Pentose Phosphate Pathway (PPP)

what is the pentose phosphate pathway (PPP) also called

the hexose monophospahte shunt

where does the PPP occur

cytosol

what major metabolic pathways is PPP closely related to

- glycolysis

- gluconeogenesis

- fatty acid synthesis

- nucleotide synthesis

why is PPP considered biomedically important

essential for:

- NADPH production

- oxidative stress defense

- biosynthesis (fat, cholesterol, nucleotides)

what are 3 main functions of the PPP

1. produce NADPH

2. reduce oxidative stress (ROS) detoxification

3. produce ribose-5-phosphate for nucelotide synthesis

what is NADPH

a reducing molecule similar to NADH but with an extra phosphate

what is main role of NADPH

reducing power for anabolic reactions

what is NADH mainly used for

ATP production (energy generation)

which type of metabolism uses NADPH

anabolic (building pathway)

examples of processes that require NADPH

- fatty acid synthesis

- cholesterol synthesis

- detoxification reactions

what are reactive oxygen species (ROS)

highly reactive oxygen-containing molecules that can damage cells

natural byproducts of oxidative metabolism & oxidative stress from drug or toxin exposure

examples of ROS

Hydrogen peroxide (H₂O₂)

Superoxide (O₂⁻)

Hydroxyl radical (OH•)

Hypochlorite (OCl⁻)

why are ROS dangerous

they damage:

- DNA

- proteins

- cell membranes

what conditions are associated with excess ROS

- cancer

- aging

- inflammation

- reperfusion injury (heart attack damage)

are ROS ever beneficial

yes... used by the immune system to kill pathogenic microbes

what does oxidation mean

loss of electrons

what does reduction mean

gain of electrons

OIL RIG

why must oxidation and reduction occur together

electrons must be transferred between molecules

(paired reactions)

you need a _____ molecule to neutralize reactive oxygen species

reduced

what is glutathione

a tripeptide antioxidant containing cysteine

what functional group makes glutathione important

the -SH (thiol) group on cysteine

what happens when glutatione is oxidized

forms a disulfide bond (GSSG)

what happens when glutathione is reduced

exists as two separate SH groups (GSH)

what enzyme reduces oxidized glutathione (GSSG)

glutathione reductase

what molecule provides the reducing power for this reaction

NADPH

what enzyme uses glutathione to detoxify ROS

glutathione peroxidase

what reaction does glutathione peroxidase perform

converts H₂O₂ → H₂O

why is NADPH essential here

continously regenerates reduced glutathione

what happens if NADPH is low

- cannot regenerate glutathione

- ROS accumualtes

- leads to cell damage

what molecule enters the PPP (oxidative phase start)

glucose-6-phosphate (G6P)

what is the first enzyme of PPP

glucose 6 phosphate dehydrogenase (G6PD)

what does G6PD produce

1 NADPH

why is G6PD important

it is the rate-limiting enzyme

what activates G6PD

NADP+ (allosteric)

what inhibits G6PD (allosteric)

NADPH

hormonal regulation of PPP

insulin activates it

pentose phosphate pathways (liver, fat)

regulatory enzyme:

- G-6-P DH

activator:

- NADP+

inhibitor:

- NADPH

hormones:

insulin (increases)... promotes energy storage

what happens in the second oxidative step

another NADPH is produced

what enzyme produces the second NADPH

6-phosphogluconate dehydrogenase

what important structural change occurs here

6-carbon sugar → 5-carbon sugar

(Hexose → Pentose)

what are the 2 main products of oxidative phase

2 NADPH

ribose-5-phosphate

is the oxidative phase reversible

no... irreversible

why is ribose-5-phosphate important

it is used to make nucleotides (DNA/RNA)

is the non-oxidative phase reversible or irreversible

reversible

what is the main function of this phase

carbon shuttling between sugars

does the second part of PPP (non-oxidative) produce NADPH

no

does it use ATP

no

no high ____ ____ molecules produced or consumed in non-oxidative PPP

energy carrier

what drives the non-oxidative phase

mass action (reactant/product ratios)

what glycolysis intermediates are produced (non-oxidative)

fructose-6-phosphate

glyceraldehyde-3-phosphate

why are the intermediates important

PPP connects to:

- glycolysis

- gluconeogenesis

**feed into this pathways as needed**

key difference between oxidative vs non-oxidative PPP

oxidative:

- NADPH produced

- irreversible

- function = NADPH + ribose

non-oxidative:

- NADPH not produced

- reversible

- function = carbon shuffling

what is the most common PPP disorder

G6PD deficiency... mutations in other enzymes are rare

why are red blood cells especially vulnerable

- no mitochondria

- PPP is their ONLY source of NADPH

**rely solely on cytosolic paths: glycolysis & pentose phosphate path**

G6PD protects against oxidative damage from...

