Multienzyme Complexes and Hydrogen Transfer: the Work of Perry Frey

Quaternary Structure of Pyruvate Dehydrogenase Complex from Esherichia coli(Yang, H. C., Hainfeld, J. F., Wall, J. S., and Frey, P. A. (1985) J. Biol. Chem. 260, 16049–16051)Lysine 2,3-Aminomutase. Support for a Mechanism of Hydrogen Transfer Involving S-Adenosylmethionine(Baraniak, J., Moss, M. L., and Frey, P. A. (1989) J. Biol. Chem. 264, 1357–1360)Perry A. Frey was born in 1935 in Plain City, Ohio, a small town about 18 miles northwest of Columbus. Prior to attending college he served in the military for 2 years. He then enrolled at Ohio State University where he received his B.S. in chemistry in 1959. After graduating, Frey worked for the United States Public Health Service as an analytical chemist, studying the properties of saxitoxin, a paralytic shellfish poison. He also attended night classes in chemistry at the University of Cincinnati.Open in a separate windowPerry FreyIn 1964, based on the recommendation of a mentor at the Public Health Service, Frey decided to go to graduate school at the University of Michigan to work with Robert H. Abeles. After a short time, Abeles moved his laboratory to Brandeis University and Frey went with him. Frey spent 3 years studying catalysis by cobalamin-dependent enzymes and earned his Ph.D in biochemistry in 1968. He then began a postdoctoral fellowship at Harvard University with enzymologist Frank H. Westheimer.In 1969, Frey accepted an offer to join the chemistry department at Ohio State University. He remained there for several years, rising through the ranks to eventually become Professor of Biochemistry and Academic Vice Chair of Chemistry. During his time at Ohio State, Frey started investigating the mechanism of enzyme and coenzyme action in several molecules, including UDP-galactose 4-epimerase, pyruvate dehydrogenase, galactose-1-phosphate uridylyltransferase, UDP-glucose pyrophosphorylase, and adenylate kinase.In 1981, Frey left Ohio State to join the faculty of the Institute for Enzyme Research at the University of Wisconsin, Madison. There he continued to study enzyme mechanisms but also expanded his research to include the structure and function of multienzyme complexes. In the first Journal of Biological Chemistry (JBC) Classic reprinted here, Frey reports the results of his quaternary structural analysis of the pyruvate dehydrogenase complex from Escherichia coli. Using scanning transmission electron microscopy and radial mass analysis, Frey and his colleagues were able to confirm a model in which six dihydrolipoyl dehydrogenase (E₃) dimers are integrated into the six faces of a cubic dihydrolipoyl transacetylase (E₂) core and 12 pyruvate dehydrogenase (E₁) dimers are associated along the 12 edges of the core enzyme.Frey also began to work on lysine 2,3-aminomutase, the enzyme that catalyzed the conversion of l-lysine to l-β-lysine. The reaction involved the interchange of the 2-amino group of lysine with a hydrogen at carbon 3 to form β-lysine and was analogous to adenosylcobalamin-dependent rearrangements in which hydrogen transfer is mediated by the adenosyl moiety of the coenzyme. However, lysine 2,3-aminomutase did not appear to contain adenosylcobalamin, and it wasn''t activated by the coenzyme. To explain this phenomenon, Frey suggested that S-adenosylmethionine was involved in the hydrogen transfer reaction and proposed a mechanism in which the adenosyl-C-5′ moiety of S-adenosylmethionine functioned in the same way as the adenosyl group of adenosylcobalamin in facilitating hydrogen transfer and generating an intermediate free radical that could undergo the amino group migration (1).In the second JBC Classic reprinted here, Frey and his colleagues further tested his proposed mechanism and, by carrying out the lysine 2,3-aminomutase reaction with S-[5′-³H]adenosylmethionine, showed that both hydrogens at adenosyl-C-5′ participate in the hydrogen transfer process. Mass spectral analysis of the β-lysine for monodeutero and dideutero species also demonstrated that the hydrogen transfer is both intramolecular and intermolecular. The results of this paper confirmed that the activation of lysine 2,3-aminomutase involved a transformation of S-adenosylmethionine into a form that promotes the generation of a 5′-adenosyl free radical which abstracts hydrogen from lysine to form 5′-deoxyadenosine as an intermediate.Frey retired in 2008 and is currently an emeritus professor in the biochemistry department at the University of Wisconsin, Madison. In recognition of his contributions to science, he has received many honors and awards including the Alexander von Humboldt Senior Scientist Award (1995), the American Chemical Society Division of Biological Chemistry''s Repligen Award (2000), and the Hilldale Award (2007). Frey is a fellow of the American Association for the Advancement of Science (2003) and the American Academy of Arts and Sciences (2003) and was elected to the National Academy of Sciences (1998). He also served on the editorial board for the Journal Biological Chemistry from 1983 to 1988.