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MERTON FRANKLIN UTTER March23, 1917-November2S, 1980 BY HARLAND G. WOOD AND RICHARD W. HANSON THE MOST SIGNIFICANT CONTRIBUTION to biochem- istry made by Merton F. Utter was his demonstration that certain reactions of gluconeogenesis differ from those of gly- colysis. For many years it was widely helcl that the synthesis of glucose (gluconeogenesis) in mammalian liver occurs by reversal of the EmbJen-Meyerhof pathway by which glucose is converted to pyruvate and lactate (glycolysis). Merton Utter and his coworkers shower! that this concept is incorrect. They discovered phosphoenolpyruvate carboxykinase and pyru- vate carboxylase, two enzymes that in concert convert pyru- vate to phosphoenolpyruvate by a sequence that differs from the glycolytic pathway. This discovery opener! new vistas in the study of metab- olism, and over the past decade it has become evident that the two enzymes discovered by fitter anct coworkers are also important in the regulation of both carbohydrate and lipic} metabolism. Utter, together with Dr. Bruce Keech, clemon- strated that acetyI-CoA regulates the activity of pyruvate car- boxylase, thus providing one of the first examples of allo steric control of an enzyme. Furthermore, the rate-limiting step in gluconeogenesis is catalyzed by phosphoenolpyruvate carboxykinase, whose levels in mammalian liver and kiciney are regulated by insulin, glucagon, epinephrine, and gluco 475
476 BIOGRAPHICAL MEMOIRS corticoids. This enzyme has been extensively studied as a mode} for the action of these hormones on gene expression in mammalian tissues. Prior to his death, Utter's studies had increasingly centered on the interface between disease pro- cesses and basic biochemistry. His laboratory was considered one of the leading centers studying inborn errors in the me- tabolism of pyruvate, and his collaboration was constantly sought by clinical investigators anxious to verify the absence of specific enzymes in patients suffering from various cTis- eases. The scope of his science was broad. He stooct for pre- cise and excellent experiments, and his advice was sought on a wide variety of subjects. His was a keen intellect, but he was always moclest ant! friendly, and was possessed of a sharp wit. Merton Utter's interests extendect to all aspects of life: sci- ence, sports, politics, literature, ant! the arts. UTTER S BACKGROUND Merton Franklin Utter was born at Westboro, Missouri, on March 23, 1917. His parents were Merton Franklin Utter, Sr., anct Gertrude R. McMichae} Utter. His father and grand- parents, Mr. and Mrs. L. P. Utter, had moved to Missouri from Trempealeau, Wisconsin. His maternal grandparents were Mr. and Mrs. A. R. McMichae] of Coin, Iowa. Most of his ancestors came to New England anct New York from the British Isles in the seventeenth and early eighteenth centu- ries. When he was a few months old, Merton's parents moved to New Market, Iowa, where his father was a banker, and his early school years were spent there. His mother gave piano lessons and played piano and organ for churches most of her life. It was from her that Merton acquired a deep and lifelong love of music. In 1930, when Merton was in the eighth gracle, the family moved to Coin, Iowa. He gracluated from the high school there in 1934 and entered Simpson College at Inclianola,
MERTON FRANKLIN UTTER 477 Iowa. The cleath of his father in an auto accident in the sum- mer of ~ 935 interrupter! his college studies briefly, but he graduated from Simpson in 193S, supporting himself through scholarship aid and by managing the campus book- store. He was a fine athlete and excelled in track and basket- balI. At Simpson he clistinguishecl himself in the field of chemistry, and on the advice of his professor he enrolled in graduate school at Iowa State University at Ames. In 1942, with the sect of fellowships, he was able to complete the work for his Ph.D. degree, which he received in microbiology in the laboratory of Dr. C. H. Werkman. In that year he was appointee] an instructor in bacteriology. On September 2, 1939, while at Ames, he married Mar- jorie ManifoIcI, whom he had known since high school. Mem- bers of her family were also longtime residents of Coin and vicinity (Page County). In [944 the Utters moved to Minne- apolis, where he was assistant professor of physiological chemistry at the University of Minnesota, and in 1946 they mover! to ClevelancI, Ohio, where he was appointed associate professor of biochemistry at Western Reserve University School of Medicine. A son, Douglas Max Utter, was born on December 8, 1950. In 1956 Merton Utter was promoted to professor, and in 1965 he became chairman of the Biochem- istry Department ant] continued in that position until 1976. Thereafter he clevoted his full time to research and teaching in the Department of Biochemistry. He and his family spent three years abroad on leave of absence from Case Western Reserve University. In 1953, he traveled with his family to Aclelaicle, Australia, where he was a Fulbright Fellow at the University of South Australia. In 1960 he served as visiting professor at Oxford University in Englanc! and in 1968 at the University of Leicester. Recently, Sir Hans Kornberg reflected on the year spent by the Utter family in Leicester.
