title: Differential localization and potency of manganese porphyrin superoxide dismutase-mimicking compounds in Saccharomyces cerevisiae.
abstract: Cationic Mn(III) porphyrin complexes based on MnTM-2-PyP are among the most promising superoxide dismutase (SOD) mimicking compounds being considered as potential anti-inflammatory drugs. We studied four of these active compounds in the yeast Saccharomyces cerevisiae, MnTM-2-PyP, MnTE-2-PyP, MnTnHex-2-PyP, and MnTnBu-2-PyP, each of which differs only in the length of its alkyl substituents. Each was active in improving the aerobic growth of yeast lacking SOD (sod1∆) in complete medium, and the efficacy of each mimic was correlated with its characteristic catalytic activity. We also studied the partitioning of these compounds between mitochondria and cytosol and found that the more hydrophobic members of the series accumulated in the mitochondria. Moreover, the degree to which a mimic mitigated the sod1Δ auxotrophic phenotype for lysine relative to its auxotrophic phenotype for methionine depended upon its level of lipophilicity-dependent accumulation inside the mitochondria. We conclude that localization within the cell is an important factor in biological efficacy in addition to the degree of catalytic activity, and we discuss possible explanations for this effect.
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, 607 Charles E Young Drive East, Los Angeles, CA 90095-1569, USA.
authors.forename: Alice Ma
authors.initials: AM
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, 607 Charles E Young Drive East, Los Angeles, CA 90095-1569, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Martins
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, NC 27710, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, 607 Charles E Young Drive East, Los Angeles, CA 90095-1569, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Valentine
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, NC 27710, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: Department of Medicine and PK/PD Shared Resource of Duke Cancer Institute, Duke University Medical Center, NC 27710, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Department of Chemistry and Biochemistry, UCLA, 607 Charles E Young Drive East, Los Angeles, CA 90095-1569, USA. Electronic address: egralla@chem.ucla.edu.
authors.forename: Edith B
authors.initials: EB
authors.lastname: Gralla
mesh_terms: D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018716:Molecular Mimicry; D010084:Oxidation-Reduction; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D008665:Metalloporphyrins; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; C520507:manganese tetrakis-(N-methyl-2 pyridyl) porphyrin; D013482:Superoxide Dismutase
keywords: Lysine synthesis; Methionine synthesis; Mitochondria; Mn(III) N-alkylpyridylporphyrin; Oxidative stress; SOD mimic