Abstract
Ferrous myoglobin was oxidized by sulfur trioxide anion radical (STAR) during the free radical chain oxidation of sulfite. Oxidation was inhibited by the STAR scavenger GSH and by the heme ligand CO. Bimolecular rate constants for the reaction of STAR with several ferrous globins and biomolecules were determined by kinetic competition. Reaction rate constants for myoglobin, hemoglobin, neuroglobin, and flavohemoglobin are large at 38, 120, 2,600, and ≥ 7,500 × 10(6) m(-1) s(-1), respectively, and correlate with redox potentials. Measured rate constants for O2, GSH, ascorbate, and NAD(P)H are also large at ∼100, 10, 130, and 30 × 10(6) m(-1) s(-1), respectively, but nevertheless allow for favorable competition by globins and a capacity for STAR scavenging in vivo. Saccharomyces cerevisiae lacking sulfite oxidase and deleted of flavohemoglobin showed an O2-dependent growth impairment with nonfermentable substrates that was exacerbated by sulfide, a precursor to mitochondrial sulfite formation. Higher O2 exposures inactivated the superoxide-sensitive mitochondrial aconitase in cells, and hypoxia elicited both aconitase and NADP(+)-isocitrate dehydrogenase activity losses. Roles for STAR-derived peroxysulfate radical, superoxide radical, and sulfo-NAD(P) in the mechanism of STAR toxicity and flavohemoglobin protection in yeast are suggested.
Highlights
Sulfite, an intermediate in sulfur metabolism, can be oxidized to the potentially toxic sulfur trioxide anion radical (STAR)
GSH, a STAR scavenger [22], inhibited metMb formation catalyzed by Cu,ZnSOD (Fig. 1C)
Reaction rate constants ranged over nearly 3 orders of magnitude from 3.8 ϫ 107 MϪ1 sϪ1 for deoxyMb to a remarkable 2.1 ϫ 1010 MϪ1 sϪ1 for Ec flavoHb, a value exceeding that for 1⁄7NO dioxygenation by ϳ9-fold [47, 48]
Summary
An intermediate in sulfur metabolism, can be oxidized to the potentially toxic sulfur trioxide anion radical (STAR). Ferrous myoglobin was oxidized by sulfur trioxide anion radical (STAR) during the free radical chain oxidation of sulfite. Present address: Chemical Engineering Program, Ohio State University, W. Present address: Biology and Chemistry Program, Illinois College, 1101 W. The abbreviations used are: STAR, sulfur trioxide anion radical; Mb, myoglobin; GSH, glutathione; Cu,ZnSOD, copper and zinc-containing superoxide dismutase; MnSOD, manganese-containing superoxide dismutase; HbA, hemoglobin A; Ngb, neuroglobin; flavoHb, flavohemoglobin; IDH, isocitrate dehydrogenase; cyt c, cytochrome c; cyt b5, cytochrome b5; Sc, initiate a O2-consuming free radical chain reaction [5, 10, 12, 13]. We report that the reaction of STAR with ferrous globins is exceptionally rapid with STAR reacting 260- and ϳ1000-fold faster with Ngb and flavoHb, respectively, than with GSH, suggesting a STAR detoxification function. By studying STAR formation, STAR reactivities, and Saccharomyces cerevisiae flavoHb-deficient mutants, we identify targets and modes for STAR toxicity and sulfite stress that help define the STAR detoxification function
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