1. naturally oxidative compounds (fava beans, henna)

2. oxidative drugs (ex. anti-malarials, antibotics, analgesics)

3. inflammatory injections

what happens in G6PD deficiency

↓ NADPH

↓ glutathione

↑ ROS

→ hemolysis

what can trigger hemolysis in G6PD deficiency

- fava beans

- drugs (antimalarials, antibiotics)

- infections

what condition results from G6PD deficiency

acute hemolytic anemia

why is G6PD deficiency maintained in populations

provides protection against malaria

what is glycogen

branched polymer of glucose used for energy storage in animals

glucose from a meal only lasts hours in bloodstream

Longer term fuels needed:

• Glycogen (Carbohydrates = 4 kcal/g)

• Fat = 9 kcal/g)

• Protein = 4 kcal/g)

(Not good fuel, but alcohol = 7 kcal/g)

where is glycogen stored

primarily in:

liver → maintains blood glucose

skeletal muscle → used for muscle contraction

glycogen stored in ____ can maintain blood glucose levels for ~24 hrs; glycogen stores reflect fed or ___ state

liver, fasting

glycogen stored in muscle fuels ____ production for muscle contraction; glycogen stores reflect exercise intensity

ATP

glycogen → glucose 6-P → energy (ATP for work)

how many glucose molecules make up glycogen

55,000

structural features of glycogen

α-1,4 glycosidic bonds → linear chains

α-1,6 glycosidic bonds → branch points (every 8-12 residues)

highly branched → allows rapid synthesis and breakdown

why is glycogen highly branched

increases solubility

provides multiple ends for enzymes → rapid glucose release

what is glycogeneis

process of synthesizing glycogen from glucose

when does glycogenesis occur

in the fed state (high glucose, high insulin)

what is the overall goal of glycogenesis

convert excess glucose → glycogen for storage

key points of glucose phosphorylation

- irreversible

- consumes energy

- traps glucose in the cell

- feedback inhibition by end product G6P (allosteric)

- branch point-- also enters pentose phosphate & glycogen synthesis pathways

what is the first step of glycogenesis

glucose → glucose-6 phosphate (G6P)

phosphorylation of glucose

what catalyzes this step

hexokinase (most tissues)

glucokinase (liver)

why is phosphorylation important

traps glucose inside the cell

prepares it for metabolism

what happens to glucose-6-phospahte next (isomerization)

converted to glucose-1-phosphate (G1P)

which enzymes catalyzes G6P to G1P

phosphoglucomutase (irreversible)

why is G1P important

direct precursor for glycogen synthesis

what happens to glucose-1-phosphate

converted to UDP-glucose

which enzyme is involved

UDP-glucose pyrophosphorylase

why is UDP-glucose needed

- activated form of glucose

- provides energy for bond formation

what drives this reaction forward

breakdown of pyrophosphate PPi

what enzyme builds glycogen chains

glycogen synthase

what type of bonds does glycogen synthase form

α-1,4 glycosidic bonds at non-reducing end

can glycogen synthase start a new chain from scratch

no

what is required to start glycogen synthesis

a primer protein called glycogenin

how does glucogenin work

- attached first glucose to a tyrosine residue

- builds a short chain (~4 residue chain

- glycogen synthase then takes over

what enzyme creates branches in glycogen

branching enzyme (amylo-1,4 → 1,6 transglycosylase)

what does branching enzyme do

- transfers a segment of glucose chain

- creates α-1,6 bond

why are branches important

- increase solubility

- allow rapid glucose release

what is glycogenolysis

breakdown of glycogen → glucose

**chain shortening**

when does glycogenolysis occur

- fasting state

- exercise

what is the key enzyme in glycogen breakdown

glycogen phosphorylase

what is role of glycogen phosphorylase

-cleaves α-1,4 bonds

-produces glucose-1-phosphate

why phosphorylation instead of hydrolysis

- conserves energy

- produces G1P (already phosphorylated)

how far can glycogen phosphorylase degrade glycogen

stops 4 residues before a branch point

a(1"4) bonds broken sequentially until 4 residues from a branch - "limit dextran"

glycogen phosphorylase cleaves sequentially until ___ residues from a branch remain

4

what enzyme handles branch points

debranching enzyme

two activities of debranching enzyme

glucotransferase activity → moves 3 glucose units to non-reducing end of another chain

α-1,6 glucosidase (amylo-glucosidase)→ removes branch point glucose & releases free glucose

debranching enzyme (bifunctional)

Glycogen phosphorylase breaks a-1,4 bonds, releasing Glucose-1-Phosphate, but stops 4 residues from a branch

the transferase activity of GDE moves 3 glucose residues

a-1,6 glucosidase: hydrolyzes the remaining

a-1,6 glycosidic bond at the branch point.

free glucose molecule is released (not Glucose-1-Phosphate).