7. Heme Metabolism

Porphyrin and Heme Structure

• Porphyrins (collection of pyrrole rings) and heme are produced virtually in ____ tissues, but it is more pronounced in the ______ _______ (hemoglobin) and in the _____ (cytochromes)

• Attachment of ____ to the _____ of the porphyrin ring gives rise to _____

• Heme is largely a _______ structure with the iron slightly _________ ____ of the plane

• Heme is a critical component of all _______ chains and is responsible for _________ oxygen

• Iron has __ planar bonds coordinated with the __________ of the prophyrin

• The 5th bond from the heme Iron is __________ to the plane and binds ____________ _________ of the __________ chain

• The 6th bond from the heme iron is ___________ of the plane and is available to bind ___________

• Only Iron in the ________ ( ___ ) state will bind oxygen, Iron in the _________ + globin is called ___________

Porphyrin and Heme Structure

• Porphyrins (collection of pyrrole rings) and heme are produced virtually in all tissues, but it is more pronounced in the bone marrow (hemoglobin) and in the liver (cytochromes)

• Attachment of iron to the center of the porphyrin ring gives rise to heme

• Heme is largely a planar structure with the iron slightly sticking out of the plane

• Heme is a critical component of all globin chains and is responsible for binding oxygen

• Iron has 4 planar bonds coordinated with the nitrogens of the porphyrin

• The 5th bond from the heme Iron is perpendicular to the plane and binds histidine imidazole of the globin chain

• The 6th bond from the heme iron is adjacent/to the side of the plane and is available to bind oxygen

• Only Iron in the ferrous Fe2+ (reduced) state will bind oxygen, Iron in the ferric Fe3+ + globin is called methemoglobin (HbM)

Functions of Heme in:

• Hemoglobin

• Myoglobin

• Cytochrome C

• Cytochrome P450

• Catalase

• tryptophan pyrrolase

Functions of Heme in:

• Hemoglobin → oxygen transport in blood

• Myoglobin → storage of oxygen in the muscles

• Cytochrome C → Involvement in e- transport chain

• Cytochrome P450 → Hydroxylation of xenobiotics

• Catalase → degradation of hydrogen peroxide

• Tryptophan pyrrolase → oxidation of tryptophan

• Biosynthesis of heme involves both ______ and _________ reactions and intermediates

• Heme biosynthesis occurs in most mammalian cells except __________ _______________ because they lack _____________

• Approximately %85 of heme synthesis occurs in ____________ precursors in the _______ __________

• Biosynthesis of heme involves both cytosolic and mitochondrial reactions and intermediates

• Heme biosynthesis occurs in most mammalian cells except mature erythrocytes because they lack mitochondria

• Approximately %85 of heme synthesis occurs in erythroid precursors in the bone marrow

Heme biosynthesis steps

1. Succinyl CoA + glycine — ALA synthase→ delta-aminolevulinate (ALA)

   • Rate-limiting step

   • Pyridoxal phosphate dependent

   • Occurs in mitochondria and then ALA exits and enters cytosol

2. two molecules of ALA — ALA dehydratase/porphobilinogen synthase→ Porphobilinogen

3. 4 Porphobilinogen molecules —uroporphyrinogen I synthase → hydroxymethylbilane

4. Hydroxymethylbilane —uroporphyrinogen III synthase→ Type III Porphyrinogen

   OR

   Hydroxymethylbilane —spontaneous cyclization → Type I Porphyrinogen (CAUSES PROPHYRIA BC SUBSTITUENTS ARE INVERSE)

5. TOO MANY STEPS THAT ARE IRRELEVANT IMO, JUST RECOGNIZE THE ORDER:

   1. Coproporphyrinogen II : uroporphyrinogen carboxylase

   2. Protoporphyrinogen III → Enzyme: Coproporphyrinogen oxidase

   3. Protoporphyrin IX → Enzyme: Protoporphyrinogen oxidase

Porphyrinogens are __________ but when they are oxidized they become _________

Porphyrinogens are colorless but when they are oxidized they become colored

ALA synthase 1 (ALA1) vs ALA2 synthase

ALA synthase 1: expressed throughout the body, inhibited by heme

ALA synthase 2: expressed only in erythrocyte precursor cells, inhibited by erythropoetin (produced by kidney)

3 most important Porphyrias

• Major symptoms of Porphyrias → “Vampire disease”

