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GLYCOLYSIS - Complete MBBS Exam Notes

Source: Lippincott Illustrated Biochemistry 8e, Basic Medical Biochemistry 6e, Harper's Biochemistry 32e

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DEFINITION

• Glycolysis = breakdown of 1 glucose (6C) into 2 pyruvate (3C)
• Occurs in the cytoplasm of ALL cells
• Does NOT need oxygen to start
• Site: Cytosol

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FLOWCHART - 10 STEPS OF GLYCOLYSIS

TWO PHASES:

• Phase 1 (Steps 1-5): Energy Investment Phase - ATP is USED (spent)
• Phase 2 (Steps 6-10): Energy Generation Phase - ATP is MADE (earned)

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PHASE 1 - Energy Investment Phase (Steps 1-5)

GLUCOSE (6C)
     |
     | Step 1: HEXOKINASE (muscle/most tissues)
     |         GLUCOKINASE (liver/pancreas)
     |         ATP → ADP used
     ↓
GLUCOSE-6-PHOSPHATE (G6P)
     |
     | Step 2: PHOSPHOGLUCOSE ISOMERASE
     |         (just changes shape)
     ↓
FRUCTOSE-6-PHOSPHATE (F6P)
     |
     | Step 3: PHOSPHOFRUCTOKINASE-1 (PFK-1) ← MOST IMPORTANT REGULATORY STEP
     |         ATP → ADP used
     ↓
FRUCTOSE-1,6-BISPHOSPHATE
     |
     | Step 4: ALDOLASE
     |         (splits into 2 three-carbon pieces)
     ↓
DHAP + GLYCERALDEHYDE-3-PHOSPHATE (G3P)
     |
     | Step 5: TRIOSE PHOSPHATE ISOMERASE
     |         (DHAP → G3P; now we have 2 × G3P)
     ↓
2 × GLYCERALDEHYDE-3-PHOSPHATE (G3P)

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PHASE 2 - Energy Generation Phase (Steps 6-10)

2 × G3P
     |
     | Step 6: GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE
     |         NAD+ → NADH (energy captured)
     |         + Inorganic Phosphate added
     ↓
2 × 1,3-BISPHOSPHOGLYCERATE
     |
     | Step 7: PHOSPHOGLYCERATE KINASE
     |         ADP → ATP (substrate-level phosphorylation) ×2
     ↓
2 × 3-PHOSPHOGLYCERATE
     |
     | Step 8: PHOSPHOGLYCERATE MUTASE
     |         (moves phosphate from carbon 3 to carbon 2)
     ↓
2 × 2-PHOSPHOGLYCERATE
     |
     | Step 9: ENOLASE
     |         (removes water → forms high-energy compound)
     ↓
2 × PHOSPHOENOLPYRUVATE (PEP)
     |
     | Step 10: PYRUVATE KINASE ← Regulatory step
     |          ADP → ATP ×2
     ↓
2 × PYRUVATE (final product)

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THREE IRREVERSIBLE STEPS (Very Important for Exam!)

Memory trick: HePP - Hexokinase, PFK-1, Pyruvate kinase = 3 irreversible steps

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REGULATION OF GLYCOLYSIS

Key Rule: When energy is LOW (less ATP, more AMP/ADP) → glycolysis is TURNED ON. When energy is HIGH (lots of ATP) → glycolysis is TURNED OFF.

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1. Hexokinase (Step 1) - In muscle, brain, RBC

• Inhibited by its own product (feedback inhibition)
• Glucokinase (liver version): NOT inhibited by G6P - works even when glucose is very high after a meal

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2. PFK-1 (Step 3) - THE MOST IMPORTANT REGULATORY ENZYME

F-2,6-BP is the MOST POTENT activator of PFK-1

• Insulin raises F-2,6-BP → stimulates glycolysis
• Glucagon lowers F-2,6-BP → inhibits glycolysis

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3. Pyruvate Kinase (Step 10)

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Summary of Regulation (Simple Table)

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AEROBIC vs ANAEROBIC GLYCOLYSIS

Aerobic Glycolysis (O2 is present)

• Pyruvate enters mitochondria → converted to Acetyl CoA
• Acetyl CoA enters TCA cycle → complete oxidation to CO2 + H2O
• NADH produced in glycolysis is oxidized by the electron transport chain (ETC)
• End product: Pyruvate → CO2 + H2O
• Occurs in: All cells with mitochondria + adequate oxygen (liver, heart, brain in normal conditions)