478 BIOGRAPHICAL MEMOIRS it seemeci appropriate that 7 years later they, Marge, Mert and Doug, should come back to Leicester. They lived around the corner from us and every morning either Mert would come and ring my doorbell and I would hastily wipe the last vestiges of breakfast toast off my face and then walk with him across the park; or I would call for him on wet days in a mon- strous car, a 12 seater. When you walk with someone for a whole year you get to know him pretty well. Mert had a tremendous interest in the com- parative side of biological phenomena. We used to talk about this sort of thing trying to discover the reason why, for example, you have a perfectly good enzyme, pyruvate carboxylase, which a perfectly good bacteria like E. cold should resolutely refuse to use, and instead it used PEP carboxylase but used the same mechanism of control. And we would play games like what if, and supposing that. This to me brought out the one feature of my association with Mert which I remember distinctly with the strongest af- fection. He was a tremendous person to be with because he would toss ideas around and he, like me, had this fatal fascination for playing on words. We would usually end our walks giggling helplessly as we went into the department where they must have thought us ready for certification as lunatics. A SUMMARY OF HIS RESEARCH Early Research. Utter's first scientific paper was published in the Iowa State College journal of Science (1940) and was en- titled "The Preparation of an Active Juice from Bacteria." Utter was always modest and unpretentious. A title such as, "A Unique and New Procedure for Preparation of Active En- zymes from Bacteria" would have been more to the point and sounded more sophisticated, but that was not his style. The solubilization of bacterial enzymes was a significant accom- plishment. At that time, soluble enzyme systems capable of fermenting carbohydrates hac! not been demonstrated in bacteria, ant] consideration of their intermediary metabolism was in large part based on what was known from studies of enzymes from yeast anct animal tissue. Those were the "horse and buggy" clays of biochemistry. The citric acid cycle had just been described by Krebs, and
MERTON FRANKLIN UTTER 479 many details of the Embden-Meyerhof pathway were not completely understood. There were no commercial sources of enzymes or of coenzymes such as adenosinetriphosphate (ATP) and nicotinamide diphosphate and triphosphate (NAD and NADP). It was a time of "do-it-yourself or go with- out." To solubilize enzymes, bacteria were mixed with ground glass and the mixture was forced between the interface of two tightly interfitting cones. For this purpose, a glass tube was sealed to the neck of one ErIenmeyer flask and the bot- tom of the flask was cut off. A second ErIenmeyer flask was sealed off at the neck so that it fit inside the open end of the first Erienmeyer flask. The inner flask was attached to a mo- tor to cause it to rotate within the outer flask. A mixture of the bacteria, together with ground glass, was placed in the tube of the outer flask, and the mixture was forced, using considerable effort, from the tube between the rotating cones using a plunger. These were the depression years, so if a beaker was broken, it was saved and the glass was put in a ball mill to replenish the ground glass. This procedure for the preparation of bacterial enzymes was used for many years by researchers in C. H. Werkman's department. At about the same time, a mass spectrometer for mea- surement of i3C was being constructed by the group in the laboratory, as well as a thermal diffusion column five stories high for concentration of this stable isotope. It was the in- genuity and hard work of graduate students such as Merton Utter that made the laboratory of C. H. Werkman, which was situated in the middle of the farm belt of Iowa, a leading center for study of microbial metabolism. This is the environment in which Merton Utter started his research. He had a nine-month fellowship that paid $50 monthly. His wife Marjorie worked as a secretary with Dr. Theodore Schultz in the Department of Economics at Iowa State College, now Iowa State University. Interestingly, Dr.
480 BIOGRAPHICAL MEMOIRS Schultz, who by then had moved to Chicago, was a winner of the Nobel Prize in Economics in 1979. Merton Utter's research was truly pioneering. In 1941 a paper was publishecI in the journal of Bacteriology entitled "The Occurrence of the Aldolase anc! Isomerase Equilibria in Bacterial Metabolism." Alclolase and isomerase are two im- portant enzymes of carbohydrate metabolism. There were two more papers publishecI in the Journal of Biological Chem- istry in 1942: "Effect of Metal ions on the Reactions of Phos- phopyruvate by Escherichia coli" and "The Dissimilation of Phosphoglyceric Acid by Escherichia coli." Phosphoglyceric acid hac! been shown at that time to be a key compound in the metabolism of carbohydrate by yeast and mammalian tis- s-ues. In 1943 Utter published "The Role of Phosphate in the Anaerobic Dissimilation of Pyruvic Acid" and in 1944 the "Formation and Reactions of Acety~phosphate in Escherichia coli" and "Reversibility of the Phosphorociastic Split of Pyr- uvate." (At that time, Fritz Lipmann had just discoverecI the role of acety~phosphate in metabolism.) Anyone who is fa- miliar with the history of biochemistry recognizes from the titles that Merton Utter's early work was at the forefront of biochemistry, just as it has been at the forefront of carbohy- ctrate metabolism to this clay. Methods of isolation of enzymes and study of their properties were in their infancy. Utter's studies helped to show that bacteria share similar metabolic pathways with mammals and that all forms of life exist in large part by the same biochemical processes. Soon bacteria were to become the major subject for study of intermediary metabolism and molecular biology. Studies on Fixation of CO2. The fixation of CO2 by hetero- trophic organisms was discovered by H. G. Wood and C. H. Werkman in 1936. Later they proposed that the fixation oc- curred as follows:
