9 Pentose Phosphate Pathway and NADPH

Pentose phosphate pathway

Occurs in the cytoplasm of all cells.

Pentose phosphate pathway activity

Especially active in the liver

Main function of the pentose phosphate pathway

To produce NADPH.

NADPH

Required for fatty acid synthesis in the liver

Pentose phosphate pathway protection

Protects against oxidative stress by regenerating glutathione.

Pentose phosphate pathway production

Produces ribose-5-phosphate for nucleotide synthesis.

Oxidative phase of the pentose phosphate pathway

Irreversible.

Key enzyme of the oxidative phase

Glucose-6-phosphate dehydrogenase (G6PD).

Conversion by G6PD

Glucose-6-phosphate is converted to 6-phosphogluconolactone.

G6PD reaction generation

Generates NADPH.

Conversion by 6-phosphogluconate dehydrogenase

6-phosphogluconate is converted to ribulose-5-phosphate.

6-phosphogluconate dehydrogenase reaction products

Produces NADPH and CO₂.

Committed

rate-limiting

Non-oxidative phase of the pentose phosphate pathway

Reversible.

Non-oxidative phase production

Allows cells to make ribose-5-phosphate or glycolytic intermediates.

Glycolytic intermediates produced in non-oxidative phase

Glyceraldehyde-3-phosphate (G3P) and Fructose-6-phosphate (F6P).

Enzyme that transfers 2-carbon units

Transketolase.

Cofactor required by transketolase

Thiamine.

Enzyme that transfers 3-carbon units

Transaldolase.

Insulin effect on G6PD expression

Induces G6PD expression.

Increased NADP⁺ effect

Activates G6PD.

Increased NADPH effect

Inhibits G6PD.

Deficiency of G6PD

Leads to reduced NADPH production in RBCs.

RBCs in G6PD deficiency

Cannot regenerate glutathione.

Lack of glutathione regeneration

Makes RBCs vulnerable to oxidative stress.

G6PD deficiency outcome

Leads to hemolysis of RBCs.

Triggers for hemolysis in G6PD deficiency

Sulfamethoxazole or Chloramphenicol (antibiotic).

Fava beans

Hemolysis in G6PD deficiency may occur after ingestion of Fava beans.

Infection

Another common trigger of hemolysis in G6PD deficiency is Infection.

Hydrogen peroxide (H₂O₂)

NADPH helps reduce Hydrogen peroxide (H₂O₂) to protect against oxidative damage.

Cytochrome P450 monooxygenase system

The Cytochrome P450 monooxygenase system uses NADPH to hydroxylate substrates with oxygen.

Steroid hormones

In the mitochondrial P450 system

Detoxification

The microsomal P450 system in the endoplasmic reticulum is involved in Detoxification.

Nitric oxide (NO)

NADPH is also required for synthesis of Nitric oxide (NO).

Nitric oxide synthase

The enzyme responsible for nitric oxide synthesis is Nitric oxide synthase.

FMN

FAD

Smooth muscle relaxant

Nitric oxide acts as a Smooth muscle relaxant.

Platelet aggregation

Nitric oxide prevents Platelet aggregation.

Neurotransmitter

Nitric oxide acts as a Neurotransmitter in the nervous system.

Guanylate cyclase

The main target of nitric oxide is Guanylate cyclase in the target cell.

cGMP

Guanylate cyclase converts GTP into cGMP.

Second messenger

cGMP acts as a Second messenger.

Neurotransmitter release

cGMP modulates Neurotransmitter release.

NADPH molecules

The oxidative phase of PPP produces a total of 2 NADPH molecules per glucose-6-phosphate.

Hexose monophosphate (HMP) shunt

Another name for the pentose phosphate pathway is the Hexose monophosphate (HMP) shunt.

6-phosphogluconolactone

The first product formed in the oxidative phase is 6-phosphogluconolactone.

6-phosphogluconate

6-phosphogluconolactone is converted into 6-phosphogluconate before forming ribulose-5-phosphate.

Glycolysis

The non-oxidative phase helps link PPP to Glycolysis.

Transketolase

Thiamine deficiency impairs the enzyme Transketolase.

TCA cycle

Patients with thiamine deficiency may also show reduced activity in the TCA cycle (due to PDH and α-KGDH dependence).

Reduced glutathione (GSH)

The oxidative stress defense role of NADPH is mediated by regeneration of Reduced glutathione (GSH).

Glutathione peroxidase

The enzyme that uses GSH to neutralize peroxides is Glutathione peroxidase.

Glutathione reductase

The enzyme that regenerates GSH from GSSG using NADPH is Glutathione reductase.

Hemolytic anemia

A deficiency of G6PD causes Hemolytic anemia.

Glucose-6-phosphate

The main substrate of the pentose phosphate pathway is Glucose-6-phosphate.

Ribulose-5-phosphate

The end product of the oxidative phase is Ribulose-5-phosphate.

Ribose-5-phosphate

Ribulose-5-phosphate can be isomerized to Ribose-5-phosphate.

Nucleotide synthesis

Ribose-5-phosphate is required for Nucleotide synthesis.

Nucleotide

A basic building block of nucleic acids.

CO₂

One carbon lost in the oxidative phase.

Mitochondria

Organelles that are absent in RBCs.

Oxidative damage

Damage that NADPH protects against in RBCs.

Reactive oxygen species (ROS)

Increased production during infections in G6PD deficiency.

Oxygen

One atom incorporated into substrates by the NADPH-dependent P450 system.

Solubility

Increased by the hydroxyl group (-OH) introduced by P450.

Metabolism

The detoxifying function of microsomal P450 helps in drug.

Steroid hormone

Synthesis involving the mitochondrial P450 system.

ATP

Not produced by the PPP

Lipid

Synthesis that the PPP is more active in.

G6PD

Enzyme that catalyzes the committed step of PPP.

Oxidant

Drugs that worsen oxidative stress in G6PD deficiency.

X-linked recessive

Inheritance pattern of G6PD deficiency.

Guanylate

Cyclase activated by NO.

Relaxation

Mediated by cGMP in smooth muscle.

Inhibits

Excess NADPH does this to G6PD.

Activates

Increased NADP⁺ does this to G6PD.

DNA and RNA

Synthesis that requires ribose sugars provided by the PPP.

6-phosphogluconate dehydrogenase

Enzyme involved in the oxidative step producing CO₂.

Fatty acid

Synthesis in adipose tissue using PPP-derived NADPH.

B1 (Thiamine)

Essential cofactor for transketolase.

Non-oxidative

Phase of PPP that may be impaired by thiamine deficiency.

Reactive oxygen

Species that reduced glutathione (GSH) protects against.

Hexose monophosphate

Another name for the PPP.

Fatty acid and cholesterol

Synthesis that NADPH provides reducing equivalents for.

Oxidative

Stress that leads to RBC destruction in G6PD deficiency.

Metabolic

Needs that the reversible phase of PPP provides flexibility for.

Reductive

Biosynthesis and detoxification that NADPH is a key cofactor in.

Arginine

Amino acid from which nitric oxide is synthesized.