• Acute Intermittent Porphyria

• Congenital Erythropoietic Porphyria

• Porphyria cutaneatarda

• Mutations in various genes leads to abnormalities in heme synthesis enzymes which leads to

  • Porphyrinogens → photosensitivity

  • ALA and PBG accumulation → Neuropsychiatric symptoms and signs

All 3 Porphyrias learned

• Defective enzyme

• Symptoms

• occurrence

• Acute Intermittent Porphyria:

  • Defective Uroporphyrinogen synthase I

  • Symptoms: Severe abdominal pain, vomiting, confusion, psychosis, seizures

  • Symptoms caused mostly by ALA and PBG (porphobilinogen) accumulation NOT little heme

• Congenital Erythropoietic Porphyria: extremely rare

  • Defective uroporphynogen synthase III

  • Dark urine, sunlight sensitivity, erythrodontia/fluorescent teeth, increased hair growth

• Porphyria Cutanea Tarda: most common

  • Defective Uroporphyrinogen decarboxylase

  • Symptoms: Sensitivity to sunlight and fragility of exposed skin, increased hair growth (especially face)

Plubism

• Cause

• Symptoms

• How is it related to porphyria

Plubism = Lead Poisoning

• Strongly inhibits: ALA dehydratase and Ferrochelatase

• Mimics Porphyria symptoms: severe abdominal pain, vomiting, fatigue. irritability and developmental delays

• Heme Catabolism/Degradation

1. Where does it take place and by which cells

2. What components are recycled?

3. Steps

• Takes place in liver, spleen and bone marrow by reticuloendothelial cells

• Recycled: iron back to iron poop, globin degraded into constituent AA

• Steps:

  1. Heme —heme oxygenase → Biliverdin

     • Iron and CO2 released

  2. Biliverdin —biliverdin reductase → Bilirubin

     • NADPH needed

  3. Biliverdin binds to Albumin to travel in the blood and go to the liver

  4. Biliverdin + UDP-gluconic acid - UDP- glucuronosyl transferase→ Bilirubin diglucuronide

     • Conjugation step

  5. Bilirubin diglucuronide → Bile

When Bilirubin diglucuronide is turned into Bile, the glucuronosyl moiety is removed by intestinal bacterial ______________

Similarly, the fecal flora reacts with ___________ to make them colorless

Most (95%) of the bile is reabsorbed back into the_______ and only a small amount enters _______ and is excreted in the ________ by _________ through the spontaneous oxidization to ________

_________ gives brown appearance to feces

When Bilirubin diglucuronide is turned into Bile, the glucuronosyl moiety is removed by intestinal bacterial beta-glucuronidases

Similarly, the fecal flora reacts with urobilinogens to make them colorless

Most (95%) of the bile is reabsorbed back into the liver and only a small amount enters circulation and is excreted in the urine by kidney through the spontaneous oxidization to urobilin

Stercobilin gives brown appearance to feces

• What are the laboratory plasma bile levels for Hyperbilirubinemia and Jaundice/Icterus?

• Unconjugated bilirubin vs. Conjugated bilirubin

• Hyperbilirubemia >1.0 mg/dL

• Jaundice/Icterus > 2.0-2.5 mg/dL

• Unconjugated bilirubin (hydrophobic)

  • Does not appear in urine

  • Can cross brain-blood barrier and enter CNS, causing Kernicterus (encephalopathy due to hyperbilirubemia)

  • Moderately unconjugated bilirubin in Pre-hepatic (hemolytic anemias)

• Conjugated bilirubin (hydrophilic)

  • Can appear in urine

  • Frequent in Hepatic and Post-hepatic (liver diseases and biliary tree obstruction)

Prehepatic, Posthepatic and Hepatic

• Pre-hepatic

  • Caused by acute or chronic hemolytic anemia

    • Too many hemolyzed RBC’s cannot be turnt into bilirubin fast enough

    • Unconjugated bilirubin

    • Increased urobilinogen and stercobilinogen

• Hepatic (Liver Disease)

  • Caused by Hepatocellular disturbances (cirrhosis and hepatitis), Neonatal/physiologic jaundice, Gilbert syndrome (benign), Crigler-Najjart, Bilirubin transport disturbance (Dubin-Johnson Syndrome)

• Post-hepatic obstruction:

  • Caused by diseases that obstruct the bile duct

  • Conjugated bilirubin

  • Decreased urobilinogen, increased bilirubin diglucuronide

  • White feces because no stercobilin

Bile Duct Obstruction