MERTON FRANKLIN UTTER *CO2 + CH3 CO COOH > HOO*C CH2 CO COOH 481 This reaction became known as the Wood and Werkman re- action. It was not until 194X, however, that S. Ochoa, A. H. MehIer, and A. Kornberg purified an enzyme that fixed CO2 to form a dicarboxylic acid. Subsequently, the enzyme was named the malic enzyme and shown to catalyze the following reaction: malic enzyme CON + pyruvate + NADPH ~ ~ malate + NADP Following this discovery, Ochoa and collaborators suggested that this enzyme catalyzed the primary reaction in the fixa- tion of CO2 and that oxalacetate is former! by coupling the following two reactions: malic enzyme CO' + pyruvate + NADPH ~ ~ malate + NADP malic dehydrogenase Malate + NAD _ - oxalacetate + NADH Sum: CO, + pyruvate + NADPH + NAD ~ oxalacetate + NADP + NADH Ephraim Racker summarized the status of work in this field at a meeting on CO2 fixation in 1950, when he proposed a toast to the "wouldn't work reaction." Although the enzymatic basis for the Wood and Werkman reaction continued to be elusive, Utter and K. Kurahashi showed that chicken liver forms oxalacetate without the in- volvement of malic enzyme. They isolated a new enzyme, . P-enolpyruvate carboxykinase, which catalyzes the formation of oxalacetate with fixation of CO2, using guanosine di- and triphosphate (GDP and GTP) as high-energy intermecliates:
482 BIOGRAPHICAL MEMOIRS P-ellolpyrtl vale cart~oxykinase P-enolpyruvate + COW + GDP ~ oxalacetate + GTP Utters Discovery of the Mechanism of Conversion of Pyravate to P-enolpyravate. It was the finding of P-enolpyruvate carboxy- kinase that launched Utter into the studies of gluconeoge- nesis. He was aware that because of the high, negative free energy change it was r. ~ unlikely that P-enolpyruvate was formed trom pyruvate by a simple reversal of the pyruvate . . . Gnash reaction. pyruvat e kinase P-enolpyruvate + ADP ~ pyruvate + ATP (AG° = - 7 kcal/mole) As a possible solution, both H. A. Krebs and Utter (1954) inclepenclently proposed that pyruvate might be converted to P-enolpyruvate by the combined action of the malic en- zyme and P-enolpyruvate carboxykinase by the following se- quence: malic enzyme Pyruvate + CO2 + NADPH ~ ~ malate + NADP malic dehydrogenase Malate + NAD - oxalacetate + NADH P-er~olpyruvate Oxalacetate + GTP ~ - P-enolpyruvate + GDP + CO2 carboxykinase Sum: Pyruvate + GTP + NADPH + NAD > P-enolpyruvate + GDP + NADP + NADH The thermodynamics of this sequence are not particularly favorable, but by coupling the oxidation of NADH to other reactions it was considered possible to maintain a high ratio of NADPH/NAD, thereby favoring the synthesis of the P-enolpyruvate.
MERTON FRANKLIN UTTER 483 It was an investigation of the above reaction sequence that lecl to the discovery of the major anaplerotic enzyme, pyru- vate carboxykinase. Utter and coworkers then fount} that mi- tochonciria from chicken liver contained only trace amounts of either pyruvic kinase or malic enzyme, but they could still form significant amounts of P-enolpyruvate from pyruvate. These experiments provider! the first clear evidence that nei- ther of these enzymes was required for the net synthesis of P-enolpyruvate. Since Utter knew that P-enolpyruvate could be formed from oxalacetate, it was natural to look for an enzyme that could form oxalacetate from pyruvate. In 1963 Utter and D. B. Keech fount! such an enzyme in the mito- chondria of chicken liver (later named Pyruvate carboxylase), which catalyzed the direct carboxylation of pyruvate. Utter tract thus found the enzymatic basis of the "wouldn't work re- action," twenty-five years after it had been postulated as a possible mechanism for the formation of dicarboxylic acids by CO2 fixation. Pyruvate carboxylase, when coupled with P- enolpyruvate carboxykinase, catalyzecI the formation of P- enolpyruvate as illustrated below. Pyruvate carboxylase Pyruvate + CO2 + ATP ~- oxalacetate + ADP + P P-er~olpyravate Oxalacetate + GTP ~ ~ P-enolpyruvate + CON + GDP carboxy k'nase i Sum: Pyruvate + ATP + GTP ~ P-enolpyruvate + ADP + GDP + Pi This sequence is energetically favorable because it combines cleavage of two high-energy phosphates from ATP and GTP to drive the overall synthesis of P-enolpyruvate. A beautiful summary of this research was published in a 1963 article by
484 BIOGRAPHICAL MEMOIRS Utter in the Iowa State College Journal of Science, which con- tained a compilation of papers by C. H. Werkman's students. Toclay this pathway of P-enolpyruvate formation from py- ruvate is wiclely held as the key, pacesetting step in gluconeo- genesis. The degree of the regulation of the two enzymes in this sequence, pyruvate carboxylase and P-enolpyruvate car- boxykinase, now serves as a mocle] for control of metabolic pathways and remains a major legacy of Merton Utter's scien- tific work. Structure of Biotin Enzymes. One portion of Utter's research that hac! a large effect was his 1966 study, in collaboration with R. C. Valentine, N. C. Wrigley, M. C. Scrutton, and I. l. arias, using electron microscopy to determine the structure of pyruvate carboxylase from chicken liver. This was one of the earliest applications of electron microscopy for investi- gation of the quaternary structure of enzymes. Negative staining techniques showed square-planar tetramers with vivict clarity. It was these studies that convinced one of us (H. G. W.) to undertake similar studies with another biotin enzyme, transcarboxylase, and no doubt inclucect others to adopt the procedure. That pyruvate carboxylase was being visualized seemed compelling. Pyruvate carboxylase was known to contain four In accord with the observed tetrameric structure. Also, estimates from the dimensions of the profiles of the four subunits were in accord with the observer! molec- ular weight of the enzyme. These square tetramers were ob- servec! in pyruvate carboxylase preparations from the livers of a variety of animals, including the chicken, turkey, beef cattle, ant! calf. In acictition, Gottschalk and coworkers (Eu- ropean Journal of Biochemistry, 64 ~ ~ 976] :4 ~ I-2 ~ ~ at the Uni- versity of Gottingen, Federal Republic of Germany, reported that pyruvate carboxylase of rat liver hac! a square tetramer shape. Finally and most convincingly, pyruvate carboxylase biotins, which was .
