6. Heme Metabolism

Where is heme synthesized and what is its basic structure?

all tissues but mainly in bone marrow (Hb) and liver (cytochromes); composed of 4 pyrrole rings forming a porphyrin ring. largely planar

How is heme formed and what is its function?

: Fe²⁺ inserted into protoporphyrin IX → heme; essential for all globin chains.enables oxygen binding in hemoglobin.

How is iron coordinated in heme?

4 bonds to porphyrin nitrogens
• 5th to histidine (globin)
• 6th binds O₂

Fe²⁺ vs Fe³⁺ in heme?

Fe²⁺ (ferrous) = binds O₂ (functional)
• Fe³⁺(ferric) = methemoglobin (no O₂ binding)

Key functions of heme proteins?

Hb = O₂ transport
• Myoglobin = O₂ storage
• Cytochrome c = ETC

Cytochrome P450 = hydroxylation of xenobiotics
• Catalase = H₂O₂ hydrogen peroxide breakdown

Where does heme synthesis occur?

Both mitochondria + cytosol; not in mature RBCs

85% of heme synthesis occurs in _____ with remainder in hepatocytes

erythroid precursor cells (bone marrow)

First step of heme synthesis (rate-limiting)?

Succinyl-CoA + Glycine → ALA
• Enzyme: ALA synthase (ALAS)
• Requires pyridoxal phosphate- Vitamin B6

ALAS1 vs ALAS2 isozymes?

ALAS1 = expressed throughout the body feedback inhibited by heme. catalyzed rate limiting step of hepatic heme biosynthesis.
• ALAS2 = RBC eryhtrocyte precursors, regulated by erythropoietin in kidney/ iron availability

Formation of porphobilinogen?

2 ALA → porphobilinogen in cytoplasm
• Enzyme: ALA dehydratase removes 2 water molecules

Formation of uroporphyrinogen III?

4 PBG condense → hydroxymethylbilane cyclize → uroporphyrinogen III
• Enzymes: uroporphyrinogen synthases I and III (cytosilic)

How is uroporphyrinogen I formed?

• 4 porphobilinogen (PBG) → hydroxymethylbilane Spontaneous cyclization (no enzyme) → uroporphyrinogen I
• Occurs when uroporphyrinogen III synthase is absent → seen in porphyrias

Type I vs Type III uroporphyrinogens?

Type III = normal.. primary isomer
• Type I = accumulates in disease.. certain porphyrias

Conversion to coproporphyrinogen III?

uropporphynogen III Decarboxylation (acetate → methyl)
• Enzyme: uroporphyrinogen decarboxylase (cytosilic)

What happens in the first part of the final steps of heme biosynthesis?

• Occurs in mitochondria
• Coproporphyrinogen III → protoporphyrinogen III (coproporphyrinogen oxidase)
• Protoporphyrinogen III → protoporphyrin IX (nine) (protoporphyrinogen oxidase)

What is the final step of heme biosynthesis?

Fe²⁺ inserted into protoporphyrin IX 9
• Enzyme: ferrochelatase
• Produces heme

What is the key regulatory enzyme of heme synthesis?

ALA synthase (ALAS)

How does heme regulate its own synthesis?

Negative feedback inhibition of ALAS1

Effect of lead (plumbism) on heme synthesis?

Inhibits:
• ALA dehydratase → ↑ ALA
• Ferrochelatase → ↑ protoporphyrin IX

Why does lead poisoning mimic porphyria?

Accumulation of toxic intermediates → neuro + abdominal symptoms

What are porphyrias?

Disorders of heme synthesis enzyme defects → toxic intermediate accumulation

bone marrow and liver most affected

Acute vs cutaneous porphyrias?

Acute (liver): neurovisceral symptoms
• Cutaneous: photosensitivity

General mechanism of symptoms in porphyrias?

Toxic precursor buildup, not heme deficiency

Acute Intermittent Porphyria cause + key features?

Defect: uroporphyrinogen I synthase
• ↑ ALA + PBG
• Neuro: abdominal pain, psychosis, seizures, red urin
• Triggered by drugs, fasting

Congenital Erythropoietic Porphyria features?

Defect: uroporphyrinogen III synthase
• Photosensitivity, dark urine
• Erythrodontia (red teeth)

Porphyria Cutanea Tarda features?

