Abstract: Disclosed herein, are 5-Aminolevulinate synthase inhibitors and methods for their use in the treatment of porphyria.

Abstract: Disclosed herein, are 5-Aminolevulinate synthase inhibitors and methods for their use in the treatment of porphyria. In at least one specific embodiment, the 5-Aminolevulinate synthase inhibitors can include compounds or salts thereof of Formulas (I-V).

Abstract: Provided herein, is a means for development of ferrochelatase variants with improved tolerance towards N-methyl protoporphyrin. Also disclosed are cell assay systems utilizing the variants, as the variants would confer resistance to N-methyl protoporphyrin inhibition and thereby keep heme synthesis uninterrupted. The variants contain loop mutations that affect the NMPP-ferrochelatase interaction, and different degrees of NMPP tolerance are obtained with the introduction of loop mutations in wild-type ferrochelatase. Also disclosed is kinetic mechanism of inhibition of ferrochelatase by NMPP, using the disclosed variants whose mutations in the “porphyrin-interacting loop” motif weakened the potency of NMPP as an inhibitor.

Abstract: Provided herein, is a means for development of ferrochelatase variants with improved tolerance towards N-methyl protoporphyrin. Also disclosed are cell assay systems utilizing the variants, as the variants would confer resistance to N-methyl protoporphyrin inhibition and thereby keep heme synthesis uninterrupted. The variants contain loop mutations that affect the NMPP-ferrochelatase interaction, and different degrees of NMPP tolerance are obtained with the introduction of loop mutations in wild-type ferrochelatase. Also disclosed is kinetic mechanism of inhibition of ferrochelatase by NMPP, using the disclosed variants whose mutations in the “porphyrin-interacting loop” motif weakened the potency of NMPP as an inhibitor.

Abstract: Provided herein, is a means for development of ferrochelatase variants with improved tolerance towards N-methyl protoporphyrin. Also disclosed are cell assay systems utilizing the variants, as the variants would confer resistance to N-methyl protoporphyrin inhibition and thereby keep heme synthesis uninterrupted. The variants contain loop mutations that affect the NMPP-ferrochelatase interaction, and different degrees of NMPP tolerance are obtained with the introduction of loop mutations in wild-type ferrochelatase. Also disclosed is kinetic mechanism of inhibition of ferrochelatase by NMPP, using the disclosed variants whose mutations in the “porphyrin-interacting loop” motif weakened the potency of NMPP as an inhibitor.

Abstract: The rate of porphyrin biosynthesis in mammals is controlled by the activity of the pyridoxal 5?-phosphate-dependent enzyme 5-aminolevulinate synthase. Assuming the turnover in this enzyme is controlled by conformational dynamics at a highly conserved active site loop, a variant library was constructed by targeting imperfectly conserved non-catalytic loop residues and the effects on product and porphyrin production were examined. Functional loop variants of the enzyme were tested for porphyrin fluorescence, which varied widely and thus facilitated identification of clones encoding unusually active enzyme variants. Nine loop variants leading to high in vivo porphyrin production were purified and characterized kinetically. Steady-state catalytic efficiencies for the two substrates were increased by up to one hundred-fold.

Abstract: Systems and methods for increasing protoporphyrin IX accumulation in a target cell population using aminolevulinate synthase variants. Aminolevulinic acid-mediated photodynamic therapy is a promising approach to treating dysplasic disorders such as cancer and atherosclerosis, but is limited by the lack of a means to deliver optimal quantities of aminolevulinic acid selectively to the target cells, and thereby ensure the best therapeutic response. The disclosed invention provides a means for enhancing the natural production of aminolevulinic acid selectively within target cells to levels predetermined to give an optimal therapeutic response, and is expected to lead to increased efficacy of treatment, possibly broadening the scope of diseases treatable by photodynamic therapy considerably. The disclosed invention is also amenable to patient specific therapy, meaning that a patient's target cells could be used to screen for the aminolevulinic acid delivery system most appropriate for the patient's needs.