Optimized Substrate Positioning Enables Switches in the C–H Cleavage Site and Reaction Outcome in the Hydroxylation–Epoxidation Sequence Catalyzed by Hyoscyamine 6β-Hydroxylase

Wenger, Eliott S.; Martinie, Ryan J.; Ushimaru, Richiro; Pollock, Christopher J.; Sil, Debangsu; Li, Aaron; Hoang, Nhi; Palowitch, Gavin M.; Graham, Brandt P.; Schaperdoth, Irene; Burke, Evan J.; Maggiolo, Ailiena O.; Chang, Wei-chen; Allen, Benjamin D.; Krebs, Carsten; Silakov, Alexey; Boal, Amie K.; Bollinger, Jr., J. Martin

doi:10.1021/jacs.4c04406

Optimized Substrate Positioning Enables Switches in the C–H Cleavage Site and Reaction Outcome in the Hydroxylation–Epoxidation Sequence Catalyzed by Hyoscyamine 6β-Hydroxylase

Journal Article · Thu Aug 22 00:00:00 EDT 2024 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.4c04406· OSTI ID:2440967

^[1]; ^[2]; ^[3]; ^[4]; ^[5]; Li, Aaron ^[6]; Hoang, Nhi ^[7]; Palowitch, Gavin M. ^[8]; Graham, Brandt P. ^[9]; ^[10]; ^[9]; Maggiolo, Ailiena O. ^[11]; ^[12]; Allen, Benjamin D. ^[13]; ^[9]; Silakov, Alexey ^[9]; ^[9]; ^[9]

Pennsylvania State Univ., University Park, PA (United States); SLAC
Pennsylvania State Univ., University Park, PA (United States); Hamilton College, Clinton, NY (United States)
Univ. of Tokyo (Japan)
Pennsylvania State Univ., University Park, PA (United States); Cornell Univ., Ithaca, NY (United States). Wilson Laboratory
Pennsylvania State Univ., University Park, PA (United States); Indian Institute of Science Education & Research, Pune (India)
Pennsylvania State Univ., University Park, PA (United States); Spark Therapeutics, Philadelphia, PA (United States)
Pennsylvania State Univ., University Park, PA (United States); Pfizer, Pearl River, NY (United States)
Pennsylvania State Univ., University Park, PA (United States); BioNTech US, Cambridge, MA (United States)
Pennsylvania State Univ., University Park, PA (United States)
Pennsylvania State Univ., University Park, PA (United States); Dartmouth College, Hanover, NH (United States)
Pennsylvania State Univ., University Park, PA (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Pennsylvania State Univ., University Park, PA (United States); Univ. of Tokyo (Japan); North Carolina State University, Raleigh, NC (United States)
Pennsylvania State Univ., University Park, PA (United States); Tandem Repeat Technologies, Inc., Lowell, MA (United States)

Hyoscyamine 6β-hydroxylase (H6H) is an Fe(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase that catalyzes the last two steps in the biosynthesis of scopolamine, a prolifically administered anti-nausea drug. After its namesake first reaction, H6H couples the newly installed C6-bonded oxygen to C7 to form the epoxide of scopolamine. Oxoiron(IV) (ferryl) intermediates initiate both reactions by cleaving C–H bonds, but it remains unclear how the enzyme switches target site and promotes (C6)O–C7 coupling in preference to C7 hydroxylation in the second step. In one possible epoxidation mechanism, the C6 oxygen would – analogously to mechanisms proposed for the Fe/2OG halogenases and, in the preceding paper, N-acetylnorloline synthase (LolO) – coordinate as alkoxide to the C7–H-cleaving ferryl intermediate to enable alkoxyl coupling to the ensuing C7 radical. Here we provide structural and kinetic evidence that H6H instead exploits the distinct spatial dependencies of competitive C–H-cleavage (C6 vs C7) and C–O-coupling (oxygen rebound vs cyclization) steps to promote the two-step sequence without substrate coordination or repositioning for the epoxidation step. Structural comparisons of ferryl-mimicking vanadyl complexes of wild-type H6H and a variant that preferentially hydroxylates C7 of 6-hydroxyhyoscyamine suggest that only a modest (~ 10°) shift in the Fe–O–H(C7) approach angle is sufficient to change the outcome. Finally, the observation that, in wild-type H6H, ²H₂O solvent also increases the C7-hydroxylation:epoxidation ratio by ~ 8-fold implies that the latter outcome requires cleavage of the alcohol O-H bond, which, unlike in the LolO oxacyclization, is not accomplished in advance of C–H cleavage.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-76SF00515; AC02-06CH11357

OSTI ID:: 2440967

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 35 Vol. 146; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Optimized Substrate Positioning Enables Switches in the C–H Cleavage Site and Reaction Outcome in the Hydroxylation–Epoxidation Sequence Catalyzed by Hyoscyamine 6β-Hydroxylase

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