Heme synthesis template

Succinyl-CoA + glycine → δ-aminolevulinate (ALA synthase, PLP); 2 ALA → porphobilinogen (ALA dehydratase); 4 PBG → hydroxymethylbilane → uroporphyrinogen III → coproporphyrinogen III → protoporphyrinogen IX → protoporphyrin IX → heme (ferrochelatase, Fe²⁺), with the compartments.

What the template shows

• Eight glycine and eight succinyl-CoA make one heme: the first and last three steps in the mitochondrion, the middle four in the cytosol
• Committed step: ALA synthase (mitochondrial matrix)
• PLP-dependent condensation; R = CoA
• succinyl-CoA
• δ-aminolevulinate (ALA)
• Two ALA condense to the pyrrole porphobilinogen (cytosol)
• porphobilinogen (PBG)
• Overview: four PBG build the macrocycle
• bilane (linear)
• ALA dehydratase
• PBG deaminase
• ring D flipped
• ALA synthase
• imported · CPOX, −2 CO₂ (intermembrane space)
• Iron goes in last
• Ferrochelatase on the matrix side of the inner membrane; 1,3,5,8-tetramethyl-2,4-divinyl-6,7-dipropionate (type IX) side chains
• ALA synthase (ALAS1 in liver) is the control point: heme represses its synthesis and import; in red cells ALAS2 is controlled by iron.
• Lead inhibits ALA dehydratase and ferrochelatase (ALA and zinc protoporphyrin rise). Porphyrias are enzyme defects of this pathway, e.g. acute intermittent porphyria (PBG deaminase).
• Uroporphyrinogen III synthase flips ring D, making the asymmetric type III isomer; the porphyrinogens are colourless, protoporphyrin IX is the first coloured, conjugated macrocycle.
• Heme is broken down to biliverdin and bilirubin; acids are drawn neutral.

Drawn with 133 atoms, 2 arrows, 51 shapes – every one editable in MolDraw.

Sources

• Nelson & Cox, Lehninger Principles of Biochemistry, 8th ed., 2021, ch. 22 Textbook
• Berg, Tymoczko, Gatto & Stryer, Biochemistry, 9th ed., 2019 Textbook
• Voet & Voet, Biochemistry, 4th ed., Wiley 2011 Textbook
• Shemin & Rittenberg, J. Biol. Chem. 1946, 166, 621 Original paper
• Shemin, Russell & Abramsky, J. Biol. Chem. 1955, 215, 613 Original paper