| Even five years
ago, very little was known about ODCase's structure, much
less its mechanism. Researchers knew its chemical makeup.
But they didn't know where individual groups of atoms were
in relation to one another, and they didn't know what sorts
of bonds held those atoms together. Prospecting experimental
chemists tinkered with capturing a snapshot of the structure
using X-ray crystallography. Theoretical chemists, meanwhile,
hypothesized about the enzyme's mechanism and devised ways
of calculating telltale indicators of what that mechanism
might be.
In 1997 Lee and Kendall Houk touted a theory of their own
in Science. Houk is a chemistry professor at University of
California at Los Angeles and a long-time Alliance user. Lee
worked as a postdoc in Houk's lab after completing her PhD
at Harvard University in 1994. They proposed that the ODCase
enzyme lends a proton to one of orotic acid's oxygen atoms.
This protonation causes decarboxylation, or the loss of carbon
dioxide molecules from the orotic acid. The loss puts the
molecule in a state that's more favorable for the transition
into uracil and thus speeds the reaction. As the change into
uracil takes place, the proton is sloughed and returns to
the enzyme.
The new millennium brought a gold-rush mentality to the ODCase
research community, after years in the desert instead of in
the money. Four different teams struck pay dirt in 2000 and
published their X-ray crystallographic structure data within
the year. With this fresh vein of data came a variety of new
theories on ODCase's mechanism, "some quite unusual and
all rather tentative," as Houk and Lee said in a 2001
article in ChemBioChem.
The data also called into question Lee and Houk's theory,
along with other protonation theories, because the structural
data showed no available protons near the oxygen. There are
ways of explaining away the lack of an unavailable proton,
according to Lee.
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