62 - Heme Metabolism

Porphyrins

Cyclic compounds that readily bind metal ions, usually ferrous (Fe2) or Ferric (Fe3) iron forming metalloporphyrin (a prosthetic group).

Structure of Heme prophyrin

One Fe2+ coordinated in the center of the tetrapyrrole ring of protophyrin IX

Function of Porphyrins

serve as a prosthetic group for

• Hemoglobin and myoglobin

• Cytochromes in ETC

• Cytochrome P450 monooxygenase system

• other enzymes

Tissue Locations in Heme biosynthesis

Liver, RBC Precursor Cells

Stages of Heme Biosynthesis

1. Synthesis of Pyrrole ring

2. Conversion into Tetrapyrrole

3. Incorporation of Iron

Stage 1: Synthesis of Pyrrole Ring in the Mitochondria (heme biosynthesis)

• Enzyme : Aminolevulinic Acid Synthase (ALAS) makes ALA

  • PLP is a required coenzyme

• Rate-limiting committed step

  • ALAS1 in the liver is inhibited by excess heme with Fe3+

    • represses transcription

  • ALAS2 in erythroid tissues is regulated only by iron availability

Effect of Drugs on ALAS1

• Drugs metabolized by microsomal CYP MOA system result in the increase in the activity of ________ enzyme in hepatic tissues.

  • In response of drugs, CYP protein synthesis increases, leading to enhanced consumptom of heme, leading to increase of ________

X-linked Sideroblastic Anemia

• LOF mutatons in ALAS2

• Results in reduction in the amount of heme present, preventing erythroid cells from making enough hemoglobin

• This causes buildup of excess iron → iron overload

Stage 1: Synthesis of Pyrrole Ring in the Cytosol (heme biosynthesis)

• Enzyme: ALA Dehydratase makes Prophobilinogen from ALA

  • Inhibited by Lead → contributes to the cause of anemia in lead poisoning

Enzyme defect in heme syntehsis before tetrapyrrol ring formation (Stage 2)

Abdominal and Neuropsychiatric signs

Enzyme defect in heme syntehsis after tetrapyrrol ring formation (Stage 2)

Photosensitivity due to the formation of ROS

Stage 3 heme biosynthesis

• Enzyme: Ferrochelatase incorportates iron into the tetrapyrrole ring

  • inhibited by lead

Lead Poisoning

• ALA dehydratase and Ferrochelatase are sensitive to inhibition by lead

• Protophyrin and ALA accumulate in the urine

• ALAD deficiency porphyria is a very rare AR acute hepatic porphyria

• NO photosensitivity

Acute Intermittent Porphyria (AIP)

• deficiency in hydroxymethylbilane synthase (AD)

• Porphobilinogen and ALA accumulate in the urine

• urine darkens on exposure to light and air

• NO photosensitivity

Congenital Erythropoietic Porphyria (CEP)

• Deficiency in uroporphyrinogen III synthase (AR)

• Uroporphyrinogen I and coproporphyrinogen I accumulate in the urine

• Photosensitivity

Porphyria Cutanea Tarda (PCT)

• Deficiency in uroporphyringoen decarboylase (AR)

• most common porphyria

• Chronic disease of the liver

• Clinical onset during the 4th/5th decade of life

• Presents with cutaneous symptoms and urine that is red to brown in natural light and pink in fluroescent light

• Photosensitivity

Hereditary Coproporphyria (HCP)

• deficiency in coproporphyrinogen III oxidase (AD)

• coproporphyrinogen III and other precursors accumulate in the urine

• Photosensitivity

Variegate Porphyria (VP)

• Deficiency in protoporphyrinogen oxidase (AD)

• Protoporphyrinogen IX and other intermediates prior to the block accumulate in the urine

• photosensitivity

Erthropoietic Protoporphyria (EPP)

• Deficiency in Ferrochelatase (can be AR or AD)

• Protoporphyrin accumulates in RBCS, bone marrow, and plasma

• Photosensitivity

The Acute liver porphyrias

• AIP, VP, and HCP

• characterized by acute GI attacks, neuropsyh and motor symptoms with photosensitivity

• Can be induced by drugs metabolized by the CYP450 system

The Erythropoietic Porphyrias

• CEP and EPP

• Result in photosensitivity that appear in early childhood

Treatment for Porphyria Attacks

IV injection of hemin and glucose, which ecreases activity of ALAS1

Treatment for photosensitivity caused by Porphyrias

protection, Beta-caretene to scavenge free radicals, phlebotomy

Location of heme breakdown

Macrophages of mononuclear phagocyte system in the liver and spleen

Deficiencies of Bilirubin UDP-gluconosyltransferase

• Crigler-Najjar Syndrome Type I and II → most severe (I)

• Gilbert Syndrome → often mild and undiagnosed

• Symptoms: high levels of Unconjugated bilirubin can be toxic to nervous tissue

Jaundice

Secondary condition caused by deposition of bilirubin

Hemolytic Jaundice

Conditions where hemolytic anemia overwhelms the ability of the liver to conjugate bilirubin → Increased serum UB

Hepatocellular Jaundice

When any liver damage results in defect in conjugation or secretion of bilirubin → increased serum UCB

Obstructive Jaundice

Blocking of the bile duct leads to accumulation of CB in the liver → increased serum CB

Neonatal Jaundice

Transient, physiologic jaundice seen in the first postnatal week → inceased of UB

Treat with phototherapy