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William J. Ray, Jr.
Professor of Biological Sciences
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.
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.
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.