Defect: uroporphyrinogen decarboxylase deficiency
• MOST COMMON
• Blistering, photosensitivity, hyperpigmentation

Management of porphyrias?

Avoid triggers (CYP450 drugs)
• High carbs ↓ ALAS1
• Sunscreen + β-carotene

Mechanism of plumbism

Lead interacts with zinc cofactors, disrupting enzyme function

Where does heme breakdown occur?

Reticuloendothelial system (liver, spleen, bone marrow)

Steps of heme degradation?

Heme → biliverdin (heme oxygenase) → bilirubin (biliverdin reductase)

What happens to globin, porphyrin, and iron?

• Globin → amino acids

porphyrin (iron free) - degraded
• Iron → reused

How is bilirubin transported in blood?

Bound to albumin (unconjugated) and carried to liver

Liver processing of bilirubin (3 steps)?

• Uptake by liver

• Conjugation with glucuronic acid (UDP-glucuronosyltransferase)

• Secretion of cvonjugated bilirubin into bile (needs ATP by MOAT

What is conjugated bilirubin?

Water-soluble bilirubin diglucuronide

Fate of bilirubin in intestine?

→ urobilinogen in intestine via bacterial b-glucurronidases and fecal flora
• 95% reabsorbed

Urine: urobilin (yellow)
• 5% Feces: stercobilin (brown)

Definition of hyperbilirubinemia vs jaundice?

plasma bilirubin:

>1 mg/dL = hyperbilirubinemia
• >2–2.5 mg/dL = jaundice

Unconjugated vs conjugated bilirubin differences?

Unconjugated: insoluble, no urine, crosses BBB (Kernicterus)
• Conjugated: soluble, appears in urine

Common causes of unconjugated bilirubin?

hemolytic anemia, liver is healthy

Common causes of conjugated bilirubin?

Biliary tree obstruction and liver diseases (hepatit

What are the three major causes of jaundice?

Prehepatic: Hemolysis
• Hepatic: Liver disease
• Posthepatic: Bile duct obstruction

What causes pre-hepatic (hemolytic) jaundice and what is the mechanism?

• Cause: Acute or chronic hemolytic anemia
• ↑ Hemolysis → ↑ heme breakdown → ↑ unconjugated bilirubin
• Liver overwhelmed → cannot conjugate fast enough → ↑ plasma unconjugated bilirubin

What are the clinical/lab findings in pre-hepatic jaundice?

• ↑ Stercobilin (dark stools)
• ↑ Urobilinogen in urine and plasma
• No bilirubin in urine (unconjugated is not water-soluble)

Hepatic jaundice causes?

• Conjugation defect (e.g., neonatal, Gilbert)
• Hepatocellular damage (hepatitis, cirrhosis)

What causes neonatal (physiologic) hepatic jaundice?

Occurs day 2–8 of life
• Immature liver → ↓ UDP-glucuronosyltransferase
• Leads to ↑ unconjugated bilirubin

What is the course and risk of neonatal jaundice?

Occurs ~2nd-8th day of life in full-term infants• Resolves by ~2 weeks
• If bilirubin >15 mg/dL → risk of kernicterus (brain deposition)

What is the cause and pathophysiology of post-hepatic (obstructive) jaundice?

Cause: Bile duct obstruction (gallstones, tumors)
• ↓ conjugated bilirubin reaching intestine
• ↓/absent urobilinogen production

What are the clinical findings in post-hepatic jaundice?

Stool: Pale/clay-colored (↓ stercobilin)
• Blood: ↑ conjugated bilirubin
• Urine: ↑ bilirubin, ↓ urobilinogen

Neonatal jaundice cause?

Immature UDP-glucuronosyltransferase

Gilbert (AD) vs Crigler-Najjar (AR)?

Gilbert: mild, benign. mild decrease UDP-glucuronosyltransferase
• Crigler-Najjar: severe, fatal without liver transplant. kernicterus. complete deficiency UDP-glucuronosyltransferase

What is Dubin-Johnson syndrome (bilirubin transport disturbance)?

• AR disorder with impaired hepatic secretion (MOAT deficiency)
• Causes ↑ conjugated bilirubin
• Typically benign

What is hepatocellular disturbance in hepatic jaundice?

• Seen in hepatitis & cirrhosis (liver damage)
• ↓ bilirubin uptake + ↓ conjugation
• Leads to ↑ unconjugated bilirubin in blood