| 1991
McCoy Award Recipient
William J. Ray, Jr.
Professor of Biological
Sciences
Chemical catalysis
The recipient
of the Herbert Newby McCoy
Award for 1991 is William
J. Ray, Jr., Professor
of Biological Sciences.
William Ray is a biochemist
whose early interest was
in chemical catalysis.
After obtaining a Ph.D.
degree in organic chemistry
in 1957 at Purdue University,
he did postdoctoral work
at the Brookhaven National
Laboratory. After two years
as an assistant professor
at Rockefeller University,
he joined the faculty of
the Biological Sciences
Department at Purdue, where
he won successive National
Institutes of Health Career
Development Awards. In
1988 he served as co-chair
for the Gordon Conference
on Enzymes, Coenzymes and
Metabolic Pathways. Professor
Ray is married and has
two children and two grandsons.
He spends part of his leisure
time camping and in ecological
management at home with
his wife. He also regularly
plays squash and has won
the Purdue Squash Club
title on several occasions.
Abstract of Talk
Life is a continual trade-off between stability and instability. Without stability there would be no lasting structure.
Without instability there would be no immediate response to stimuli. The chemical instability that characterizes living
systems and that drives growth, adaptation, and reproduction involves a host of chemical reactions that, from an energetic
stand- point, are "downhill." Such reactions would proceed in the absence of catalysts, but would proceed slowly and in a
haphazard manner. But living systems utilize catalysts, many of which can be regulated, to facilitate arrays of downhill
reactions, selected according to need. These catalysts are specialized proteins called enzymes. The reactions they
facilitate involve the making and breaking of chemical bonds that convert one metabolite into another. This talk will
focus on one such catalyst; what we know about its structure, how it facilitates the bond making/breaking that
interconverts two specific metabolites, and how it fits into the general biochemical scheme. The enzyme is
phosphoglucomutase. It is a ubiquitous enzyme, and likely is present in all living systems. It is involved with the
metabolism of glucose, where it functions to interconvert glucose 1-phosphate and glucose 6-phosphate so that regulation of
those enzymes involved with the subsequent degradation of glucose 6-phosphate or the storage of glucose 1-phosphate can be
used to control the relative importance of immediately-usable versus stored energy. While catalysis by some enzymes is
relatively nonspecific, catalysis by phosphoglucomutase is exquisitely selective and amazingly efficient. Thus, the enzyme
is able to convert a molecule of glucose 1-phosphate to glucose 6-phosphate even in the presence of other sugar phosphates
at a ratio of 1:50,000, without disturbing the surrounding population, and it accomplishes with 0.001 sec what would require
hundreds of years in the absence of a catalyst. While most enzymes simply accelerate the normal solution process of bond
breaking/making, phosphoglucomutase appears to utilize a reaction mechanism that never occurs in the absence of the enzyme.
The three dimensional structure of phosphoglucomutase also is unusual. Together, these observations suggest an intriguing
scenario for its evolutionary development that will be considered in this talk.
Research
William J. Ray studied the mechanism of the butyl lithium catalyzed rearrangement of methyldiaryl sulfones during his
graduate work at Purdue. His study of enzymes began during his postdoctoral training with the development of a procedure
for analyzing the results obtained during chemical modification of enzymes. His "all-or none", which was part of that
procedure, was among the first of the many stoichiometric assays that now are used to distinguish between completely active
and partially active enzymes. During this time, when almost nothing was known about structure/function relationships in
enzymes, Ray began working with phosphoglucomutase. Rather than specialize in the application of a single technique to the
study of various enzymes to which that technique is suited, Ray's interest has been in the application of a variety of
techniques to phosphoglucomutase - techniques selected for their ability to illuminate specific aspects of its
structure-function relationship. However, early on he collaborated in the first study demonstrating that the identity of
the aminoacyl-RNA was the critical factor in determining where an amino acid was incorporated into the polypeptide chain of
a protein. Ray's initial studies with phosphoglucomutase defined the reaction pathway of the enzyme and were the first to
define the order of substrate-metal ion binding in a metal-ion activated enzymic reaction. He then assessed the
thermodynamic stability of the active-site phosphate group and was the first to obtain a nuclear magnetic resonance
spectrum of such a group in an enzyme. He subsequently studied the structural change that metal ion-binding produces in the
enzyme during the activation step, and obtained the first electron paramagnetic resonance spectrum of a protein containing
bound Mn. His use of the electronic spectrum ofbound Ni2+ and Co2+ bound to specify the coordination geometry of a metal
ion-activated enzyme also represented a first. He later employed nuclear magnetic resonance techniques to show that the
bound metal ion interacts directly with the enzymic phosphate group in the resting enzyme and that the phosphate group was
dianionic. Recently he showed that this phosphate-metal ion interaction is maintained in the enzyme-substrate complex, and
increases markedly in the transition state. Ray also was among the first to measure the internal equilibria involving
substrate/intermediate/product complexes in an enzymic system and to provide evidence that the structure of the enzyme
changes during catalysis. His treatment of the quantitative relationship between the rate-limiting step in an enzymic
reaction and the isotopic sensitivity of that step provided a general and definitive quantitative description of rate
limitations in multi-step enzymic reactions. By taking advantage of the metal ion-binding properties of phosphoglucomutase,
Ray devised the only currently available assay with sufficient sensitivity to measure the blood-plasma concentration of
free Zn2+, an essential metal ion. After devising a procedure to isolate gram quantities of the enzyme, he determined its
amino acid sequence, crystallized it, and studied aspects of the crystal growth process. He then began an ongoing X-ray
crystallographic study of the enzyme that has produced an intermediate-resolution atomic model. Recent work has involved
enzyme chemistry in the crystal phase. This has led to the development of systematic procedures that hold promise for
improving the informational content of protein crystals. Another current project represents the first use of Raman
spectroscopy to study chemical bonding within an enzymic phosphate group in the ground-state and in the transition state
for the catalytic process. In the course of his research, Ray worked with Seymour Benzer; Jeffrey T. Bolin; Robert
Callender; Mark A. Hermodson; Daniel F.. Koshland, Jr.; John L. Markley; Albert S. Mildvan; Carol B. Post; George H. Reed;
Michael G. Rossmann; and William E. Truce. Because of his many significant contributions to modern enzymology, Purdue
University awarded Professor Ray the Herbert Newby McCoy Award in 1991.
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