In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121

Nguyen, Romie C.; Davis, Ian; Dasgupta, Medhanjali; Wang, Yifan; Simon, Philipp S.; Butryn, Agata; Makita, Hiroki; Bogacz, Isabel; Dornevil, Kednerlin; Aller, Pierre; Bhowmick, Asmit; Chatterjee, Ruchira; Kim, In-Sik; Zhou, Tiankun; Mendez, Derek; Paley, Daniel W.; Fuller, Franklin; Mori, Roberto Alonso; Batyuk, Alexander; Sauter, Nicholas K.; Brewster, Aaron S.; Orville, Allen M.; Yachandra, Vittal K.; Yano, Junko; Kern, Jan F.; Liu, Aimin

doi:10.1021/jacs.3c04991

Title: In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121

Journal Article · 08 November 2023 · Journal of the American Chemical Society

DOI: https://doi.org/10.1021/jacs.3c04991 · OSTI ID:2328672

Nguyen, Romie C. ^[1];

^[1]; Dasgupta, Medhanjali ^[2]; Wang, Yifan ^[1];

^[2];

^[3]; Makita, Hiroki ^[2];

^[2]; Dornevil, Kednerlin ^[1];

^[3];

^[2]; Chatterjee, Ruchira ^[2]; Kim, In-Sik ^[2]; Zhou, Tiankun ^[3]; Mendez, Derek ^[2]; Paley, Daniel W. ^[2]; Fuller, Franklin ^[4];

^[4];

^[2] more »

Univ. of Texas at San Antonio, TX (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Harwell Science and Innovation Campus, Didcot (United Kingdom); Science and Technology Facilities Council (STFC), Oxford (United Kingdom). Rutherford Appleton Lab. (RAL)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

The P450 enzyme CYP121 from Mycobacterium tuberculosis catalyzes a carbon–carbon (C–C) bond coupling cyclization of the dityrosine substrate containing a diketopiperazine ring, cyclo(l-tyrosine-l-tyrosine) (cYY). An unusual high-spin (S = 5/2) ferric intermediate maximizes its population in less than 5 ms in the rapid freeze-quenching study of CYP121 during the shunt reaction with peracetic acid or hydrogen peroxide in acetic acid solution. Here, we show that this intermediate can also be observed in the crystalline state by EPR spectroscopy. By developing an on-demand-rapid-mixing method for time-resolved serial femtosecond crystallography with X-ray free-electron laser (tr-SFX-XFEL) technology covering the millisecond time domain and without freezing, we structurally monitored the reaction in situ at room temperature. After a 200 ms peracetic acid reaction with the cocrystallized enzyme–substrate microcrystal slurry, a ferric-hydroperoxo intermediate is observed, and its structure is determined at 1.85 Å resolution. The structure shows a hydroperoxyl ligand between the heme and the native substrate, cYY. The oxygen atoms of the hydroperoxo are 2.5 and 3.2 Å from the iron ion. The end-on binding ligand adopts a near-side-on geometry and is weakly associated with the iron ion, causing the unusual high-spin state. This compound 0 intermediate, spectroscopically and structurally observed during the catalytic shunt pathway, reveals a unique binding mode that deviates from the end-on compound 0 intermediates in other heme enzymes. The hydroperoxyl ligand is only 2.9 Å from the bound cYY, suggesting an active oxidant role of the intermediate for direct substrate oxidation in the nonhydroxylation C–C bond coupling chemistry.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB); National Institutes of Health (NIH); The Welch Foundation; Biotechnology and Biological Sciences Research Council (BBSRC)

Grant/Contract Number:: AC02-76SF00515; AC02-05CH11231; AX-2110-20220331; BB/V001892/1; S10 OD023453; GM108988; GM117126; GM55302; GM149528; GM110501; GM126289; 1P41GM139687

OSTI ID:: 2328672

Journal Information:: Journal of the American Chemical Society, Vol. 145, Issue 46; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP12 Nguyen, Romie Coherent X-ray Imaging Data Bank (Lawrence Berkeley National Laboratory); LBNL https://doi.org/10.11577/2204603	dataset	January 2023

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Title: In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121

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