Biosynthetic Pathways of Heme Metabolism

The biosynthesis of haem is a multi-step enzymatic process that converts simple precursors into the iron-containing tetrapyrrole cofactor essential for oxygen transport, electron transfer and diverse enzymatic reactions. The pathway begins with the condensation of glycine and succinyl-coenzyme A to form δ-aminolaevulinic acid, which through successive enzymatic actions yields uroporphyrinogen III. Two major routes then diverge: the classical protoporphyrin-dependent pathway, widespread among eukaryotes and Gram-negative bacteria, and the coproporphyrin-dependent pathway, typical of Gram-positive organisms. In both pathways, oxidases convert porphyrinogens into porphyrins, decarboxylases remove propionate side-chains to form vinyl groups and ferrochelatases insert ferrous iron into the macrocycle to yield haem b. Recent advances have elucidated structural motifs and catalytic mechanisms of key enzymes, uncovered oxygen-independent variants adapted to anaerobic niches, and highlighted unique protein–protein interactions that channel intermediates. Understanding these biosynthetic routes has broad implications, from addressing inborn errors of metabolism and developing antimicrobial agents to engineering synthetic biology platforms for novel porphyrin-based compounds.

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Biosynthetic Pathways of Heme Metabolism publication trend

The graph below shows the total number of articles in biosynthetic pathways of heme metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Haem: Iron-containing prosthetic group derived from a tetrapyrrole macrocycle, critical for oxygen transport and redox catalysis.

Porphyrinogen: Reduced, non-conjugated tetrapyrrole intermediates that undergo enzymatic oxidation to form porphyrins.

Protoporphyrin-dependent pathway: Classic haem biosynthetic route in which protoporphyrinogen IX is oxidised to protoporphyrin IX before iron insertion.

Coproporphyrin-dependent pathway: Alternative route prevalent in monoderm bacteria, where coproporphyrinogen III is first oxidised to coproporphyrin III and then metalated.

Ferrochelatase: Enzyme that catalyses insertion of Fe2+ into a porphyrin ring to form haem b.

Coproheme decarboxylase (ChdC/HemQ): Enzyme that removes propionate side-chains from coproheme, converting it into haem b, often via hydrogen peroxide-mediated steps.

Oxidase (CgoX/PgoX): Flavin-dependent enzymes that catalyse aerobic or anaerobic oxidation of porphyrinogens to porphyrins, with oxygen or alternative electron acceptors.

References

1. Exploiting Differences in Heme Biosynthesis between Bacterial Species to Screen for Novel Antimicrobials. Biomolecules (2023).
2. Structural aspects of enzymes involved in prokaryotic Gram-positive heme biosynthesis. Computational and Structural Biotechnology Journal (2023).
3. The alternative coproporphyrinogen III oxidase (CgoN) catalyzes the oxygen-independent conversion of coproporphyrinogen III into coproporphyrin III. Frontiers in Microbiology (2024).
4. Hydrogen peroxide‐mediated conversion of coproheme to heme b by HemQ—lessons from the first crystal structure and kinetic studies. The FEBS Journal (2016).