MERTON FRANKLIN UTTER 485 was known to be cold sensitive. The enzyme dissociates to its subunits in the cold, with loss of enzymatic activity; upon rewarming, the subunits reassociate with accompanying re- turn of activity. The square planar tetramer dissociated to subunits in the cold, which were observed in the electron microscope; on rewarming, they reassociated to the square tetramer. To Utter's amazement and chagrin, thirteen years later he anct his coworkers found that the square-shaped tetramers were not pyruvate carboxylase. It was a minor, highly visible impurity present in purified pyruvate carboxylase. The py- ruvate carboxylase dissociated cluring preparation of the grids to faintly visible material, leaving the minor contami- nant highly visible. Indepenclently and at the same time, N. H. Goss, P. Y. Dyer, D. B. Keech, and I. C. Wallace at the University of Adelaide in Australia found that the square tetramer is not pyruvate carboxylase. Utter and his former collaborator, D. B. Keech, by mutual agreement, published their new results on the correct structure of pyruvate car- boxylase in the same issue of the journal of Biological Chemistry. The identity anct function of the square tetramer remains a mystery. A better design of a protein could not be con- structed by the Devil himself to mislead a brilliant scientist. Although there is not complete agreement, the overall con- figuration of pyruvate carboxylase from chicken, sheep, anct rat appears to be a tetrahedron-like structure consisting of two pairs of subunits in different planes orthogonal to each other, with the opposing pairs of subunits interacting on their convex surfaces (F. Mayer, I. C. Wallace, and D. B. Keech European journal of Biochemistry, ~ ~ 2 ~ ~ 980] :265 -72~. Inborn Errors in the Enzymes of Pyravate Metabolism. Later in his career, Merton Utter turned his attention to the causes of lactic acidosis in children. Many of the diseases in this ill- definec! category of childhooc! clisorclers are thought to in
486 BIOGRAPHICAL MEMOIRS volve inborn errors of enzymes in pyruvate metabolism. Dur ing the last decade of his life, Utter and his coworkers began a systematic study of these enzymes in human populations. He developed sensitive enzymatic assays for pyruvate dehy cirogenase, pyruvate carboxylase, P-enolpyruvate carboxyki nase, and pyruvate kinase using easily obtained tissues, such as cultured skin fibroblasts, reticulocytes, or lymphocytes. He was able to demonstrate, for example, that contrary to the prevailing opinion, Leigh's disease clid not involve a clefi ciency in pyruvate carboxylase. His skill as an enzymologist was a major factor in the development of a standard assay for pyruvate dehycirogenase in human tissues that accurately and reproducibly measured the true basal rate of activity of this enzyme. His laboratory tract, at the time of his death, rat · · · · ~ become a reference point tor many c 1nlclans interested in collaboration in determining the absences of a specific en- zyme in pyruvate metabolism in patients. PERSONAL ASPECTS IN MERTON UTTER S LIFE Merton Utter was a man of great personal charm and dignity. His life was dedicated to scholarship and the ideals of university education. He loved books and all his life react widely, particularly in history, biography, and politics. He was a quiet and unassuming gentleman whose advice was often sought by his colleagues and students. He was a man of un- failing charity who did not speak ill of others ant! whose per- sonal qualities will be long remembered by all who knew him. Paul Berg, a student in the Department of Biochemistry at Western Reserve University in the 1950s, commented recently: One of the things about Mert which I will always remember is that while we learned that science was exciting and pertinent and that it re- quired a kind of commitment, day and night preoccupation, Mert made science fun. In chatting with us, he would see the less intense side of things
MERTON FRANKLIN UTTER 487 as well as the importance of what we were trying to talk about. He would chat about music, art, baseball. He made being in the lab a great joy. It was always a pleasure for me to come into the lab, morning, noon and night and find Mert there. Merton Utter served with distinction as an associate editor ofthe~ournal of Biological Chemistry and helped to guicle the editorial policies of the journal during the period of its most rapic! expansion. He was a member of numerous study sec- tions and national committees, ant! his quiet ant! judicious manner made him a valued member of numerous national panels concerned with research policy. Merton Utter spent virtually his complete university ca- reer as a member of the Department of Biochemistry at Case Western Reserve University School of Medicine. He trainee! numerous biochemists and medical students during his ca- reer as a research scientist and teacher. His knowlecige of biochemistry was encyclopeclic, anct he was a superb teacher. His sullen death at the age of sixty-three was a serious blow to those who knew and lover! him. A symposium was helcI at Case Western Reserve University School of Medicine in May of 1982 to honor the memory of Merton Utter. The senti- ments of all who attended were expressed in a letter written at the time of his cleath by Dr. Albert S. Ivan: It was with shock, and with the deepest of sadness that I read your letter today, telling of our loss of Mert Utter. His life's work can only be described as monumental. I am grateful to have had the privilege of col- laborating with this great scientist and person. In thinking of Mert, I recall the pleasure of hearing his witty lectures on his research. With profound modesty he would make his great discov- eries sound like the result of a series of unexpected accidents. This didactic technique greatly encouraged and inspired the next generation of scien- tists, indeed all of us, who try to emulate this high example.
