Biochemistry · Enzyme
ALA synthase !
ALA synthase opens and controls heme synthesis: it joins glycine and succinyl-CoA in the mitochondrion.
Updated 2026-11-01
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Key facts
- Glycine + succinyl-CoA → δ-aminolevulinic acid (ALA) + CoA + CO₂; the rate-limiting step of the pathway.
- It needs pyridoxal phosphate (vitamin B6) bound to an active-site lysine.
- ALAS1 (chromosome 3) is in every cell and is repressed by heme; ALAS2 (X chromosome) is erythroid and is controlled by iron.
- It is made in the cytosol and imported into the mitochondrial matrix; heme blocks that import.
- Also called
- δ-aminolevulinate synthase, ALAS1 (liver), ALAS2 (erythroid)
- EC number
- 2.3.1.37
- Genes
- ALAS1, ALAS2
- Structure (PDB)
- 6HRH
Regulation
- ALAS1: heme represses its gene, speeds up decay of its mRNA and blocks its mitochondrial import.
- ALAS1 rises with P450-inducing drugs, fasting (via PGC-1α), alcohol and steroid hormones.
- ALAS2: its mRNA has a 5' IRE; without iron, IRP binds it and stops translation.
Inhibitors and toxins
- Heme and hemin (ALAS1 repression)
- Givosiran: an interfering RNA that silences liver ALAS1
- Isoniazid, indirectly, by depleting vitamin B6
Clinical notes
- Acute porphyria attacks are triggered when something induces ALAS1 (drugs, fasting, progesterone); treatment aims to switch it off (hemin, glucose, givosiran).
- Loss-of-function ALAS2 mutations cause X-linked sideroblastic anemia, which sometimes improves with vitamin B6.
- Gain-of-function ALAS2 mutations make excess protoporphyrin: X-linked protoporphyria, similar to the erythropoietic form.
Pathways
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
Which vitamin is the cofactor of ALA synthase?
B6, as pyridoxal phosphate; its deficiency can cause sideroblastic anemia.
Which ALA synthase isoform is regulated by iron, and which by heme?
Iron regulates ALAS2 (erythroid) through an IRE in its mRNA; heme represses ALAS1 (liver).
Why can fasting trigger an acute porphyria attack?
Fasting activates PGC-1α, which induces ALAS1 and raises production of ALA and porphobilinogen.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: ALAS2: 5-aminolevulinate synthase, erythroid-specific, mitochondrial (human) (UniProt, 2026); ALAS1: 5-aminolevulinate synthase, non-specific, mitochondrial (human) (UniProt, 2026); ALAS2 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 6HRH: Structure of human erythroid-specific 5'-aminolevulinate synthase, ALAS2 (RCSB Protein Data Bank, 2026).
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