HMP Shunt (Hexose Monophosphate Pathway) - Its Significance & Significance of NADPH

INTRODUCTION / DEFINITION

• It starts with Glucose-6-phosphate (just like glycolysis)
• But instead of producing ATP, it produces NADPH and Ribose-5-phosphate
• It does NOT produce any ATP
• All reactions take place in the cytosol

Simple way to remember: HMP Shunt = a "side road" that branches off from glycolysis, but leads to NADPH and ribose instead of energy.

TWO PHASES OF HMP SHUNT

PHASE 1 - Oxidative Phase (Irreversible)

• G6PD catalyzes the first, rate-limiting (committed) step
• 2 NADPH are produced per molecule of Glucose-6-phosphate
• 1 CO2 is released
• NADPH itself inhibits G6PD (feedback inhibition) - so when NADPH is needed, the pathway speeds up

PHASE 2 - Non-Oxidative Phase (Reversible)

• Ribose-5-phosphate isomerase - converts Ribulose-5-phosphate → Ribose-5-phosphate (needed for DNA/RNA)
• Transketolase (requires TPP / Vitamin B1 as cofactor) - transfers 2-carbon units between sugars
• Transaldolase - transfers 3-carbon units between sugars

• Fructose-6-phosphate and Glyceraldehyde-3-phosphate (both enter glycolysis)

PATHWAY DIAGRAM

SIGNIFICANCE OF HMP SHUNT

1. Production of NADPH (Most Important)

• HMP shunt is the main source of NADPH in the body
• NADPH is essential for many biosynthetic reactions (detailed below)

2. Production of Ribose-5-phosphate

• Ribose-5-phosphate is needed to make nucleotides (ATP, GTP) and nucleic acids (DNA and RNA)
• All rapidly dividing cells need this (bone marrow, skin, intestine)

3. Connects to Glycolysis

• The non-oxidative phase produces Fructose-6-phosphate and Glyceraldehyde-3-phosphate, which enter glycolysis directly
• So this pathway acts as a bridge between glucose oxidation and glycolysis

4. Active Tissues

• Liver - fatty acid and cholesterol synthesis
• Adipose tissue - fat synthesis
• Adrenal cortex, testes, ovaries, placenta - steroid hormone synthesis
• Red blood cells (RBCs) - protection against oxidative damage
• Lactating mammary gland - fat synthesis for milk
• Low activity in: skeletal muscle

SIGNIFICANCE OF NADPH

1. Fatty Acid Synthesis (Lipogenesis)

• NADPH is essential for synthesis of fatty acids
• Used by fatty acid synthase enzyme
• Active in liver, adipose tissue, mammary gland

2. Cholesterol and Steroid Hormone Synthesis

• NADPH is required for synthesis of cholesterol
• Cholesterol is converted to steroid hormones (cortisol, aldosterone, estrogen, testosterone) - all need NADPH
• Active in: adrenal cortex, gonads, placenta

3. Protection of Red Blood Cells (RBCs) from Hemolysis

• This is the most clinically important function of NADPH
• H2O2 (hydrogen peroxide) is a toxic oxidant produced in RBCs
• NADPH → keeps Glutathione in reduced form (GSH) via Glutathione reductase
• Reduced glutathione (GSH) then destroys H2O2 via Glutathione peroxidase
• This protects RBC membrane from oxidative damage and prevents hemolysis

Clinical link: G6PD Deficiency

• In G6PD deficiency, NADPH cannot be made
• GSH cannot be regenerated
• H2O2 accumulates → RBC membrane is damaged → hemolytic anemia
• Triggered by: primaquine (antimalarial drug), fava beans, infections
• X-linked recessive inheritance

4. Detoxification of Drugs and Xenobiotics (Drug Metabolism)

• In liver, NADPH is used by Cytochrome P450 (CYP) enzymes (mixed function oxidases)
• These enzymes hydroxylate drugs, toxins, and pollutants to make them water-soluble for excretion
• Reaction: Drug + NADPH + O2 → Drug-OH + NADP+ + H2O

5. Killing of Bacteria by White Blood Cells (Respiratory Burst)

• Neutrophils and macrophages use NADPH oxidase enzyme
• NADPH oxidase converts O2 into superoxide (O2-) which kills bacteria
• This is called the "respiratory burst" or oxidative burst
• Important defense mechanism against bacterial infections

Clinical link: Chronic Granulomatous Disease (CGD)