488 DEGREES BIOGRAPHICAL MEMOIRS HONORS AND DISTINCTIONS B.A., Simpson College, 1939 Ph.D., Iowa State University, 1942 PROFESSIONAL APPOINTMENTS Instructor in Bacteriology and Research, Associate in the Agricul- tural Experiment Station, Iowa State University, 1942-1944 Assistant Professor in Physiological Chemistry, University of Min- nesota, 1944-1946 Associate Professor of Biochemistry, Western Reserve University, 1946-1956 Professor of Biochemistry, Case Western Reserve University,1956- 1980 Director, Department of Biochemistry, Case Western Reserve Uni- versity, 1965 - 1976 PROFESSIONAL ACTIVITIES Metabolic Biology Panel, National Science Foundation Biochemistry Study Section, National Institutes of Health Program Project Committee, AMDD Institute, National Institutes of Health Associate Editor, journal of Biological Chemistry Editorial Board, Journal of Biological Chemistry Editorial Advisory Board, Biochemistry Editorial Board, Trends in the Biochemical Sciences Biochemistry Panel, National Board of Medical Examiners U.S. Representative, International Union of Biochemistry HONORS Fulbright Senior Research Fellow (Australia), 1953-1954 Paul Lewis Award in Enzyme Chemistry, 1956 National Science Foundation Senior Research Fellow (Oxford), 1960-1961 National Science Foundation Senior Research Fellow (Leicester), 1968-1969 National Academy of Sciences, 1973 American Academy of Arts and Sciences, 1972
MERTON FRANKLIN UTTER PROFESSIONAL SOCIETIES American Society of Biological Chemists American Association for the Advancement of Science American Chemical Society American Society of Microbiologists Biochemical Society (England) New York Academy of Sciences Society of Experimental Biology and Medicine 489
490 BIOGRAPHICAL MEMOIRS SELECTED B IBLIOGRAPHY 1940 With W. P. Wiggert, M. Silverman, and C. H. Werkman. Prepara- tion of an active juice from bacteria. Iowa State Coll. I. Sci., 14: 179-86. 1941 With C. H. Werkman. Occurrence of the aldolase and isomerase equilibria in bacterial metabolism. I. Bacteriol., 42 :665-76. 1942 With C. H. Werkman. Effect of metal ions on the reactions of phos- phopyruvate by Escherichia coli. ]. Biol. Chem., 146:289 -300. With C. H. Werkman. Dissimilation of phosphoglyceric acid by Escherichia coli. Biochem. I., 36:485-93. 1943 With C. H. Werkman. Role of phosphate in the anaerobic dissi- milation of pyruvic acid. Arch. Biochem., 2:491-92. 1944 With C. H. Werkman. Formation and reactions of acetyl phosphate in Escherichia coli. Arch. Biochem., 4:413-22. With C. H. Werkman and F. Lipmann. Reversibility of the phos ohoroclastic solit of pyruvate. }. Biol. Chem., 154:723-24. 1945 With F. Lipmann and C. H. Werkman. Reversibility of the phos- phoroclastic split of pyruvate. J. Biol. Chem., 158:521-31. With I. M. Reiner and H. G. Wood. Measurement of anaerobic gly- colysis in brain as related to poliomyelitis. }. Exp. Med.,82:217- 26. With H. G. Wood. Fixation of carbon dioxide in oxalacetate by pigeon liver. I. Biol. Chem., 160:375 -76. With H. G. Wood and I. M. Reiner. Anaerobic glycolysis in nervous tissue. }. Biol. Chem., 1 6 1: 1 97-2 1 7. With G. Kalnitsky and C. H. Werkman. Active enzyme prepara- tions from bacteria. I. Bacteriol., 49:595 -602.
