Heme metabolism

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Heme Metabolism

Heme is an iron-containing porphyrin ring that serves as a prosthetic group in hemoglobin, myoglobin, cytochrome P450 enzymes, and respiratory chain proteins. Its metabolism encompasses two distinct phases: synthesis (the Shemin pathway) and catabolism (the bilirubin pathway).

I. Heme Synthesis

Sites: ~85% occurs in erythroid precursor cells of the bone marrow; most of the remainder occurs in hepatocytes (primarily to make CYP enzymes). Mature RBCs lack mitochondria and cannot synthesize heme.

Compartmentalization: The first and last three steps occur in the mitochondria; the middle four steps occur in the cytosol.

The 8-Step Shemin Pathway

Porphyrin synthesis - early steps (Glycine + Succinyl-CoA → ALA → Porphobilinogen)

Porphyrin synthesis - later steps (PBG → Uroporphyrinogen → Coproporphyrinogen → Protoporphyrinogen → Protoporphyrin IX)

Step	Location	Enzyme	Substrate → Product	Clinical Relevance
1	Mitochondria	ALA synthase (ALAS)	Glycine + Succinyl-CoA → δ-Aminolevulinic acid (ALA)	Rate-limiting, committed step; requires PLP (pyridoxal phosphate)
2	Cytosol	ALA dehydratase	2 ALA → Porphobilinogen (PBG)	Inhibited by lead (Pb²⁺)
3	Cytosol	Hydroxymethylbilane (HMB) synthase (= PBG deaminase)	4 PBG → Hydroxymethylbilane	Deficiency → Acute Intermittent Porphyria (AIP)
4	Cytosol	Uroporphyrinogen III synthase	HMB → Uroporphyrinogen III	Deficiency → Congenital Erythropoietic Porphyria (CEP)
5	Cytosol	Uroporphyrinogen decarboxylase	Uroporphyrinogen III → Coproporphyrinogen III (4 CO₂ released)	Deficiency → Porphyria Cutanea Tarda (PCT)
6	Mitochondria	Coproporphyrinogen oxidase	Coproporphyrinogen III → Protoporphyrinogen IX	Deficiency → Hereditary Coproporphyria (HCP)
7	Mitochondria	Protoporphyrinogen oxidase	Protoporphyrinogen IX → Protoporphyrin IX	Deficiency → Variegate Porphyria (VP)
8	Mitochondria	Ferrochelatase (heme synthase)	Protoporphyrin IX + Fe²⁺ → Heme	Deficiency → Erythropoietic Protoporphyria (EPP)

(Only type III porphyrins are physiologically important; all enzymes from step 6 onward are specific for type III.)

Regulation of ALA Synthase

There are two ALAS isoforms with distinct regulatory mechanisms:

ALAS1 (housekeeping - all tissues, especially liver):

Feedback inhibition by heme (hemin): When heme accumulates, it represses ALAS1 gene transcription, accelerates mRNA degradation, and blocks mitochondrial import of the enzyme.
Induction by drugs/xenobiotics: Drugs metabolized by CYP enzymes (e.g., barbiturates, rifampicin, phenytoin, trimethoprim) consume heme → free heme pool falls → ALAS1 is upregulated. This is the trigger for acute porphyria attacks.

ALAS2 (erythroid-specific - bone marrow):

Regulated by intracellular iron availability (stimulated by iron)
Loss-of-function mutations → X-linked sideroblastic anemia (XLSA)
Gain-of-function mutations (exon 11) → X-linked protoporphyria (XLP)

"ALAS1 is regulated by heme; ALAS2 is regulated by iron." - Biochemistry, Lippincott Illustrated Reviews, 8th ed.

II. Heme Catabolism

Step 1: Heme → Biliverdin → Bilirubin (in macrophages)

Senescent RBCs (lifespan ~120 days) are phagocytosed by macrophages of the mononuclear phagocyte system (mainly spleen, liver, bone marrow). Hemoglobin is split into globin (recycled as amino acids) and heme. The heme ring is then opened:

Heme oxygenase cleaves the porphyrin ring, releasing:
- Fe²⁺ (recycled via transferrin)
- Carbon monoxide (CO) (only endogenous source of CO in humans)
- Biliverdin (a green, linear tetrapyrrole)
Biliverdin reductase reduces biliverdin → bilirubin (yellow-orange)

Heme catabolism: Heme → Biliverdin → Bilirubin → Urobilinogen → Urobilin

This newly formed bilirubin is unconjugated (indirect) bilirubin - lipophilic, water-insoluble, and potentially neurotoxic.

Step 2: Transport to the Liver

Unconjugated bilirubin binds non-covalently to albumin for transport through the blood (it is insoluble in plasma alone). Certain drugs (salicylates, sulfonamides) can displace bilirubin from albumin, raising the risk of kernicterus in neonates. In the hepatocyte, it enters by facilitated diffusion and binds intracellular proteins (particularly ligandin).

Step 3: Conjugation in the Liver

Hepatocytes conjugate bilirubin with glucuronic acid via bilirubin UDP-glucuronosyltransferase (UGT1A1), producing:

Bilirubin monoglucuronide
Bilirubin diglucuronide (conjugated / direct bilirubin - water-soluble)

Step 4: Secretion into Bile

Conjugated bilirubin is actively transported into bile canaliculi (energy-dependent, rate-limiting for the hepatic phase).

