HMP pathway/Pentose phosphate pathway Dr.Soumitra Chakravarty MD
Jan 18, 2016
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:
Glucose-6-P04
Pyruvate
Glycogen Ribose -5-
po4
Glycolysis
GlycogenesisHMP pathway
ATP
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
Rate limiting step
USMLE !!
VITAMIN B1
Transketolase Transfers a 2-C unit (C1 AND C2 ) of a ketose to aldehyde C of aldose
Transaldolase Transfers a 3-C unit (dihydroxyacetone) from Seduheptulose 7P to glyceraldehyde 3P
Ribulose 5P (C5)
Ribulose 5P (C5)
Ribose 5P (C5)
Ribulose 5P (C5)
Xylulose 5P (C5)
Xylulose 5P (C5)
Glyceraldehyde 3P (3C) Sedoheptulose 7P (C7)
Fructose 6P(6C)
½ Fructose 6P(6C)
Fructose 6P(6C)
½ Fructose 1,6 BP(6C)
Source of NADP:
Tryptophan
Niacin
Amino acid
Vitamin B3
SOURCE OF
NADH , NADPH
Most important source of NADPH :-HMP shunt
Other sources of NADPH 1. Cytosolic Isocitrate dehydrogenase:
2. Malic enzyme:
Malate + NADP
Pyruvate + NADPH +CO2
USMLE !!
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. Conversion of cholesterol to steroid2. Bile acid synthesis3. Hydroxylation of vitamin D.
Microsomal system: liver1. 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 Superoxide Hydrogen peroxide
NADPH Oxidase
Superoxide dismutase
NADPH oxidase system
Hydrogen peroxide
Hypochlorous acid
Myeloperoxidase
Water
Catalase
Bacterial killing
Catalase is produced by catalase positive organisms
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. Infections2. Drugs –sulpha drugs, anti malarials, aspirin,
INH, nitrofurantoin3. Fava beans4. 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