MERTON FRANKLIN UTTER 1946 491 With L. O. Krampitz and C. H. Werkman. Oxidation of acetyl phosphate and other substrates by Micrococcus Iysodeikticus. Arch. Biochem., 9:285 -300. With G. Kalnitsky and C. H. Werkman. Enzymatic nature of cell- free extracts from bacteria. Arch. Biochem., 9:407-17. With H. G. Wood. The fixation of carbon dioxide in oxalacetate by pigeon liver. J. Biol. Chem., 164:455-76. 1950 Mechanism of inhibition of anerobic glycolysis of brain by sodium ions. I. Biol. Chem., 185 :499-517. With V. Lorber, H. Rudney, and M. Cook. The enzymatic forma- tion of citric acid studied with C~4-labeled oxalacetate. }. Biol. Chem., 185 :689-99. The mechanism of the fixation of carbon dioxide in dicarboxylic acids. Brookhaven Natl. Lab. Symp. CO2 Assimilation Reaction, pp. 37-55. 1951 Interrelationships of oxalacetic and 1-malic acids in carbon dioxide fixation. I. Biol. Chem., 188:847-63. Adenosine triphosphate and carbon dioxide fixation. In: Phospho- rus Metabolism, ed. W. D. McElroy and B. Glass, Vol. 1, pp. 646- 56. Baltimore: The Johns Hopkins Press. With H. G. Wood. Mechanism of fixation of carbon dioxide by het- erotrophs and autotrophs. Adv. Enzymol., 12:41-151. 1953 With K. Kurahashi. Mechanism of action of oxalacetic carboxylase from liver. I. Am. Chem. Soc., 75:758. 1954 With K. Kurahashi. Purification of oxalacetic carboxylase from chicken liver. }. Biol. Chem., 207:787-802. With K. Kurahashi and I. A. Rose. Some properties of oxalacetic carboxylase. I. Biol. Chem., 207:803 -l 9. With K. Kurahashi. Mechanism of action of oxalacetir carboxylase. }. Biol. Chem., 207:821-41.
492 BIOGRAPHICAL MEMOIRS 1955 With K. Kurahashi. Oxalacetate synthesizing enzyme. Methods En- zymol., 1:758-63. 1956 With I. L. Graves, B. Vennesland, and R. I. Pennington. The mech- anism of the reversible carboxylation of phosphoenolpyruvate. I. Biol. Chem., 233:551-57. 1957 With K. Kurahashi and R. }. Pennington. Nucleotide specificity of oxalacetic carboxylase. }. Biol. Chem., 226: 1059-75. With H. E. Swim. Isotopic experimentation with intermediates of the tricarboxylic acid cycle. Methods Enzymol., 4:584-608. 1958 With D. B. Keech and P. M. Nossal. Oxidative phosphorylation of subcellular particles from yeast. Biochem. I., 68:431-40. Carbohydrate metabolism. Annul Rev. Biochem., 27:245-84. Guanosine and inosine nucleotides. The Enzymes, II:75-88. 1959 The role of CON fixation in carbohydrate utilization and synthesis. N.Y. Acad. Sci., 72:451-61. With }. T. McQuate. Equilibrium and kinetic studies of the pyruvic kinase reaction. }. Biol. Chem., 234:2151-57. 1960 With D. B. Keech. Formation of oxaloacetate from pyruvate and CON. I. Biol. Chem., 235: PC 17-18. Nonoxidative carboxylation and decarboxylation. The Enzymes, V:319-40. 1962 With }. Mendicino. Interaction of soluble and mitochondrial mul- tienzyme systems in hexose phosphate synthesis. I. Biol. Chem., 237: 1716-22.
MERTON FRANKLIN UTTER 1963 493 Pathways of phosphoenolpyruvate synthesis in glycogenesis. Iowa State Coll. }. Sci., 38:97-113. With D. B. Keech. Pyruvate carboxylase. I. Nature of the reaction. I. Biol. Chem., 238:2603-8. With D. B. Keech. Pyruvate carboxylase. II. Properties. l. Biol. Chem., 238:2609 -14. 1964 With D. B. Keech and M. C. Scrutton. A possible role for acetyl CoA in the control of gluconeogenesis. Adv. Enzyme Regul., 2:49-68. With E. A. Duell and S. Inoue. Isolation and properties of intact mitochondria from spheroplasts of yeast. }. Bacteriol., 88: 1762- 73. 1965 With M. C. Scrutton. Pyruvate carboxylase. III. Some physical and chemical properties of highly purified enzyme. J. Biol. Chem., 240: 1-9. With M. C. Scrutton and D. B. Keech. Pyruvate carboxylase. IV. Partial reactions and the locus of activation by acetyl coenzyme A. I. Biol. Chem., 240:574-81. With M. C. Scrutton. Pyruvate carboxylase. V. Interaction of the enzyme with adenosine triphosphate. I. Biol. Chem., 240:3714-23. With H. G. Wood. The role of CON fixation in metabolism. Essays Biochem., 1:1-27. 1966 With M. C. Scrutton and A. S. Mildvan. Pyruvate carboxylase. VI The presence of tightly bound manganese. T. Biol. Chem. 241 :3480-87. With A. S. Mildvan and M. C. Scrutton. Pyruvate carboxylase. VII A possible role for tightly bound manganese. I. Biol. Chem. 241 :3488-98. With R. C. Valentine, N. G. Wrigley, M. C. Scrutton, and I. I. Irias.
