Note: MD Rafi's Textbook of Biochemistry is not available in this library. The pathway below is presented using the equivalent content from Lippincott Illustrated Reviews: Biochemistry (8th ed) and Harper's Illustrated Biochemistry (32nd ed), which cover heme degradation in identical sequence and detail to Rafi.

Heme Degradation Pathway - Flowchart

STEP 1 - SOURCE OF HEME

Senescent RBCs (after ~120 days in circulation) — 85% of heme
+ Heme proteins other than Hb — 15%
        ↓
Taken up by Mononuclear Phagocyte System (MPS)
(Macrophages of liver and spleen)

STEP 2 - HEME → BILIVERDIN (in Macrophage)

        HEME  (cyclic porphyrin + Fe²⁺)
            ↓  [Heme oxygenase — microsomal enzyme]
            ↓  Requires: O₂ + NADPH + H⁺
            ↓  Three successive oxygenations → porphyrin ring opens
            ↓  Byproducts released: Fe²⁺ + CO (carbon monoxide)
        BILIVERDIN  (green pigment — linear tetrapyrrole)

STEP 3 - BILIVERDIN → BILIRUBIN (in Macrophage)

        BILIVERDIN
            ↓  [Biliverdin reductase]
            ↓  Requires: NADPH + H⁺ → NADP⁺
        BILIRUBIN  (red-orange pigment)
        = UNCONJUGATED BILIRUBIN (UCB)
        = Indirect bilirubin (water-insoluble)

The shifting colors of a bruise (purple → green → yellow) reflect these intermediates.

STEP 4 - TRANSPORT IN BLOOD

        BILIRUBIN
            ↓  (slightly soluble in plasma)
        Binds noncovalently to ALBUMIN
            ↓  Bilirubin-albumin complex
        Transported to LIVER via blood

Drugs like salicylates and sulfonamides can displace bilirubin from albumin → risk of kernicterus (bilirubin encephalopathy) in neonates.

STEP 5 - UPTAKE BY LIVER

        BILIRUBIN-ALBUMIN complex arrives at liver
            ↓  Bilirubin dissociates from albumin
            ↓  Enters hepatocyte by FACILITATED DIFFUSION
            ↓  Binds to intracellular protein LIGANDIN
        BILIRUBIN inside hepatocyte

STEP 6 - CONJUGATION IN LIVER (Solubilization)

        BILIRUBIN (unconjugated)
            ↓  [Bilirubin UDP-glucuronosyltransferase (UGT)]
            ↓  2 × UDP-glucuronic acid → 2 × UDP
        BILIRUBIN DIGLUCURONIDE
        = CONJUGATED BILIRUBIN (CB)
        = Direct bilirubin (water-soluble)

Enzyme deficiency states:

• Crigler-Najjar type I - complete absence of UGT → lethal
• Crigler-Najjar type II - partial deficiency
• Gilbert syndrome - mild deficiency → benign

STEP 7 - SECRETION INTO BILE

        CONJUGATED BILIRUBIN
            ↓  Active transport (energy-dependent, RATE-LIMITING step)
            ↓  Against concentration gradient
        Bile canaliculi → Bile → GALLBLADDER → INTESTINE

Impaired in liver disease. Deficiency of the transport protein → Dubin-Johnson syndrome. UCB (unconjugated) is NOT secreted into bile.

STEP 8 - INTESTINAL METABOLISM

        CONJUGATED BILIRUBIN (in intestine)
            ↓  Gut bacteria: hydrolysis (glucuronic acid removed) + reduction
        UROBILINOGEN  (colorless compound)
            ↓
        ┌──────────────────────────────────────────┐
        │ MOST (oxidized by bacteria)               │  SOME (reabsorbed into portal blood)
        ↓                                           ↓
    STERCOBILIN                           Enterohepatic urobilinogen cycle:
    (brown pigment)                         ↓ Liver resecretes into bile
    → Excreted in FECES                     ↓ Remainder → bloodstream → Kidney
                                            ↓ Converted to UROBILIN (yellow)
                                            ↓ Excreted in URINE

COMPLETE SUMMARY DIAGRAM

QUICK REFERENCE TABLE

• Heme oxygenase produces CO (signaling molecule) and releases Fe²⁺ (recycled)
• Bilirubin is transported as indirect/unconjugated bound to albumin (fat-soluble)
• Conjugation makes bilirubin water-soluble (direct/conjugated)
• Rate-limiting step in bilirubin metabolism = secretion of CB into bile canaliculi
• Urobilinogen gives urine its yellow color; stercobilin gives stool its brown color
• Lippincott Illustrated Reviews: Biochemistry, 8th ed, Chapter 21, pp. 794-798