• NADPH oxidase is defective
• Neutrophils cannot kill bacteria properly
• Repeated life-threatening infections

6. Synthesis of Nitric Oxide (NO)

• NO synthase uses NADPH to produce Nitric Oxide (NO) from arginine
• NO causes vasodilation (widening of blood vessels)
• Important in blood pressure regulation

7. Regeneration of Vitamin C and Vitamin E (Antioxidants)

• NADPH helps regenerate these antioxidant vitamins in their active reduced forms

REGULATION OF HMP SHUNT

SUMMARY TABLE

EASY MEMORY TIPS

• "HMP shunt = NADPH factory" - remember it makes NADPH, not ATP
• "G6PD deficiency = broken NADPH factory = fragile RBCs"
• NADPH uses: "Fat Steroid Glutathione Detox Burst" = Fatty acids, Steroids, Glutathione (protect RBCs), Detoxification, Burst (respiratory burst in WBCs)
• Transketolase needs Vitamin B1 (thiamine) - so B1 deficiency = transketolase test used to diagnose it

Fluid Mosaic Model of Cell Membrane

INTRODUCTION

What does the name mean?

• "Fluid" - the lipid bilayer is not rigid/solid; the lipid molecules and some proteins can move freely sideways (like people moving in a crowd)
• "Mosaic" - the proteins are scattered throughout the lipid bilayer like tiles in a mosaic pattern

THE DIAGRAM

COMPONENTS OF THE CELL MEMBRANE

1. LIPID BILAYER (The Main Framework)

• The membrane is made of two layers of phospholipid molecules arranged back-to-back
• Each phospholipid molecule has:
  • A hydrophilic "polar head" (loves water) - faces OUTSIDE (towards ECF and ICF)
  • A hydrophobic "fatty acid tail" (hates water) - faces INSIDE (towards each other)
• This is called an amphipathic molecule (has both water-loving and water-fearing parts)
• Cholesterol molecules are also present in between the phospholipids - they help control fluidity of the membrane

Easy analogy: Think of the lipid bilayer like a sandwich - the bread (polar heads) is on the outside touching water, and the filling (fatty acid tails) is on the inside, hidden away from water.

2. PROTEINS (The Mosaic Pattern)

3. CARBOHYDRATES (The Identity Tags)

• Short carbohydrate chains (oligosaccharides) are attached to proteins and lipids on the outer surface only
• When attached to proteins = Glycoproteins
• When attached to lipids = Glycolipids
• Together, they form the Glycocalyx (cell coat) on the outer surface
• Functions of carbohydrates: cell-to-cell recognition, cell adhesion, acting as receptors

KEY PROPERTIES OF THE FLUID MOSAIC MODEL

1. Fluidity

• The lipid molecules can move laterally (sideways within the same layer) - this is fast
• Movement across layers ("flip-flop" / transverse movement) is extremely slow
• Cholesterol regulates fluidity:
  • At high temperature: cholesterol reduces fluidity (prevents too much movement)
  • At low temperature: cholesterol prevents rigidity (prevents freezing/solidification)

2. Asymmetry (Inside is different from Outside)

• The outer leaflet has: Phosphatidylcholine, Sphingomyelin, Glycolipids, Glycoproteins
• The inner leaflet has: Phosphatidylserine, Phosphatidylethanolamine
• Carbohydrates are only on the outer surface - never on the inner surface

3. Selective Permeability

• Small, nonpolar molecules (O2, CO2, fatty acids) cross freely
• Polar molecules and ions need protein channels or transporters to cross

LIPID RAFTS (Modern Addition to the Model)

• Lipid rafts are small, special regions in the membrane that are rich in cholesterol and glycosphingolipids
• They are more ordered/rigid than the surrounding membrane
• They act as "platforms" for receptor signaling and protein sorting
• (This is why it is now called the "Modified Fluid Mosaic Model")

FUNCTIONS OF CELL MEMBRANE (Based on this Model)

EASY SUMMARY TO REMEMBER

"A fluid, dynamic, lipid bilayer with floating proteins - like icebergs floating in a lipid sea"

• FLUID = lipids and proteins can move laterally
• MOSAIC = proteins scattered like mosaic tiles in the bilayer
• ASYMMETRIC = inside and outside surfaces are different
• SELECTIVE = only certain things can cross
• Proposed by Singer & Nicolson, 1972

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