Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of delta-aminolevulinic acid (ALA), as it occurs in acute intermittent porphyria (AIP), is the origin of an endogenous source of reactive oxygen species (ROS), which can exert oxidative damage to cell structures. In the present work we examined the ability of different antioxidants to revert ALA-promoted damage, by incubating mouse astrocytes with 1.0 mM ALA for different times (1-4 hr) in the presence of melatonin (2.5 mM), superoxide dismutase (25 units/mL), catalase (200 units/mL) or glutathione (0.5 mM). The defined relative index [(malondialdehyde levels/accumulated ALA) x 100], decreases with incubation time, reaching values of 76% for melatonin and showing that the different antioxidants tested can protect astrocytes against ALA-promoted lipid peroxidation. Concerning porphyrin biosynthesis, no effect was observed with catalase and superoxide dismutase whereas increases of 57 and 87% were obtained with glutathione and melatonin, respectively, indicating that these antioxidants may prevent the oxidation of porphobilinogen deaminase, reactivating so that the AIP genetically reduced enzyme. Here we showed that ALA induces cell death displaying a pattern of necrosis. This pattern was revealed by loss of cell membrane integrity, marked nuclear swelling and double labeling with annexin V and propidium iodide. In addition, no caspase 3-like activity was detected. These findings provide the first experimental evidence of the involvement of ALA-promoted ROS in the damage of proteins related to porphyrin biosynthesis and the induction of necrotic cell death in astrocytes. Interestingly, melatonin decreases the number of enlarged nuclei and shows a protective effect on cellular morphology.
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PMID:Necrotic cell death induced by delta-aminolevulinic acid in mouse astrocytes. Protective role of melatonin and other antioxidants. 1282 7

Synthesis of protoporphyrin IX (PpIX) by malignant cells is essential for the success of ALA-based photodynamic therapy (PDT). Two key enzymes that were described as affecting PpIX accumulation during ALA treatment are porphobilinogen deaminase (PBGD) and ferrochelatase. Here, we show that down regulation of ALA dehydratase (ALAD) expression and activity by specific shRNA induced a marked decrease in PpIX synthesis in K562 erythroleukemic cells. Photo-inactivation efficacy following ALA-PDT was directly correlated with ALAD-silencing and cellular levels of PpIX. MTT metabolism following ALA-PDT was shown to be 60% higher in ALAD-silenced cells in comparison to control cells, indicating that mitochondria were protected in the silenced cells. Morphological analysis by scanning electron microscopy (SEM) of cells treated by ALA-PDT showed no morphological changes in ALAD-silenced cells, in contrast to controls exhibiting cell deformations and lysis. Membrane integrity following ALA-PDT was kept intact and undamaged in ALAD-silenced cells as examined by Annexin V-FITC/PI staining and LDH-L leakage. We conclude that ALAD, although it is present in the cell at abundant levels, has a major and limiting role in regulating PpIX synthesis and ALA-PDT outcome.
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PMID:Silencing of ALA dehydratase affects ALA-photodynamic therapy efficacy in K562 erythroleukemic cells. 1978 17