Blood and Body Fluids BLF 103 Quiz

Course Information

• Academic Year: 2024-2025
• Year: 1
• Semester: 1
• Module: Blood and Body Fluids (BLF) 103
• University: Helwan National University

Heme Synthesis and Porphyria

• Topic: Heme synthesis and Porphyria
• Lecturer: Dr. Marwa Ali
• Department: Medical Biochemistry and Molecular Biology
• University: Ain Shams University
• Objectives:
  • Outline the structure of porphyrins
  • Illustrate the steps of heme synthesis
  • Discuss the regulatory steps of heme synthesis
  • Outline different types of porphyria
  • Correlate the biochemical basis of porphyria with its clinical manifestations

What is Heme?

• Heme is the colored prosthetic group of hemoglobin and several other proteins called hemeproteins.

Some Important Heme-Proteins

• Hemoglobin
• Myoglobin
• Electron transport chain cytochromes (cyt aa3, cyt.c)
• Cytochrome P450
• Catalase and peroxidase (degradation of H2O2)
• Tryptophan pyrrolase
• Cytoplasmic guanyl cyclase (activated by NO)

Structure of Heme

• Heme = Iron in the ferrous state + porphyrin
• Porphyrins are cyclic compounds formed of four pyrrole rings.

Porphyrins

• Porphyrins are cyclic compounds formed of four pyrrole rings linked by methenyl bridges.
• They form complexes with metal ions that bind to the nitrogen of pyrrole rings, such as iron porphyrins (heme) and magnesium porphyrins (chlorophyll).

Porphyrinogens

• Porphyrinogens are reduced forms of porphyrins that have no conjugated double bonds and are colorless.

Structure of Porphyrins

• Porphyrins have a system of conjugated double bonds that absorb light.

MCQ - Porphyrin Ring

• Xanthine oxidase is the exception to all the examples listed that contains a porphyrin ring

Biosynthesis of Heme

• Primarily occurs in the bone marrow (for hemoglobin synthesis) and the liver (for cytochrome P450 synthesis).
• The pathway is partly mitochondrial and partly cytosolic.
• The reactions are irreversible.

Steps in Porphyrin Formation

• Initial and final three steps occur in mitochondria
• Intermediate steps occur in the cytosol
• Porphyrin formation starts with Succinyl CoA and glycine.

Formation of 8-Aminolevulinic Acid (ALA)

• Glycine and succinyl-CoA condense to form ALA by mitochondrial ALA synthase (ALAS).
• This is a committed step in porphyrin biosynthesis.

Formation of Porphobilinogen

• Two molecules of ALA condense to form porphobilinogen by zn-containing ALA dehydratase (porphobilinogen synthase).
• Inhibited by heavy metal ions, like lead.

Formation of Uroporphyrinogen

• Four porphobilinogens condense and form uroporphyrinogen III by uroporphyrinogen III synthase.

Formation of Heme

• Uroporphyrinogen III undergoes decarboxylation to yield coproporphyrinogen III.
• Coproporphyrinogen III enters the mitochondrion and undergoes oxidation reactions.
• Iron (Fe2+) is introduced to protoporphyrin by ferrochelatase.

Overall Reactions of Heme Biosynthesis

• Overview of the steps in heme synthesis, showing the reactants and enzymes involved.

MCQ - Amino Acid for Porphyrin Synthesis

• Glycine is required for porphyrin synthesis.

Regulation of Heme Synthesis

• Heme is a feedback inhibitor of ALA synthase.
• Glucose inhibits ALA synthase.
• Hemin (oxidized form of heme) decreases ALAS activity
• Lead inhibits ALAS and ferrochelatse

Effect of Drugs (Liver Only)

• Drugs metabolized by cytochrome P450 induce cytochrome P450 synthesis.
• Consumption of heme increases ALAS synthesis

Effect of Lead

• Lead inhibits ALA dehydratase and ferrochelatase.
• Lead poisoning results in ALA and protoporphyrin accumulation in the urine.

Effect of Glucose

• Glucose inhibits ALA synthase.

MCQ - 8-Aminolevulinic Acid Synthase Activity

• Catalyzes a rate-limiting reaction in porphyrin biosynthesis.

Porphyria

• Porphyrias are rare, inherited (or occasionally acquired), defects in heme synthesis that result in the accumulation and increased excretion of porphyrins or porphyrin precursors.
• Porphyria refers to the red-blue color caused by pigment-like porphyrins in the urine of patients with heme synthesis defects.

Classification of Porphyrias

• Porphyrias are classified as erythropoietic or hepatic based on the location of enzyme deficiency (bone marrow or liver).

Clinical Manifestations of Porphyrias

• Clinical symptoms depend on whether the enzymatic defect occurs before or after the formation of porphyrinogens.
• Defects prior to porphyrinogen formation cause abdominal and neuropsychiatric signs.
• Defects after porphyrinogen formation cause photosensitivity (skin reactions to light).

Porphyria Cutanea Tarda (PCT)

• Most common type of porphyria.
• Caused by deficiency in uroporphyrinogen decarboxylase enzyme.
• Frequently appears in the fourth or fifth decade of life; and characterized by cutaneous symptoms and red to brown urine.

Why Drugs Are Contraindicated in Porphyria

• Some drugs that induce cytochrome P450 synthesis can increase the synthesis of ALA, leading to the accumulation of porphyrins and an exacerbation of symptoms.

Treatment

• No cure for porphyrias, but medical support during acute attacks and symptomatic treatment for pain and vomiting is necessary.
• Treatment may include intravenous injection of hemin and glucose to decrease the synthesis of ALA synthase.
• Avoid drugs known to induce P450, and protect from sunlight.
• Use antioxidants like vitamin A (beta-carotene) and E to treat photosensitivity

MCQ - Biochemical Basis of Porphyria Precipitation

• Derepression of ALA synthase is the biochemical basis of porphyria precipitation by barbiturates.

MCQ - Most Common Porphyria

• Uroporphyrinogen decarboxylase deficiency is the most common cause of porphyria.

Summary

• Heme structure, biosynthesis steps, and regulatory enzymes are reviewed.
• Common porphyrias and their causes are explained.
• Symptoms and treatments for lead poisoning and various porphyrias are covered.