Heme is an iron-containing porphyrin that serves as the prosthetic group for hemoglobin, myoglobin, cytochromes (which function in oxidative phosphorylation), catalase, and nitric oxide synthase. Its biosynthesis and degradation involve eight enzymatic steps and are tightly regulated to maintain iron homeostasis and prevent accumulation of toxic intermediates.
Heme Biosynthesis
Heme synthesis begins in the mitochondria and continues in the cytoplasm before returning to the mitochondria for completion. The first reaction condenses glycine with succinyl-CoA to form aminolevulinic acid, catalyzed by ALA synthase. This is the rate-limiting step of the pathway, requiring pyridoxal phosphate as a cofactor. ALA synthase is regulated by heme through feedback inhibition and transcriptional repression. Two isoforms exist: ALAS1 is the housekeeping form, and ALAS2 is erythroid-specific.
ALA is exported to the cytoplasm, where two molecules are condensed by ALA dehydratase to form porphobilinogen. This enzyme is inhibited by lead, contributing to the anemia of lead poisoning. Four PBG molecules are then joined by porphobilinogen deaminase to form a linear tetrapyrrole called hydroxymethylbilane.
Uroporphyrinogen III Formation
Hydroxymethylbilane can cyclize spontaneously to uroporphyrinogen I, an unusable isomer, or be converted to the correct uroporphyrinogen III by uroporphyrinogen III synthase. This enzyme flips one of the pyrrole rings, creating the asymmetric structure characteristic of natural porphyrins. Deficiency of this enzyme causes congenital erythropoietic porphyria.
Uroporphyrinogen III is decarboxylated to coproporphyrinogen III by uroporphyrinogen decarboxylase, which removes the four carboxyl groups from the acetate side chains. Coproporphyrinogen III enters the mitochondria, where coproporphyrinogen oxidase converts two propionate side chains to vinyl groups, forming protoporphyrinogen IX.
Protoporphyrin IX and Iron Insertion
Protoporphyrinogen oxidase oxidizes the porphyrinogen ring to the fully conjugated protoporphyrin IX, creating the characteristic red color. This enzyme requires molecular oxygen and is inhibited by some herbicides. Finally, ferrochelatase inserts ferrous iron into the center of protoporphyrin IX to form heme. Lead also inhibits ferrochelatase, impairing heme synthesis.
Regulation
Heme synthesis is regulated primarily at the level of ALA synthase by the concentration of free heme. Heme inhibits ALAS1 transcription, destabilizes ALAS1 mRNA, and blocks mitochondrial import of ALAS1. Heme also induces heme oxygenase, the first enzyme in heme degradation, providing coordinated regulation of heme levels. In erythroid cells, iron availability is the major regulator, with ALAS2 translation controlled by iron-responsive elements and iron regulatory proteins.
Porphyrias
Porphyrias are disorders caused by defects in heme biosynthesis enzymes, classified as hepatic or erythropoietic based on the primary site of enzyme expression. Acute intermittent porphyria results from PBG deaminase deficiency, causing accumulation of ALA and PBG. Acute attacks present with severe abdominal pain, neuropsychiatric symptoms, and autonomic dysfunction, often triggered by drugs that induce CYP450 enzymes and deplete heme.
Porphyria cutanea tarda, caused by uroporphyrinogen decarboxylase deficiency, is the most common porphyria. It presents with skin fragility, blistering, and hypertrichosis in sun-exposed areas. Hepatocellular carcinoma risk is increased. Erythropoietic protoporphyria, from ferrochelatase deficiency, causes painful photosensitivity without blistering.
Heme Degradation
Heme degradation occurs primarily in the reticuloendothelial system, particularly the spleen and liver. Heme oxygenase, the rate-limiting enzyme, cleaves the porphyrin ring at the alpha-methene bridge, producing biliverdin, ferrous iron, and carbon monoxide. HO is induced by heme itself and by oxidative stress. HO-1 is the inducible isoform; HO-2 is constitutively expressed.
Biliverdin reductase reduces biliverdin to bilirubin, a yellow pigment. Unconjugated bilirubin is lipophilic and transported to the liver bound to albumin. In the liver, bilirubin is conjugated with glucuronic acid by UDP-glucuronosyltransferase, producing water-soluble bilirubin diglucuronide. Conjugated bilirubin is secreted into bile and transported to the intestine.
In the intestine, bacterial beta-glucuronidases deconjugate bilirubin, and the resulting bilirubin is reduced to urobilinogen and stercobilinogen, which give feces its brown color. Some urobilinogen is reabsorbed and excreted in urine. Jaundice occurs when bilirubin accumulates in blood, causing yellow discoloration of skin and sclera.
