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Resonance Raman Spectroscopy Reveals That Substrate Structure Selectively Impacts the Heme-Bound Diatomic Ligands of CYP17
An important function of steroidogenic
cytochromes P450 is the
transformation of cholesterol to produce androgens, estrogens, and
the corticosteroids. The activities of cytochrome P450c17 (CYP17)
are essential in sex hormone biosynthesis, with severe developmental
defects being a consequence of deficiency or mutations. The first
reaction catalyzed by this multifunctional P450 is the 17α-hydroxylation
of pregnenolone (PREG) to 17α-hydroxypregnenolone (17-OH PREG)
and progesterone (PROG) to 17α-hydroxyprogesterone (17-OH PROG).
The hydroxylated products then either are used for production of corticoids
or undergo a second CYP17 catalyzed transformation, representing the
first committed step of androgen formation. While the hydroxylation
reactions are catalyzed by the well-known Compound I intermediate,
the lyase reaction is believed to involve nucleophilic attack of the
earlier peroxo- intermediate on the C20-carbonyl. Herein, resonance
Raman (rR) spectroscopy reveals that substrate structure does not
impact heme structure for this set of physiologically important substrates.
On the other hand, rR spectra obtained here for the ferrous CO adducts
with these four substrates show that substrates do interact differently
with the Fe-C-O fragment, with large differences between the spectra
obtained for the samples containing 17-OH PROG and 17-OH PREG, the
latter providing evidence for the presence of two Fe-C-O conformers.
Collectively, these results demonstrate that individual substrates
can differentially impact the disposition of a heme-bound ligand,
including dioxygen, altering the reactivity patterns in such a way
as to promote preferred chemical conversions, thereby avoiding the
profound functional consequences of unwanted side reactions