Pentose phosphate pathway (HMP shunt)

 

Pentose phosphate pathway (HMP shunt)

Definition

The pentose phosphate pathway (PPP), also called the hexose monophosphate (HMP) shunt, is an alternative pathway of glucose metabolism that occurs in the cytosol. Its primary functions are:

• generation of NADPH

• production of ribose-5-phosphate

• interconversion of sugars (C3–C7 carbohydrates)

Unlike glycolysis, PPP does not directly generate ATP.

Cellular location

Occurs in the cytosol of all cells.

Highest activity in:

• liver

• adipose tissue

• adrenal cortex

• testes and ovaries

• lactating mammary gland

• rapidly proliferating cells

• red blood cells (RBCs)

RBCs rely heavily on PPP because it is their only major source of NADPH.

Phases of the pathway

The pathway consists of two phases.

1. Oxidative phase (irreversible)

2. Non-oxidative phase (reversible)

Oxidative phase (irreversible)

Purpose

• generates NADPH

• forms ribulose-5-phosphate

• releases CO₂

Reaction 1

Glucose-6-phosphate → 6-phosphoglucono-δ-lactone

Enzyme:

Glucose-6-phosphate dehydrogenase (G6PD)

Reaction:

$$\text{G6P} + \text{NADP}^+ \rightarrow 6\text{-phosphoglucono-}\delta\text{-lactone} + \text{NADPH} + H^+$$

Features:

• first committed step

• rate-limiting step

• irreversible

Reaction 2

6-phosphoglucono-δ-lactone → 6-phosphogluconate

Enzyme:

6-phosphogluconolactonase

Reaction:

$$6\text{-phosphoglucono-}\delta\text{-lactone} + H_2O \rightarrow 6\text{-phosphogluconate}$$

Reaction 3

6-phosphogluconate → ribulose-5-phosphate

Enzyme:

6-phosphogluconate dehydrogenase

Reaction:

$$6\text{-phosphogluconate}+{\text{NADP}}^{+}\to \text{ribulose-5-phosphate}+\text{NADPH}+C{O}_{\mathrm{2}}$$

This is an oxidative decarboxylation reaction.

Net oxidative reaction

$$\text{G6P}+2{\text{NADP}}^{+}+H_{2}O\to \text{ribulose-5-phosphate}+2\text{NADPH}+2H^{+}+C{O}_{\mathrm{2}}$$

Each molecule of glucose-6-phosphate produces 2 NADPH.

Non-oxidative phase (reversible)

Purpose

Interconversion of pentoses and glycolytic intermediates.

Main products:

• fructose-6-phosphate

• glyceraldehyde-3-phosphate

Reaction 1

Isomerization

Ribulose-5-phosphate ⇌ ribose-5-phosphate

Enzyme:

Phosphopentose isomerase

Converts:

ketopentose → aldopentose

Reaction 2

Epimerization

Ribulose-5-phosphate ⇌ xylulose-5-phosphate

Enzyme:

Phosphopentose epimerase

Transketolase reaction 1

Reactants:

• xylulose-5-phosphate (C5)

• ribose-5-phosphate (C5)

Products:

• glyceraldehyde-3-phosphate (C3)

• sedoheptulose-7-phosphate (C7)

Enzyme:

Transketolase

Cofactor:

Thiamine pyrophosphate (TPP)

Reaction:

$$\text{X5P} + \text{R5P} \rightarrow \text{G3P} + \text{S7P}$$

Transfers a 2-carbon unit.

Transaldolase reaction

Reactants:

• glyceraldehyde-3-phosphate (C3)

• sedoheptulose-7-phosphate (C7)

Products:

• fructose-6-phosphate (C6)

• erythrose-4-phosphate (C4)

Enzyme:

Transaldolase

Reaction:

$$\text{G3P} + \text{S7P} \rightarrow \text{F6P} + \text{E4P}$$

Transfers a 3-carbon unit.

Transketolase reaction 2

Reactants:

• xylulose-5-phosphate (C5)

• erythrose-4-phosphate (C4)

Products:

• fructose-6-phosphate (C6)

• glyceraldehyde-3-phosphate (C3)

Enzyme:

Transketolase

Cofactor:

TPP

Reaction:

$$\text{X5P} + \text{E4P} \rightarrow \text{F6P} + \text{G3P}$$

Net non-oxidative reaction

$$3\text{Ribulose-5-phosphate} \rightarrow 2\text{Fructose-6-phosphate} + \text{Glyceraldehyde-3-phosphate}$$

Overall pathway reaction

$$3\text{G6P} + 6\text{NADP}^+ + 3H_2O \rightarrow 2\text{F6P} + \text{G3P} + 3CO_2 + 6\text{NADPH} + 6H^+$$

This equation is frequently tested in CSIR NET.

