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Heme Biosynthesis

For medical students2 min readUpdated 2026-10-10

Heme is the prosthetic group of essential proteins in the body, such as hemoglobin, myoglobin, cytochromes, catalase, and peroxidase. Its biosynthesis is a strict cascade of enzymatic reactions that takes place in all cells of the body, alternating between the mitochondria and the cytoplasm.

Main substratesGlycine, succinyl-CoA, and ferrous iron ions (Fe²⁺)

Highest synthesis activityLiver (for cytochromes) and bone marrow (for hemoglobin)

CompartmentalizationMitochondria → Cytoplasm → Mitochondria

InducersBarbiturates, diclofenac, estrogens, and sulfonamides stimulate the process

Role of Heme and Localization of the Process

Heme biosynthesis occurs in virtually all cells of the human body, as heme is required for cellular enzymes of the respiratory chain and antioxidant defense. However, this process is most active in two tissues:

In the liver — where heme is massively consumed to produce cytochromes.
In the bone marrow — in erythroid cells, where heme is synthesized for incorporation into hemoglobin molecules.

The process of heme assembly is compartmentalized, meaning it is strictly divided between cellular organelles. The initial steps take place in the mitochondrial matrix, intermediate metabolites then move to the cytoplasm to form a complex ring structure, and the final step returns to the mitochondria. Assembly of a complete molecule requires simple precursors: the amino acid glycine, succinyl-CoA, and iron ions (Fe²⁺).

Stages of Heme Biosynthesis

Heme synthesis is a multi-step enzymatic cascade. It can be conditionally divided into three key stages based on intracellular localization.

Stage I: Initiation in Mitochondria The process begins in the mitochondrial matrix with the condensation of glycine and succinyl-CoA. This reaction is catalyzed by the pyridoxal-dependent enzyme δ-aminolevulinic acid synthase (ALA synthase), with pyridoxal phosphate (a vitamin B6 derivative) acting as a cofactor. The reaction yields carbon dioxide and coenzyme A as byproducts, with δ-aminolevulinic acid (ALA) as the primary product.

Stage II: Cytoplasmic Reactions ALA leaves the mitochondria and enters the cytosol. Here, the enzyme ALA dehydratase (porphobilinogen synthase) joins two molecules of ALA, releasing water to form a cyclic compound called porphobilinogen (PBG). This is followed by a linear sequence of transformations where four molecules of porphobilinogen assemble into porphyrinogens:

Hydroxymethylbilane.
Uroporphyrinogen III.
Coproporphyrinogen III.
Protoporphyrinogen IX.

The cytoplasmic phase concludes with the formation of protoporphyrin IX, which is transported back into the mitochondria.

Stage III: Final Assembly in Mitochondria The final stage of assembly occurs in the mitochondrial matrix. The enzyme ferrochelatase inserts a ferrous iron ion (Fe²⁺) into the protoporphyrin IX ring, resulting in the formation of the finished heme molecule.

Mechanisms of Regulation

Heme biosynthesis is tightly controlled by feedback inhibition and enzymatic induction, preventing both deficiency and toxic accumulation of porphyrins.

Negative Feedback (Inhibition): The end product of the pathway—heme itself—acts as an allosteric inhibitor. It suppresses the activity of the first two key enzymes of the cascade: ALA synthase and ALA dehydratase.

Stimulation (Induction):

Iron ions (Fe²⁺) in reticulocytes act as a powerful inducer, stimulating the synthesis of the rate-limiting enzyme ALA synthase.
Heme as a coordinator: Heme induces the translation of α- and β-polypeptide chains of globin, synchronizing the production of the protein moiety (globin) and the prosthetic group (heme) for hemoglobin assembly.
External inducers: Certain drugs and hormones (barbiturates, diclofenac, sulfonamides, estrogens, and progestins) can increase heme production by inducing the synthesis of ALA synthase.

Mnemonic

To remember the localization of heme biosynthesis stages, use the abbreviation "MCM": Mitochondria (start) — Cytoplasm (middle) — Mitochondria (finish).

Frequently asked questions

What diseases are caused by inherited defects in heme biosynthetic enzymes?

Inherited defects in heme biosynthetic enzymes lead to primary (inherited) porphyrias, which are disorders caused by genetic mutations in the pathway.

Inherited porphyrias include:

Acute intermittent porphyria;
Congenital erythropoietic porphyria;
Hereditary coproporphyria.

For acute porphyrias, patients carry an inherited defect in the gene for one of the heme-synthesizing enzymes. The vast majority of acute porphyrias are inherited in an autosomal dominant manner with incomplete penetrance. An extremely rare form—ALA dehydratase deficiency porphyria—is inherited in an autosomal recessive manner. Most carriers of the mutations remain asymptomatic, and clinical manifestation as an acute attack occurs upon exposure to specific triggers.

How does heme catabolism occur in macrophages of the reticuloendothelial system?

Heme catabolism in macrophages of the bone marrow and spleen proceeds in two consecutive steps:

Heme oxygenase reaction — mediated by the enzyme heme oxygenase, heme is first converted to verdoglobin, followed by the formation of the green pigment biliverdin. The byproducts of this reaction are ferric iron ($Fe^{3+}$) and carbon monoxide (CO).
Biliverdin reductase reaction — the enzyme biliverdin reductase, utilizing NADPH and $H^+$, reduces biliverdin to the yellow-orange pigment unconjugated (free) bilirubin.

Subsequently, unconjugated bilirubin binds to albumin for transport through the blood to the liver.

Which vitamins are required for normal heme biosynthesis?

The cofactor pyridoxal phosphate is required for the initial synthesis reaction. This is a vitamin B6 derivative, without which the enzyme ALA synthase cannot function.

In what oxidation state is iron incorporated into heme?

Iron is incorporated into the protoporphyrin IX molecule strictly in its ferrous state (Fe²⁺). This reaction is catalyzed by ferrochelatase during the final mitochondrial stage.

How does heme regulate the production of the protein portion of hemoglobin?

Heme acts as an inducer of globin synthesis. It stimulates the translation of α- and β-polypeptide chains, ensuring tight coordination between the formation of the protein and non-protein components of hemoglobin.

Go deeper

Structural formulas of intermediate porphyrinogens
Mechanism of allosteric inhibition of ALA synthase
Specifics of heme biosynthesis in bone marrow reticulocytes
Molecular basis of enzyme induction by barbiturates and estrogens