 forms

1. Oxidized (GSSG)
2. Reduced (2GSH - two molecules) - disulfide bond is broken

Glutathione and glutathione peroxidase function to reduce H2O2 —> H2O and O2…

2GSH —-> GSSG in the process (glut peroxidase reduces it back…needs NADPH for reducing power)

Question 20

Drug-induced hemolytic anemia and favism

Answer 20

If something decreases G6PDH … NADPH levels can drop…depleting reduced GSH levels

—> drug-induced hemolytic anemia

G6PDH gene = X chromosome

G6PDH deficiency = most common enzymopathy

Question 21

Anti-malaria drugs

Answer 21

Example = quinone

Can cause serious shit if have G6PDH deficiency

Question 22

Symptoms of hemolytic crisis

Answer 22

Sudden rise in body temp

Yellow skin

Urine dark yellow - Hb in urine

Patient history = clue —> take sulfa drug? Or any other oxidative drug?

Question 23

Alcoholics and hemolytic crisis

Answer 23

Can occur cause alcoholics can have a deficiency in TPP (cofactor for transketolase)