Study Notes on Heme and Porphyrin Metabolism

The Porphyrins, Haem and Haem Synthesis

Introduction to Haem Proteins

  • Heme-Containing Proteins include:

    • Hemoglobin in red blood cells

    • Myoglobin in red muscle

    • Cytochromes in the respiratory chain

    • Catalase

    • Some peroxidases

    • Tryptophan pyrrolase

    • Prostaglandin synthase

    • Guanylate synthase

    • Nitric Oxide synthase

Example: Myoglobin

  • Characteristics:

    • Globular structure

    • Monomeric form

    • Tertiary structure

    • Haem component: Ferroprotoporphyrin IX (C34H32FeN4O4)

Structure and Origin of Porphyrins

  • Porphyrins are derived from Porphin which has several structural characteristics:

    • Macrocyclic: a large cyclic structure

    • Highly Unsaturated: contains multiple double bonds

    • Four Pyrrole Rings: five-sided hydrocarbon rings with nitrogen at the apex

    • Bonding: Pyrrole rings are joined by four methene bridges (-CH=).

Structure of Porphin

  • Chemical Formula: C<em>20H</em>14N4C<em>{20}H</em>{14}N_{4}

  • Visual representation (depicted in figure page 6) included.

Origin of Porphin

  • Formation of the macrocyclic porphin structure occurs through a series of chemical reactions. This structure is fundamental for derivatives such as chlorophyll, vitamin B12, protoporphyrin, heme, and bilirubin, playing critical roles in processes like photosynthesis, respiration, and digestion.

Haem Synthesis Overview

Series of Compounds Encountered

  • The synthesis pathway involves:

    • Uroporphyrin (I, II, III)

    • Coproporphyrins

    • Protoporphyrins

Isomeric Forms

  • Uroporphyrins:

    • There are multiple isomeric forms depending on the arrangement of side chains.

  • Protoporphyrins:

    • There are 15 isomeric forms, with Protoporphyrin IX being the most significant in heme proteins.

Recognizing the Molecule

  • Side chains in various positions:

    • Methyl: C1,3,5,8

    • Vinyl: C2,4

    • Propionate: C6,7

Formation of ALA (8-Aminolevulinic Acid)

  • Initiation of Heme Synthesis:

    • Begins with the condensation of glycine and succinyl-CoA.

    • Reaction involves decarboxylation to form extd−AminolevulinicAcid(ALA)ext{d-Aminolevulinic Acid (ALA)}.

Mechanism of ALA Formation

  1. Glycine + Succinyl-CoA → 8ext−Aminolevulinate8 ext{-Aminolevulinate}

  2. Enzyme: extALASynthaseext{ALA Synthase}

    • Reaction also results in the release of CO₂ and Ammonia (NH₃).

Condensation of ALA and Formation of Porphobilinogen

  • Mechanism further breaks down into:

    • 8ext−Aminolevulinate8 ext{-Aminolevulinate} → extPorphobilinogenext{Porphobilinogen}

    • 8-ALA Dehydrase (PBG Synthase) catalyzes this step.

Porphobilinogen Deaminase

  • Contains a Dipyrromethane Prosthetic Group, linked at the active site via a cysteine residue.

  • Catalyzes the formation of hydroxymethylbilane from Porphobilinogen.

Hydrolysis and Formation of Uroporphyrinogen III

  1. Hydrolysis reaction mechanism leads to the release of tetrapyrrole Hydroxymethylbilane.

  2. Conversion to Uroporphyrinogen III catalyzed by the enzyme Uroporphyrinogen III Synthase.

  3. Ring closure converts linear tetrapyrrole to a macrocyclic form.

Distribution of Acetyl & Propionyl Chains

  • Action of UPGIII decarboxylase and CPG oxido-decarboxylase lead to structural changes during synthesis.

Haem Synthesis Regulation

  1. ALA Synthase is the rate-limiting step in heme synthesis, regulated at the transcription level.

  2. Internal heme concentration provides feedback inhibition.

  3. For erythrocytes, availability of iron regulates heme synthesis via Iron-Sulfur Clusters.

Hepatic and Erythroid Haem Synthesis

Liver

  • Main non-RBC source for heme synthesis.

  • Heme produced is primarily for cytochrome P450 synthesis involved in detoxification.

Red Blood Cells (RBCs)

  • 85% of heme synthesis occurs in immature RBCs.

  • Synthesis ceases upon maturation.

Lead Poisoning and Its Effects on Heme Synthesis

  • Lead inhibits the activity of:

    • d-ALA Synthase

    • d-ALA Dehydrase

    • Ferrochelatase

  • Resulting Accumulation:

    • Increased levels of precursors like d-ALA, protoporphyrin, and coproporphyrin in urine, mimicking symptoms of acute intermittent porphyria.

Inborn Errors of Metabolism: Porphyrias

  • Group of disorders caused by deficiencies of heme biosynthetic pathway enzymes.

  • Typically inherited in an autosomal dominant manner:

    • Accumulation of toxic porphyrin precursors triggers clinical episodes, which can be aggravated by drugs, chemicals, foods, and sun exposure.

Types of Porphyrias

  1. Acute Intermittent Porphyria:

    • Caused by deficiency in porphobilinogen deaminase.

    • Symptoms: Neuropsychiatric in nature, abdominal pain.

  2. Porphyria Cutanea Tarda:

    • Most common form characterized by uroporphyrinogen decarboxylase deficiency.

    • Symptoms: Photosensitivity leading to skin damage due to oxygen radical formation from porphyrins converted by light.

Additional Information on Hemin (Panhematin)

  • Chemical Name: Chloro[3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2−)]iron(III)

    • Regulatory Status: Prescription-only (US)

    • Used in management of porphyria attacks.

    • Comparison with hematin, which has a hydroxide ligand instead of chloride, but both may be referred to interchangeably.

Conclusion

  • Heme synthesis involves complex biochemical pathways regulated at multiple levels with various implications for health, particularly in conditions like lead poisoning and porphyrias.

  • Understanding these pathways is critical for recognizing the biochemical basis of associated disorders and developing therapeutic strategies.