描述
The first reaction in porphyrin ring biosynthesis takes place in the mitochondria and involves the condensation of glycine and succinylCoA by δ-aminolevulinic acid synthase (ALAS). Delta-aminolevulinic acid (ALA) is also called 5-aminolevulinic acid. Following its synthesis ALA is transported to the cytosol, where ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen. The next step in the pathway involves the head-to-tail condensation of 4 molecules of porphobilinogen to produce hydroxymethylbilane. The enzyme for this condensation is porphobilinogen deaminase (PBG deaminase). This enzyme is also called hydroxymethylbilane synthase or uroporphyrinogen I synthase. Hydroxymethylbilane has two main fates. The most important fate is conversion to uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by uroporphyrinogen synthase and uroporphyrinogen III cosynthase. Hydroxymethylbilane can also non-enzymatically cyclized to form uroporphyrinogen I. In the cytosol, the acetate substituents of uroporphyrinogen (uroporphyrinogen III or uroporphyrinogen I) are all decarboxylated by the enzyme uroporphyrinogen decarboxylase. The resultant products have methyl groups in place of acetate and are known as coproporphyrinogens, with coproporphyrinogen III being the important normal intermediate in heme synthesis. Coproporphyrinogen III is transported to the interior of the mitochondrion, where 2 propionate residues are decarboxylated, yielding vinyl substituents on the 2 pyrrole rings. The colorless product is protoporphyrinogen IX. In the mitochondrion, protoporphyrinogen IX is converted to protoporphyrin IX by protoporphyrinogen IX oxidase. The final reaction in heme synthesis also takes place in the mitochondria and involves the insertion of the iron atom into the ring system generating heme b. The enzyme catalyzing this reaction is known as ferrochelatase. Heme is broken down when the heme ring is opened by the endoplasmic reticulum enzyme, heme oxygenase. This oxidation step requires heme as a substrate, and any hemin (Fe3+) is reduced to heme (Fe2+) prior to oxidation by heme oxygenase. The oxidation occurs on a specific carbon producing the linear tetrapyrrole biliverdin, ferric iron (Fe3+), and carbon monoxide (CO). This is the only reaction in the body that is known to produce CO. In the next reaction a second bridging methylene (between rings III and IV) is reduced by biliverdin reductase, producing bilirubin. Bilirubin is significantly less extensively conjugated than biliverdin causing a change in the color of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). In hepatocytes, bilirubin-UDP-glucuronyltransferase (bilirubin-UGT) adds 2 equivalents of glucuronic acid to bilirubin to produce the more water soluble, bilirubin diglucuronide derivative.