Regulation

Rate-limiting enzyme

Glucose-6-phosphate dehydrogenase (G6PD)

Activated by

• NADP⁺

• insulin

• oxidative stress

Inhibited by

• NADPH

The NADP⁺/NADPH ratio is the major regulator.

High NADP⁺ stimulates PPP.

High NADPH suppresses PPP.

Functions of NADPH

NADPH is required for:

Reductive biosynthesis

• fatty acid synthesis

• cholesterol synthesis

• steroid hormone synthesis

Antioxidant defense

Reduction of glutathione.

Reaction:

$$\text{GSSG} + \text{NADPH} + H^+ \rightarrow 2\text{GSH} + \text{NADP}^+$$

Enzyme:

Glutathione reductase

GSH protects cells from hydrogen peroxide and reactive oxygen species.

Respiratory burst

In neutrophils and macrophages.

NADPH oxidase produces:

• superoxide

• hydrogen peroxide

• hypochlorous acid

Cytochrome P450 reactions

• drug detoxification

• xenobiotic metabolism

• steroid hydroxylation

Nitric oxide synthesis

NADPH is required by nitric oxide synthase (NOS).

Importance in red blood cells

RBCs lack:

• mitochondria

• significant alternative NADPH-producing pathways

PPP maintains:

• reduced glutathione (GSH)

• membrane integrity

• hemoglobin in reduced form

Without NADPH, RBCs undergo oxidative damage.

G6PD deficiency

Mechanism

Decreased G6PD causes:

decreased NADPH

↓

decreased GSH

↓

oxidative damage

↓

hemolysis

Triggers

• primaquine

• sulfonamides

• dapsone

• infections

• fava beans

Findings

• Heinz bodies

• bite cells

• episodic hemolytic anemia

• neonatal jaundice

This is an X-linked recessive disorder.

Thiamine and transketolase

Transketolase requires:

Thiamine pyrophosphate (TPP)

Thiamine deficiency:

• decreases transketolase activity

• affects PPP

• contributes to Wernicke-Korsakoff syndrome

RBC transketolase activity is used to assess thiamine deficiency.

Carbon accounting

Compound	Carbon number
Glucose-6-phosphate	C6
Ribulose-5-phosphate	C5
Ribose-5-phosphate	C5
Xylulose-5-phosphate	C5
Sedoheptulose-7-phosphate	C7
Erythrose-4-phosphate	C4
Fructose-6-phosphate	C6
Glyceraldehyde-3-phosphate	C3

Carbon transfer summary

Transketolase

Transfers:

2-carbon unit

Requires:

TPP

Transaldolase

Transfers:

3-carbon unit

No TPP required.

Connection with glycolysis

PPP is linked with glycolysis through:

• fructose-6-phosphate

• glyceraldehyde-3-phosphate

These intermediates can:

• enter glycolysis

• enter gluconeogenesis

• regenerate glucose-6-phosphate

Metabolic modes of PPP

Mode 1: ribose-5-phosphate needed more than NADPH

Example:

rapid nucleotide synthesis

Flow:

glycolysis → non-oxidative PPP (reverse direction)

Produces ribose-5-phosphate without NADPH.

Mode 2: equal need for NADPH and ribose-5-phosphate

Uses oxidative phase only.

Mode 3: NADPH needed more than ribose-5-phosphate

Oxidative phase generates NADPH.

Non-oxidative phase converts pentoses back to glycolytic intermediates.

These regenerate G6P.

This allows continuous NADPH production.

Mode 4: NADPH and ATP required

PPP connects with glycolysis.

Comparison with glycolysis

Pentose phosphate pathway	Glycolysis
Cytosolic	Cytosolic
Produces NADPH	Produces NADH
No ATP production	ATP produced
Ribose-5-phosphate synthesis	Pyruvate synthesis
Oxidative + non-oxidative phases	Single linear pathway

Standard references

1. Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. W.H. Freeman.

2. Berg JM, Tymoczko JL, Gatto GJ, Stryer L. Biochemistry. 9th ed. W.H. Freeman.

3. Voet D, Voet JG. Biochemistry. 5th ed. Wiley.

4. Rodwell VW, et al. Harper’s Illustrated Biochemistry. 32nd ed. McGraw-Hill.

5. Alberts B, et al. Molecular Biology of the Cell. 7th ed. Garland Science.