HMP pathway/Pentose phosphate
pathway
Dr.Soumitra Chakravarty MD
Learning objectives

Describe the important steps in the HMP pathway and its
importance

List the byproducts of HMP pathway and its uses

List the uses of NADPH in various biological reactions

Briefly describe the role of glutathione and NADPH in
maintaining the integrity of RBC membranes

Describe G-6PD deficiency and its clinical presentation
Fate of glucose-6-PO4 molecule:
ATP
Pyruvate
Glycolysis
Glucose-6-P04
HMP pathway
Ribose -5-po4
Glycogenesis
Glycogen
Energy Storage
Functions of HMP pathway:
Occurs in the cytosol:

Generation of NADPH – required for biosynthesis of
fatty acids and steroids.

Generation of Ribose-5-phosphate for nucleotide
synthesis

Interconversion of carbohydrates into glycolytic and
gluconeogenic intermediates.
Primary tissues – for HMP shunt

Liver, mammary glands and adipose tissue – synthesis
of fatty acids

Adrenal glands, testes and ovaries – synthesis of
steroids.

RBCs – for maintaining Glutathione in reduced form.
HMP shunt has two pathways:

Oxidative pathway – irreversible
- mainly occurs in tissues which require NADPH.

Non oxidative pathway – reversible
- Occurs in the tissues which require ribose for
nucleotide synthesis.
Oxidative pathway
USMLE !!
Rate limiting step
Ribulose 5P (C5)
Xylulose 5P (C5)
Glyceraldehyde 3P (3C)
Ribulose 5P (C5)
Ribulose 5P (C5)
Ribose 5P (C5)
Xylulose 5P (C5)
Sedoheptulose 7P (C7)
Fructose 6P(6C)
Transketolase
Transfers a 2-C unit
(C1 AND C2 )
of a ketose to
aldehyde C of
aldose
Fructose 6P(6C)
½ Fructose 1,6 BP(6C)
Transaldolase
Transfers a 3-C unit
(dihydroxyacetone)
from Seduheptulose 7P
to glyceraldehyde 3P
½ Fructose 6P(6C)
Source of NADP:
Tryptophan
Amino acid
SOURCE OF
Niacin
NADH , NADPH
Vitamin B3
USMLE !!
Most important source of NADPH :-HMP
shunt
Other sources of NADPH
1. Cytosolic Isocitrate dehydrogenase:
2. Malic enzyme:
Malate + NADP
Pyruvate + NADPH +CO2
Transketolase




Wernicke-Korsakoff’s syndrome :- Genetic disease where a
mutation in gene for transketolase which decreases the
affinity of enzyme transketolase for Thiamine pyrophosphate
(TPP)
Treatment :- Give thiamine
Beri Beri  Thiamine deficiency
Thiamine dependent enzymes

Transketolase
+

3 TENDER LOVING CARE FOR NANCY ENZYMES



PDH
ALPHA KETO GLUTARATE DH
BRANCH CHAIN AA DH
ALCOHOL AND THIAMINE




ALCOHOL INHIBITS THIAMINE ALCOHOL
VERY LITTLE THIAMINE IN ALCOHOLIC BEVERAGES
POOR NUTRITION IN ALCOHOLICS
CHRONIC ALCOHOLICS WILL HAVE WERNICKE’S
KORSAKOFF’S SYNDROME + SYMPTOMS OF
THIAMINE DEFICIENCY
Uses of NADPH:

REDUCTIVE BIOSYNTHESIS e.g.

Biosynthesis of steroids

Fatty acid synthesis

Drug metabolism – cytochrome p 450 system

Glutathione reductase

NADPH Oxidase  respiratory burst  phagocytosis.

Reduction of hydrogen peroxide

Synthesis of NO.
1.Cytochrome p-450 system

Group of Monooxygenase
enzymes:

Converts hydrophobic
substances into hydrophilic
substances.

Types

Mitochondrial

Microsomal
Cyt p -450 system:

Mitochondrial system:
1.
2.
3.

Conversion of cholesterol to steroid
Bile acid synthesis
Hydroxylation of vitamin D.
Microsomal system: liver
1.
Detoxification of drugs, carcinogens, petroleum products,
pesticides etc.
2.Phagocytosis by Neutrophils and
macrophages:

Oxygen dependent killing:
Respiratory burst  NADPH oxidase
Myeloperoxidase system 

Oxygen Independent killing:
phagolysosome formation  acidity
3.Respiratory burst: NADPH
Oxidase

NADPH aids in synthesis of
superoxide radical during
respiratory burst.

Deficiency of enzyme NADPH
oxidase – Chronic
Granulomatous Disease.

Infection with Catalase positive
bacteria
Oxygen dependent killing
Oxygen
NADPH
Oxidase
Superoxide
Superoxide
dismutase
Hydrogen
peroxide
NADPH oxidase system
Myeloperoxidase
Hydrogen
peroxide
Hypochlorous acid
Water
Catalase is produced by catalase positive organisms
Bacterial killing
Chronic Granulomatous Disease

Defect in the enzyme NADPH oxidase

Catalase Negative organisms produce hydrogen peroxide –
used by myeloperoxidase of the host to kill it

Catalase positive organisms – have catalase which neutralise
hydrogen peroxide – cannot be destroyed – granulomas –
chronic recurrent infections and abscess formation

Staphylococcus, klebsiella, Serratia and Aspergillus fungus.
4.Glutathione reductase :

NADPH acts as a co-enzyme along with Glutathione
reductase  converts oxidized glutathione to reduced
glutathione.

Function of reduced glutathione: acts along with
Glutathione Peroxidse  reduce hydrogen peroxide to
water in RBCs. (Neutralization of free radicals)
Glutathione in RBC:
NADH
Super Oxide
Dismutase
(SOD)
Heinz Bodies
Membrane Damage
Modified from Kaplan USMLE lecture notes
G6PD deficiency:
X linked recessive: (-) G6PD
 Decreased production of NADPH
 Hemolysis of RBCs due to oxidative insult.
 Causes for increased oxidative stress:
1. Infections
2. Drugs –sulpha drugs, anti malarials, aspirin, INH,
nitrofurantoin
3. Fava beans
4. Certain chemicals


Protection against malaria – mainly in African and middle
eastern population.

Heinz bodies:
Elevation of LDH-2 iso-enzyme
Hemoglobinuria
Decreased haptoglobin
Increased destruction in spleen - cross-bonding and
protein deposition in the red cell membranes.




Nitric Oxide:

Relaxes vascular smooth muscles:

Prevent platelet aggregation

Acts as a neurotransmitter.

Role in macrophage function.
NADPH is co-factor in synthesis of
NO

NO synthase – 3 types.

Arginine  Citrulline

NADPH is the co-enzyme.

A 19-year-old, African American male military recruit is
about to be sent to Iraq on his assignment. In preparation
for his tour of duty, he is given a prophylactic dose of
primaquine to prevent malaria. Several days after he
begins taking the drug, he develops fatigue and hemolytic
anemia. Which of the following proteins is likely deficient?





Glucose -6- phosphatase
Glucose 6-phosphate dehydrogenase
Aldolase B
Muscle phosphorylase
Pyruvate kinase

Chronic granulomatous Disease is a condition where the
macrophages cannot kill the bacteria with the help of
oxygen mediated respiratory burst due to deficiency of
which of the following enzymes?





Glucose-6-PO4 dehydrogenase
NADPH Oxidase
Glutathione peroxidase
Peroxidase
Catalase