Porphyrins, porphyrin metabolism and porphyrias. I. Update

The biosynthesis of porphyrins is one of the most conserved parthways known , about the same sequence of reactions taking place in all species. By asso ciating different metals, porphyrins give rise to the "pigments of life": c hlorophyll, haem and cobalamin. The unique tetrapynolic structure enables i t to function in an array of reactions as a single electron carrier and as a catalyst for redox reactions. In this capacity, it constitutes the prosth etic group of enzymes participating in cellular respiration, in conversion reactions involving steroids and lipophilic xenobiotics, in protective mech anisms directed against oxidative stress and in pathways providing central messenger molecules. The formation of haem is accomplished by a sequence of eight dedicated enzymes encoded by different genes, some being active in u biquitous as well as in erythroid isoforms. Large differences between the p articipating enzymes with regard to catalytic power, with low capacity step s positioned early in the catalytic chain, constitute a bar against substra te overloading of enzymes processing porphyrins, thus preventing accumulati on in the body of these phototoxic compounds under physiological conditions . Most of the haem in the body is produced by the liver and bone marrow, but the mechanisms applied for the control of the synthesis differ between the two organs. The extremely potent hemeprotein enzymes formed in the liver ar e rapidly turned over in response to current metabolic needs. They have hal f-lives in the order of minutes or hours and are restored by fast-acting me chanisms for the de novo synthesis, when needed. Uninterrupted and instant availability of the compound is secured by acute deinhibition of the initia l enzyme of the synthetic chain, ubiquitous 5-aminolevulinate synthase (ALA S-I), in response to drain of the free cellular haem pool caused by prevail ing demands for hemeproteins or by increased catabolism of the compound. In contrast, in the erythroid progenitor cell the haem synthetic machinery is designed for uninterrupted production of huge amounts of haem for combinat ion with globin chains to form hemoglobin at a steady rate. In the erythron the synthesis of the enzymes participating in the formation of haem is und er control of erythropoietin, formed under hypoxic conditions. In the absen ce of iron, to be incorporated in the porphyrin formed in the last step of the synthesis, the mRNA of erythroid 5-aminolevulinate synthase (ALAS-2) is blocked by attachment of an iron-responsive element (IRE) binding cytosoli c protein, and transcription of this key enzyme is inhibited. In humans, the genes for each of the haem synthetic enzymes may become the target of mutations that give rise to impaired cellular enzyme activity. Se ven of the enzyme deficiencies are associated with accumulation of toxic in termediaries and with disease entities termed porphyrias. The acute porphyr ins are characterized by attacks of neuropsychiatric symptoms, which may be due to a toxic surplus of the porphyrin presursor 5-aminolevulinic acid, o r a consequence of a deficit of vital hemeproteins resulting from impaired synthesis of haem. In the cutaneous porphyrias, impairment of enzymatic ste ps where porphyrins are processed gives rise to solar hypersensitivity due to accumulation of phototoxic porphyrins in the skin. Early diagnosis, information to the patient regarding the nature of the ill ness and counselling aimed at avoidance of triggering factors are cornersto nes in the handling of the porphyric diseases. Gene analysis is of incompar able diagnostic reliability in carrier detection, but biochemical methods m ust be applied in the important task of monitoring porphyric disease activi ty. In most forms of porphyria the gene carriers run the risk of developmen t of associated diseases in liver or kidneys, a circumstance that prompts a pplication of well-structured surveillance programs.