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Anaerobic Glycolysis (O2 is absent or very low)

• Pyruvate CANNOT enter mitochondria (no O2 to drive the process)
• Pyruvate is converted to LACTATE by enzyme Lactate Dehydrogenase (LDH)
• This step uses up NADH → regenerates NAD+ so glycolysis can CONTINUE
• Net reaction:

  Glucose + 2 ADP + 2 Pi → 2 Lactate + 2 ATP + 2 H2O + 2 H+

• Occurs in: RBCs (no mitochondria), cornea and lens of eye, white blood cells, exercising skeletal muscle, any hypoxic tissue

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Comparison Table: Aerobic vs Anaerobic

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ENERGETICS OF GLYCOLYSIS

ATP Balance Sheet

• Step 1 (Hexokinase): -1 ATP used
• Step 3 (PFK-1): -1 ATP used
• Total invested = 2 ATP consumed

• Step 7 (Phosphoglycerate kinase): +2 ATP made (×2 for 2 molecules)
• Step 10 (Pyruvate kinase): +2 ATP made (×2 for 2 molecules)
• Total generated = 4 ATP

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Total Energy from Complete Oxidation (Aerobic)

Anaerobic glycolysis gives only 2 ATP. Aerobic gives ~30-32 ATP.

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CLINICAL SIGNIFICANCE

1. Lactic Acidosis

• When O2 supply is low (shock, heart failure, severe infection, anemia), cells switch to anaerobic glycolysis
• Lactate builds up in blood → blood pH falls → lactic acidosis
• Signs: rapid breathing, confusion, low blood pressure
• Blood lactate level is used to monitor severity of shock and organ failure
• Normal blood lactate: <2 mmol/L; >4 mmol/L = severe lactic acidosis

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2. Warburg Effect (Cancer)

• Cancer cells use anaerobic glycolysis EVEN when O2 is available - called aerobic glycolysis or Warburg effect
• Cancer cells produce lots of lactate even with oxygen present
• This is why PET scan (uses radiolabeled glucose) lights up tumors - cancer cells take up glucose rapidly
• Targeted by drugs that inhibit glycolytic enzymes in tumors

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3. Hemolytic Anemia - Pyruvate Kinase (PK) Deficiency

• RBCs have NO mitochondria - they fully depend on glycolysis for ATP
• If PK is deficient → less ATP made → RBC membrane pump fails → RBC swells and bursts → hemolytic anemia
• Features: jaundice, anemia, splenomegaly

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4. RBC Metabolism - 2,3-BPG (Rapoport-Luebering Shunt)

• In RBCs, a side reaction at Step 7 produces 2,3-bisphosphoglycerate (2,3-BPG)
• 2,3-BPG binds to hemoglobin → reduces oxygen affinity → hemoglobin releases O2 more easily to tissues
• Important in adaptation to high altitude and anemia

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5. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• G6PD is in the pentose phosphate pathway (NOT glycolysis directly), but connected
• Without G6PD, RBCs cannot protect themselves from oxidative damage
• Triggered by: antimalarial drugs (primaquine), fava beans, infections
• Causes: hemolytic anemia, jaundice, dark urine
• Common in Africans, Mediterraneans, South Asians

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6. Hypoxia and Ischemia

• During heart attack or stroke, blood flow stops → O2 drops → cells switch to anaerobic glycolysis
• ATP production falls sharply → cells die
• Lactate monitoring helps doctors know how much tissue is at risk

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7. Diabetes and Glycolysis

• In Type 2 diabetes, glucose enters cells poorly → glycolysis is impaired
• Glucokinase mutations cause MODY (Maturity Onset Diabetes of the Young) - Type 2 in young patients

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QUICK MEMORY TRICKS

• "Graceful Girls Pick FADS to Generate Phospho-Energy Proteins"
  • G = Glucose, G6P, F6P, F1,6-BP, DHAP/G3P, 1,3-BPG, 3-PG, 2-PG, PEP, Pyruvate
  • (10 intermediates = 10 steps)
• 3 irreversible enzymes = HePP: Hexokinase / glucokinase, PFK-1, Pyruvate kinase
• PFK-1 activators = low energy state: AMP, ADP, F-2,6-BP, Pi
• PFK-1 inhibitors = high energy state: ATP, Citrate, H+ (acidosis)
• Anaerobic glycolysis = only 2 ATP | Aerobic = 30-32 ATP
• RBC lives on glycolysis alone - no mitochondria

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