494 BIOGRAPHICAL MEMOIRS Pyruvate carboxylase. VIII. The subunit structure as examined by electron microscopy. Biochemistry, 5:3111-16. With C. Bernofsky. Mitochondrial isocitrate dehydrogenase from yeast. I. Biol. Chem., 241:5561-66. Oxalacetic decarboxylase and related enzymes. Handb. Physiol. Pa- thol. Chem. Anal., 10:498-502, Berlin: Springer-Verlag. 1967 With C. Bernofsky. Secondary activation effects of mitochondrial isocitrates dehydrogenases from yeast. Biochim. Biophys. Acta, 132:244-55. With M. C. Scrutton, M. R. Young, B. Tolbert, I. C. Wallace, ~ I Irias, and R. C. Valentine. Pyruvate carboxylase. The relation- ship of enzymic structure to catalytic activity, 7th Internatl. Cong. Biochem., Tokyo. 1968 With C. Bernofsky. Interconversions of mitochondrial pyridine nu- cleotides. Science, 159: 1362-63. The carboxylation of Pyruvate by biotin-enzymes. l. Vitamin, 14:68-76. With M. C. Scrutton and M. R. Olmsted. Pyruvate carboxylase from chicken liver. Methods Enzymol., 13:235-49. With M. R. Young and B. Tolbert. Pyruvate carboxylase from Sac- charomyces cerevisiae. Methods Enzymol., 13:257-65. With E. A. Duell and C. Bernofsky. Alterations in the respiratory enzyme of the mitochondria of growing and resting yeast. In: Aspects of Yeast Metabolism, ed. A. K. Mills, pp. 197 - 212. Oxford: Blackwell Scientific Publications. With M. C. Scruttor~. The regulation of glycolysis and gluconeo- genesis in animal tissues. Annul Rev. Biochem., 37:249-302. 1969 With M. C. Scrutton. Pyruvate carboxylase. In: Current Topics in Cellular Regulation, vol. 1, ed. B. L. Horecker and E. R. Stadt- man, pp. 253-96. New York: Academic Press. With I. A. Rose, E. L. O'Connell, P. Noce, H. G. Wood, I. M. Wil- lard, T. C. Cooper, and M. Benziman. Stereochemistry of the
MERTON FRANKLIN UTTER 495 enzymatic carboxylation of phosphoenolpyruvate. J. Biol. Chem., 244: 6130-33. With I. }. Irias and M. R. Olmsted. Pyruvate carboxylase. Revers- ible inactivation by cold. Biochemistry, 8:5136-48. Pyruvate carboxylase. FEES Symp., 19:91-98. 1970 Metabolic roles of oxalacetate. In: Citric Acid Cycle, ed. J. M. Low- enstein, pp. 249-96. New York: Marcel Dekker. With M. C. Scrutton and M. R. Young. Pyruvate carboxylase from bakers' yeast. The presence of bound zinc. I. Biol. Chem., 245:622-27. 1971 With C.-H. Fung. Possible control mechanisms of liver Pyruvate carboxylase. Regulation of gluconeogenesis, 9th Conf. of the Gesellschaft fur Biologische Chemie, ed. H.-D. Soling and B. Willms, pp. 1-10. New York: Academic Press. 1972 With R. E. garden, C.-H. Fung, and M. C. Scrutton. Pyruvate car- boxylase from chicken liver. Steady state kinetic studies indicate a "two-site" ping pony mechanism. I. Biol. Chem., 247:1323- 33. With B. L. Taylor and R. E. garden. Identification of the reacting form of Pyruvate carboxylase. I. Biol. Chem., 247:7383-90. With H. M. Kolenbrander. Formation of oxalacetate by CO2 fixa- tion on phosphoenolpyruvate. The Enzymes, 6: 117-68. 1974 With B. L. Taylor. The removal of nucleic acids from microbial extracts by precipitation with lysozyme. Anal. Biochem., 62:588-91. 1975 With B. L. Taylor and S. Routman. The control of the synthesis of Pyruvate carboxylase in Pseudomonas citronellolis. ]. Biol. Chem., 250:2376-82.
