ABSTRACT
Heme biosynthesis takes place in all cells of the human body except erythrocytes (Ponka 1999). The first step takes place inside the mitochondria. ALA is formed by ALA synthase-catalyzed condensation of succinyl-coenzyme A and glycine (Figure 23.1). Two ALA molecules are transported into the cytosol and condensed into porphobilinogen (PBG) by ALA dehydratase. Four PBGs are then joined by PBG deaminase into a single molecule, hydroxymethylbilane, which then undergoes dehydratation by uroporphyrinogen III synthase to form uroporphyrinogen III. In the next step, uroporphyrinogen III decarboxylase transforms it into coproporphyrinogen III. Coproporphyrinogen III is transported back into the mitochondria, where it undergoes decarboxylation by coproporphyrinogen oxidase and forms protoporphyrinogen IX. Another oxidation process, catalyzed by protoporphyrinogen oxidase, leads to the creation of PpIX. The last step of heme biosynthesis is the incorporation of iron into PpIX by the enzyme ferrochelatase and the creation of heme. Both the first and the last steps of heme biosynthesis are rate-limiting steps. The amount of available ALA synthase is tightly regulated according to the amount of heme present in the cells by a negative-feedback control system. A high concentration of heme blocks both ALA synthase transcription and translation. On the other hand, the concentration of heme is dependent on the availability of iron in the cell. This regulation prevents accumulation of any of the intermediate products in concentrations high enough for photosensitization. Addition of
23.1 The Early History of 5-Aminolevulinic Acid-Photodynamic Therapy ....................... 267 23.2 Heme Biosynthesis ................................................................................................................. 267 23.3 Selective PpIX Formation in Neoplastic Tissues ............................................................... 268
Photoactivation of PpIX 23.4 Weak Points of ALA-PDT ..................................................................................................... 269
Shallow Penetration Depth • Pain and Erythema 23.5 ALA and Its Derivative-Based PDT and PDD ....................................................................271 References ............................................................................................................................................ 272
exogenous ALA bypasses this feedback control and, with limited amounts of iron, allows for accumulation of PpIX in phototoxic concentrations.
