Cytochrome P450The Wonderful Nanomachine Revealed
through Dynamic Simulations of the Catalytic Cycle
Version 2 2019-01-11, 18:22
Version 1 2019-01-11, 18:20
Posted on 2019-01-11 - 18:22
ConspectusThis Account addresses the catalytic cycle of the enzyme cytochrome
P450 (CYP450) as a prototypical biological machine with automatic
features. CYP450 is a nanomachine that uses dioxygen and two reducing
and two proton equivalents to oxidize a plethora of molecules (so-called
substrates) as a means of supplying bio-organisms with essential molecules
(e.g., brain neurotransmitters, sex hormones, etc.) and protecting
biosystems against poisoning. An enticing property of CYP450s is that
entrance of an oxidizable substrate into the active site initiates
a series of events that constitute the catalytic cycle, which functions
“automatically” in a regulated sequence of events culminating
in the production of the oxidized substrates (e.g., hydroxylated,
epoxidized, etc.), oftentimes with remarkable stereo- and regioselectivities.
It is timely to demonstrate how theory uses molecular dynamics (MD)
simulations and quantum-mechanical/molecular-mechanical (QM/MM) calculations
to complement experiments and elucidate the choreography by which
the protein regulates the catalytic cycle.CYP450 is a heme
enzyme that contains a ferric ion (FeIII) coordinated by
a porphyrin ligand, a water molecule, and a cysteinate
ligand that is provided by a strategic residue of the encapsulating
protein. While many of the individual steps are sufficiently well-understood,
we shall provide here an overview of the factors that cause all of
the steps to be sequentially coordinated. To this end, we use examples
from three different CYP450 enzymes: the bacterial ones CYP450BM3 and CYP450CAM and the mammalian enzyme CYP4503A4. The treatment is limited to the catalytic cycle, as aspects
of two-state reactivity were reviewed previously (e.g., Shaik, S.; et al. Chem. Rev. 2005, 105, 2279).What are the principles
that govern the seeming automatic feature?
For example, how do substrate entrance and binding gate the enzyme?
How does the reductase attachment to the enzyme affect the next steps?
What triggers the attachment of the reductase? How does the electron
transfer (ET) that converts FeIII to FeII occur?
Is the ET coordinated with the entrance of O2 into the
active site? What is the mechanism of the latter step? Since the entrance
of the substrate expels the water molecules from the active site,
how do water molecules re-enter to form a proton channel, which is
necessary for creating the ultimate oxidant Compound I? How do mutations
that disrupt the water channel nevertheless create a competent oxidant?
By what means does the enzyme produce regio- and stereoselective oxidation
products? What triggers the departure of the oxidized product, and
how does the exit occur in a manner that generates the resting state
ready for the next cycle? This Account shows that the entrance of
the substrate triggers all of the ensuing events.
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Dubey, Kshatresh Dutta; Shaik, Sason (2019). Cytochrome P450The Wonderful Nanomachine Revealed
through Dynamic Simulations of the Catalytic Cycle. ACS Publications. Collection. https://doi.org/10.1021/acs.accounts.8b00467
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