Cysteine Oxidation Reactions Catalyzed by a Mononuclear Non-heme Iron Enzyme (OvoA) in Ovothiol Biosynthesis

Song, Heng; Her, Ampon Sae; Raso, Fiona; Zhen, Zhi-Bin; Huo, Yuda; Liu, Pinghua

doi:10.1021/ol5005438

Cited by 47 publications

(88 citation statements)

References 44 publications

(109 reference statements)

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“…When fed an HID, both wild‐type and Slc7a11 –/– mice develop severe tissue iron overload, and serum transferrin binding approaches saturation (http://onlinelibrary.wiley.com/doi/10.1002/hep.29117/suppinfo), suggesting the presence of non‐transferrin‐bound iron in the circulation. Circulating non‐transferrin‐bound iron depletes GSH and oxidizes cysteine to form cysteine, which can then be imported into cells through the Slc7a11 transporter. Consistent with this process, we found increased levels of Slc7a11 mRNA in iron‐overloaded wild‐type mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of ferroptosis in murine models of hemochromatosis

et al. 2017

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Ferroptosis is a recently identified iron‐dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow–derived macrophages. Next, we screened for ferroptosis in mice fed a high‐iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high‐iron diet and in two knockout mouse lines that develop severe iron overload (Hjv–/– and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload (Hfe –/– mice). Moreover, we found that iron overload–induced liver damage was rescued by the ferroptosis inhibitor ferrostatin‐1. To identify the genes involved in iron‐induced ferroptosis, we performed microarray analyses of iron‐treated bone marrow–derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis‐related gene, was significantly up‐regulated in iron‐treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron‐treated hepatocytes and bone marrow–derived macrophages isolated from Slc7a11–/– mice fed a high‐iron diet. Conclusion: We found that iron treatment induced ferroptosis in Slc7a11–/– cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high‐iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11‐mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. (Hepatology 2017;66:449–465).

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Section: Discussionmentioning

confidence: 99%

Characterization of ferroptosis in murine models of hemochromatosis

et al. 2017

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“…4d). Hints of mechanistic similarities between EgtB/OvoA and CDO existed prior to the report of the crystal structure, such as the observation that OvoA incubated with hercynine (the normal substrate for EgtB oxidation) and cysteine produces primarily CSA, the product of CDO-type chemistry[97]. Thus it seems that the reactive oxygen species is poised to effect dioxygenation of sulfur in OvoA if the sulfur is not precisely oriented for addition to the imidazole ring.…”

Section: Sulfoxide-synthases: Egtb and Ovoamentioning

confidence: 99%

“…Thus it seems that the reactive oxygen species is poised to effect dioxygenation of sulfur in OvoA if the sulfur is not precisely oriented for addition to the imidazole ring. More careful reexamination revealed that, even when OvoA was incubated with its native substrates (L-Cys and L-His), approximately 10% of the cysteine is converted to CSA [97]. Very recently, the structural insights gleaned from the EgtB crystal structure were used to assess the importance of various active site residues [98].…”

Section: Sulfoxide-synthases: Egtb and Ovoamentioning

confidence: 99%

Go it alone: four-electron oxidations by mononuclear non-heme iron enzymes

Peck

Donk

2016

J Biol Inorg Chem

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“…These enzymes perform different reactions, including sulfur oxidation (IPNS) and sulfur oxygenation (CDO, ETHE1). 8–12 …”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Electronic Structure Study of ETHE1: Elucidating the Factors Influencing Sulfur Oxidation and Oxygenation in Mononuclear Nonheme Iron Enzymes

et al. 2018

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ETHE1 is a member of a growing subclass of nonheme Fe enzymes that catalyzes transformations of sulfur containing substrates without a cofactor. ETHE1 dioxygenates glutathione persulfide (GSSH) to glutathione (GSH) and sulfite in a reaction that is similar to that of cysteine dioxygenase (CDO), but with monodentate (vs. biden-tate) substrate coordination and a 2-His/1-Asp (vs. 3-His) ligand set. In this study, we demonstrate that GSS− binds directly to the iron active site causing coordination unsaturation to prime the site for O2 activation. Nitrosyl complexes without and with GSSH were generated and spectroscopically characterized as unreactive analogs for the invoked ferric superoxide intermediate. New spectral features from persulfide binding to the FeIII include the appearance of a low energy FeIII ligand field transition, an energy shift of a NO− to FeIII CT transition, and two new GSS− to FeIII CT transitions. Time-dependent density functional theory calculations were used to simulate the experimental spectra to determine the persulfide orientation. Correlation of these spectral features with those of monodentate cysteine binding in isopenicillin N synthase (IPNS) shows that the persulfide is a poorer donor, but still results in an equivalent frontier molecular orbital for reactivity. The ETHE1 persulfide dioxygenation reaction coordinate was calculated, and while the initial steps are similar to the reaction coordinate of CDO, an additional hydrolysis step is required in ETHE1 to break the S-S bond. Unlike ETHE1 and CDO, which both oxygenate sulfur, IPNS oxidizes sulfur through an initial H-atom abstraction. Thus, factors that determine oxygenase vs. oxidase reactivity were evaluated. In general, sulfur oxygenation is thermodynamically favored and has a lower barrier for reactivity. However, in IPNS, second sphere residues in the active site pocket constrain the substrate raising the barrier for sulfur oxygenation relative to oxidation via H-atom abstraction.

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Cysteine Oxidation Reactions Catalyzed by a Mononuclear Non-heme Iron Enzyme (OvoA) in Ovothiol Biosynthesis

Cited by 47 publications

References 44 publications

Characterization of ferroptosis in murine models of hemochromatosis

Characterization of ferroptosis in murine models of hemochromatosis

Go it alone: four-electron oxidations by mononuclear non-heme iron enzymes

Spectroscopic and Electronic Structure Study of ETHE1: Elucidating the Factors Influencing Sulfur Oxidation and Oxygenation in Mononuclear Nonheme Iron Enzymes

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