How Do Enzymes Really Work?

Abstract

M y understanding is that "reflections" can cover a multitude of sins. I have previously written a brief history of my career and do not want to duplicate that exposition (1). Instead, this "reflection" will trace a primary focus of my laboratory for many decades, namely how enzymes achieve their remarkable catalytic efficiency. (Indeed, this has been a focal point of the field of biochemistry for a much longer period.) This discussion will include personal interjections that trace my progress from undergraduate years to the present, as well as describe some of the other areas pursued in my research program. The answer to the question posed in molecular terms has been elusive, even though it has been a central theme of many research programs, including my own. A complete review of this subject is far beyond the scope of this article. Instead, I will review this subject as reflected in my personal interests and research program, although some historical perspective is included. I apologize in advance for not including all of the many noteworthy people and references that have significantly advanced the understanding of enzyme catalysis.My entry into the field of enzymology as an independent investigator occurred in 1960 when I was hired as an instructor at the Massachusetts Institute of Technology (MIT). My background included a graduate degree in Physical Chemistry from the University of Wisconsin, where I did my graduate work in the laboratory of Robert Alberty, a wonderful mentor as well as a leading figure in the field of steady-state enzyme kinetics. This was followed by a postdoctoral year in Göttingen in the laboratory of Manfred Eigen, who developed the field of relaxation methods and received the Nobel Prize in 1967. These methods revolutionized the field of solution kinetics, and I was very fortunate to have the opportunity to work closely with him.At this juncture, the importance of kismet should be noted. My choice of the University of Wisconsin for graduate school was not based on a careful analysis of graduate schools. It was a knee jerk reaction to my undergraduate years at Princeton University. Princeton provided a great education, but it was a social desert with no women coeds in the area and cars banned for students. This was especially difficult for a student coming from a high school in a small town in Wisconsin. After my Princeton experience, I wanted to return to the warmth (not referring to temperature) of the Midwest. My selection of a research supervisor was based on a single conversation with Robert Alberty after I arrived at graduate school. My choice of postdoctoral study was based on a seminar I heard Manfred Eigen give at the University of Wisconsin; he was relatively unknown at that time, but I found the work very exciting. Perhaps today's students are worried too much about these decisions and their importance. My faculty position at MIT was also very fortunate. Walter Stockmayer, a senior professor at MIT and a brilliant scientist, visited Eigen's laboratory, and I had lunch with ...

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