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

Goudarzi, Serra; Babicz, Jeffrey T.; Kabil, Omer; Banerjee, Ruma; Solomon, Edward I.

doi:10.1021/jacs.8b09022

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

Journal Article · Tue Oct 16 00:00:00 EDT 2018 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.8b09022· OSTI ID:1490961

Goudarzi, Serra ^[1]; Babicz, Jeffrey T. ^[1]; Kabil, Omer ^[2];

^[2];

^[3]

Stanford Univ., Stanford, CA (United States)
Univ. of Michigan, Ann Arbor, MI (United States)
Stanford Univ., Stanford, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)

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 which is similar to that of cysteine dioxygenase (CDO), but with monodentate (vs bidentate) 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 analogues for the invoked ferric superoxide intermediate. New spectral features from persulfide binding to the Fe^III include the appearance of a low-energy Fe^III ligand field transition, an energy shift of a NO– to Fe^III CT transition, and two new GSS– to Fe^III 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. Furthermore, 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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Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515; HL58984; GM 11245; GM 40392

OSTI ID:: 1490961

Journal Information:: Journal of the American Chemical Society, Vol. 140, Issue 44; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 12 works

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