496 BIOGRAPHICAL MEMOIRS With P. S. Noce. Decarboxylation of oxalacetate to pyruvate by pur- ified avian liver phosphoenolpyruvate carboxykinase. I. Biol. Chem., 250:9099-106. With R. E. garden, B. L. Taylor, F. Isohashi, W. H. Frey II, G. Zan- der5 and J. G. Lees. Structural properties of pyruvate carbox- ylase from chicken liver and other sources. Proc. Natl. Acad. Sci. USA, 72 :4308-12. With R. E. Barden and B. L. Taylor. Pyruvate carboxylase: An eval- uation of the relationships between structure and mechanism and between structure and catalytic activity. Adv. Enzymol., 42:1-73. 1976 With G. I. Barritt and G. L. Zander. The regulation of pyruvate carboxylase activity in gluconeogenic tissues. In: Gluconeogene- sis, ed. Hanson/Mahlman, pp. 3-46. New York: John Wiley & Sons, Inc. The biochemistry of manganese. Med. Clin. N. Am., 6:713-27. 1977 With W. H. Frey II. Binding of acetyl-CoA to chicken liver pyru- vate carboxylase. I. Biol. Chem., 252:51-56. With R. W. O'Brien, D. T. Chuang, and B. L. Taylor. Novel enzymic machinery for the metabolism of oxalacetate, phosphoenolpy- ruvate and pyruvate in Pseudomonas citronellolis. ]. Biol. Chem., 252: 1257-63. 1978 With D. T. Chuang. Gluconeogenesis as a compartmentalized ac- tivity. Biochem. Soc. Trans. 572nd Meeting (London), 6: 11-16. With }. A. Swack and G. L. Zander. Use of avidin-sepharose to iso- late and identify biotin polypeptides from crude extracts. Anal. Biochem., 87: 114-26. With A. B. Leiter, M. Weinberg, and F. Isohashi. Relationship be- tween phosphorylation and activity of pyruvate dehydrogenase in rat liver mitochondria and the absence of such a relationship for pyruvate carboxylase. I. Biol. Chem., 253:2716-23. With B. L. Taylor, W. H. Frey II, and M. C. Scrutton. The use of
MERTON FRANKLIN UTTER 497 the ultracentrifuge to determine the catalytically competent forms of enzymes with more than one oligomeric structure. J. Biol. Chem., 253:3062-69. 1979 With B. M. Atkin and M. B. Weinberg. Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in leukocytes and fibroblasts from a patient with pyruvate carboxylase deficiency. Pediatr. Res., 13: 38-43. With B. Atkins, M. R. M. Buist, and A. B. Leiter. Pyruvate carbox- ylase deficiency in a retarded child without Leigh's Syndrome. Pediatr. Res., 13: 109-16. With N. D. Cohen, H. Beegen, and N. G. Wrigley. A re-examina- tion on the electron microscopic appearance of pyruvate car- boxylase from chicken liver. l. Biol. Chem., 254:1740-47. With N. D. Cohen, N. G. Wrigley, and A. N. Barrett. Quaternary structure of yeast pyruvate carboxylase: Biochemical and elec- tron microscopic studies. Biochemistry, 18:2197-203. With N. D. Cohen, I. A. Duc, and H. Beegen. Quaternary structure of pyruvate carboxylase from Pseudomonas citronellolis. 5. Biol. Chem., 254:9262-69. With M. B. Weinberg. Eject of thyroid hormone on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase. I Biol. Chem., 254:9592-99. With D. T. Chuang. Structural and regulatory properties of pyru- vate kinase from Pseudomonas citronellolis. it. Biol. Chem., 254: 8343-441. 1980 With S. D. Freytag. Introduction of pyruvate carboxylase apoen- zyme and holoenzyme in 3T3-L1 cells during differentiation. Proc. Natl. Acad. Sci. USA, 77:1321-25. With M. B. Weinberg. EEect of streptozotocin-induced diabetes mellitis on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase. Biochem. }, 1 88:60 1-8. With K.-F. R. Sheu. Biochemical mechanisms of biotin and thiamin action and relationships to genetic disease. In: Enzyme Therapy in Genetic Diseases: II, ed. R. i. Desnick, pp.289-304. New York: Alan R. Liss, Inc.
498 BIOGRAPHICAL MEMOIRS With R. L. Prass and F. Isohashi. Purification and characterization of an extramitochondrial acetyl-coenzyme A hydrolase from rat liver. I. Biol. Chem., 255:5215-23. 1981 With K.-F. R. Sheu and C. W. C. Hu. Pyruvate dehydrogenase com- plex activity in normal and deficient fibroblasts. i. Clin. Invest., 67: 1463-71. With S. O. Freytag and M. B. Weinberg. Regulation of the synthe- sis and degradation of pyruvate carboxylase in animal tissue. In: The Regulation of Carbohydrate Formation in Mammals, ed. C. M. Veneziale. Baltimore: University Park Press. With I. A. Goss and N. D. Cohen. Characterization of the subunit structure of pyruvate carboxylase from Pseudomonas citronellolis. I. Biol. Chem., 256:11819-25. With M. Watford, Y. Hod, Y. B. Chiao, and R. W. Hanson. The unique role of the kidney in gluconeogenesis in the chicken. The significance of a cytosolic form of phosphoenolpyruvate carboxykinase. }. Biol. Chem., 256:10023-27. With D. E. Meyers. The enzymatic synthesis of some potential pho- toaffinity analogs of benzoyl-coenzyme A. Anal. Biochem., 112:23-39. 1982 With Y. Hod and R. W. Hanson. The mitochondrial and cytosolic forms of avian phosphoenolpyruvate carboxykinase (GTP) are encoded by different messenger RNAs. I. Biol. Chem., 257: 13787-94. 1983 With C. W. C. Hu and M. S. Patel. Induction of pyruvate dehydro- genase in 3T3-L1 cells during differentiation. J. Biol. Chem., 258:2315-20. With S. O. Freytag. Regulation of the synthesis and degradation of pyruvate carboxylase in 3T3-L1 cells. I. Biol. Chem.,258:6307- 12. With D. E. Myers and B. Tolbert. Activation of yeast pyruvate car- boxylase: Interactions between acyl coenzyme A compounds,
MERTON FRANKLIN UTTER 499 aspartate, and substrates of the reaction. Biochemistry, 2:5090- 96. 1984 With K.-F. Sheu, H.-T. Ho, L. D. Nolan, P. Markovitz, l. P. Richard, and P. A. Frey. Stereochemical course of thiophosphoryl group transfer catalyzed by mitochondrial phosphoenolpyruvate car- boxykinase. Biochemistry, 23:1779-83.
