Heme is synthesized in every eukaryotic and prokaryotic cell and it carries out many important biologic functions. It is the prosthetic group of many hemeproteins. The best known function of heme is its oxygen binding and transport in hemoglobin, and erythroblasts synthesize 85% of the total body heme is the bone marrow (Berk et al. 1976). In addition, heme is involved in the mitochondrial respiratory chain where it transports electrons to cytochromes. CYP enzymes, which metabolize a large number of clinically important drugs as well as several endogenous and exogenous substances, contain heme. Tryptophan pyrrolase, which catalyses the oxidation of tryptophan, is also a heme-dependent enzyme.
Porphyrias are defects in heme biosynthesis. The heme biosynthesis pathway contains eight steps and dysfunction in seven of them is associated with a specific porphyria (Figure 1); defects in erythroid specific ALA synthase result in X-chromosome linked sideroblastic anemia.
Acute intermittent porphyria (AIP) is caused by a defect in the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD, also referred to as hydroxymethylbilane synthase and uroporphyrinogen I synthase, EC 220.127.116.11). It is the most common type of acute porphyria in Finland (Mustajoki and Koskelo 1976) and in most other countries (Sassa and Kappas 1981). AIP is characterized by potentially lethal acute attacks with abdominal pain, tachycardia and various other neuropsychiatric signs and symptoms (Kappas et al. 1995).
The gene coding for human PBGD was characterized in 1986 (Raich et al. 1986) which enabled the characterization of the molecular genetic background of AIP. The purpose of this series of investigations was to identify the molecular defects in Finnish AIP patients and, furthermore, to elucidate the mechanisms by which a mutation results in the deficient function of the enzyme.