Step 5: Intestinal Fate

In the terminal ileum and colon, gut bacteria:

Deconjugate (hydrolyze glucuronic acid) and reduce bilirubin → colorless urobilinogen
Most urobilinogen is oxidized → brown stercobilin (color of feces)
Some urobilinogen is reabsorbed → enterohepatic circulation; some escapes to kidneys → oxidized to yellow urobilin (color of urine)

Full bilirubin excretion pathway: macrophage → blood → liver → bile → intestine → kidney/feces

III. Jaundice - Clinical Application

Jaundice appears at serum bilirubin ≥2-3 mg/dL (normal ≤1 mg/dL). Three types:

Type	Cause	Elevated Fraction	Key Features
Hemolytic (pre-hepatic)	Excess RBC destruction (sickle cell, G6PD, pyruvate kinase deficiency)	Unconjugated	↑ urobilinogen in urine/stool, no bilirubinuria
Hepatocellular	Hepatitis, cirrhosis, drugs	Both	↑ conjugated + unconjugated; ↑ urine bilirubin
Obstructive (post-hepatic)	Gallstones, pancreatic cancer blocking bile duct	Conjugated	Pale stools, dark urine (bilirubinuria), pruritus

Neonatal jaundice: Physiological in newborns due to immature UGT1A1 activity; unconjugated bilirubin can cross the blood-brain barrier → kernicterus. Treatment: phototherapy (converts bilirubin to water-soluble photoisomers).

Inherited conjugation defects:

Crigler-Najjar syndrome type I: Complete absence of UGT1A1 → severe unconjugated hyperbilirubinemia; fatal without liver transplant
Crigler-Najjar syndrome type II: Partial deficiency; responds to phenobarbital
Gilbert syndrome: Mild UGT1A1 reduction (~30%); benign, triggers: fasting, stress
Dubin-Johnson syndrome: Defect in canalicular transport of conjugated bilirubin → conjugated hyperbilirubinemia; benign

IV. Porphyrias - Enzyme Deficiency Disorders

Porphyrias result from deficiency (usually partial) in any enzyme of the Shemin pathway, causing accumulation of toxic intermediates:

Porphyria	Deficient Enzyme	Type	Accumulates	Key Features
ADP (ALA dehydratase deficiency)	ALA dehydratase	Acute	ALA	Very rare; lead poisoning mimics this
AIP (Acute Intermittent Porphyria)	HMB-synthase (PBG deaminase)	Acute	ALA, PBG	Most common acute porphyria (5-10/100,000); abdominal pain, neurovisceral symptoms, dark urine
CEP (Congenital Erythropoietic Porphyria)	Uroporphyrinogen III synthase	Cutaneous	Uro I, Copro I	Severe photosensitivity, hemolysis, pink/red urine in infancy
PCT (Porphyria Cutanea Tarda)	Uroporphyrinogen decarboxylase	Cutaneous	Uroporphyrin	Most common porphyria overall; skin blisters/fragility in sun-exposed areas; associated with HCV, alcohol, iron overload
HCP (Hereditary Coproporphyria)	Coproporphyrinogen oxidase	Acute + Cutaneous	Coproporphyrin III	Can have both acute and skin symptoms
VP (Variegate Porphyria)	Protoporphyrinogen oxidase	Acute + Cutaneous	Proto + Copro	Common in South African whites; acute attacks + skin blisters
EPP (Erythropoietic Protoporphyria)	Ferrochelatase	Cutaneous	Protoporphyrin IX	Painful photosensitivity (rather than blisters), liver disease

Triggers for acute porphyria attacks: Drugs (barbiturates, phenytoin, rifampicin, erythromycin, OCP progestins), fasting/low carbohydrate diet, alcohol, stress, infections, hormonal changes (especially progesterone - attacks more common in women post-puberty, premenstrually).

Treatment of acute attacks: Remove triggering agent; IV glucose (suppresses ALAS1 via carbohydrate loading); hematin/hemin (directly represses ALAS1 by feedback).

Summary Diagram

MITOCHONDRIA          CYTOSOL              MITOCHONDRIA
Glycine +             
Succinyl-CoA          
    ↓ ALAS1/ALAS2     
    ALA               
    ↓ ALA dehydratase (inhibited by Pb)
    PBG               
    ↓ HMB synthase    (AIP if deficient)
    Hydroxymethylbilane
    ↓ UPG III synthase (CEP if deficient)
    Uroporphyrinogen III
    ↓ UPG decarboxylase (PCT if deficient)
    Coproporphyrinogen III
                          ↓ Copro oxidase (HCP if deficient)
                          Protoporphyrinogen IX
                          ↓ Proto oxidase (VP if deficient)
                          Protoporphyrin IX
                          ↓ Ferrochelatase + Fe²⁺ (EPP if deficient)
                          HEME

Catabolism:

HEME → (Heme oxygenase) → Biliverdin + Fe²⁺ + CO
     → (Biliverdin reductase) → Unconjugated bilirubin (binds albumin)
     → (Liver: UGT1A1) → Conjugated bilirubin (water-soluble)
     → (Bile → Gut bacteria) → Urobilinogen → Stercobilin (feces, brown)
                                             → Urobilin (urine, yellow)

Key sources:

Biochemistry, Lippincott Illustrated Reviews, 8th ed - detailed enzyme steps
Harrison's Principles of Internal Medicine, 22E (2025) - clinical porphyrias
Harper's Illustrated Biochemistry, 32nd ed - regulatory mechanisms
Miller's Anesthesia, 10e - clinical liver/heme overview
Medical Physiology (Boron & Boulpaep) - bilirubin secretion

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