Heme Synthesis

Glycine and Succinyl-CoA to create heme

Mitochondria, Cytoplasm

• Alanine (5-aminolaevulinic acid) synthesis – Glycine and Succinyl-CoA condensation
  • Alanine Synthase – controls of porphyrins and heme synthesis rate, controlling enzyme
• Porphobilinogen (PBG) subunit synthesis – Two alanines combine to form monopyrrole ring PBG
  • Alanine Dehydratase – DEC = ALA dehydratase porphyria
• Hydroxymethylbilane synthesis – Four PBGs combine to form linear tetrapyrrole—four monopyrroles strung together end to end
  • Hydroxymethylbilane Synthase/PBG Deaminase – DEC = acute intermittent porphyria (AIP).

“The open section on the left of the structure above – where two pyrrole rings lie adjacent to each other but not joined—is then closed, producing a tetrapyrrole ring. This produces the first porphyrin on the pathway, uroporphyrinogen. This step is catalysed by uroporphyrinogen lll cosynthase, which also tweaks the ring into a particular orientation called the lll isomer. This enzyme is defective in congenital erythropoietic protoporphyria.  

Uroporphyrinogen lll Four of the carboxylic acid side chains (COOH) are successively knocked off by the enzyme uroporphyrinogen decarboxylase (UROD), producing the heptacarboxylic, hexacarboxylic and pentacarboxylic porphyrinogen intermediates (not shown), ending in coproporphyrinogen lll. This enzyme is defective in porphyria cutanea tarda (PCT).  

Coproporphyrinogen lll A further two carboxylic acid side chains are knocked off by the enzyme coproporphyrinogen oxidase, which is defective in hereditary coproporphyria (HCP).  

Protoporphyrinogen lX This molecule is then oxidised from protoporphyrinogen lX to protoporphyrin lX by the enzyme protoporphyrinogen oxidase, which is defective in variegate porphyria.  

Protoporphyrin lX An iron atom (Fe2+) is inserted into the centre of the tetrapyrrole ring to form heme. This is catalysed by the enzyme ferrochelatase, which is defective in erythropoietic protoporphyria.  

HEME BREAKDOWN

The tetrapyrrole ring is broken open (See the gap between the O atoms at the top of the structure below).

This step is catalysed by the enzyme heme oxygenase.  

Biliverdin This is further reduced to bilirubin by the enzyme biliverdin reductase  

Bilirubin Bilirubin is the form in which the breakdown products of heme are excreted from the body: in the bowel, it is further broken down to urobilinogen and stercobilinogen by bacteria.” – from additional info Capetown

Salient Chemicals:

• Glycine
• Succinyl-CoA
• Alanine synthase
• Alanine

Additional Information:

• Rensselear Polytechnic Institute
• Universities of Cape Town – South Africa ty Dr. Vaso Lykourinou-Tibbs