Fritz Lipmann and the Discovery of Coenzyme A

Acetylation of Sulfanilamide by Liver Homogenates and Extracts (Lipmann, F. (1945) J. Biol. Chem. 160, 173-190)

Fritz Albert Lipmann (1899-1986) was born in Koenigsberg, Germany. He earned an M.D. degree from the University of Berlin in 1924 but toward the end of his medical studies he began to doubt whether he really wanted to practice medicine. A course in biochemistry and the opportunity to work in a laboratory at the University of Amsterdam for 6 months convinced him to get a Ph.D. in biochemistry. Thus, he joined Otto Meyerhof, author of a previous Journal of Biological Chemistry (JBC) Classic (1), at the Kaiser Wilhelm Institute in Berlin in 1926 to do his thesis research on metabolic fluoride effects.

After completing his Ph.D. in 1929, Lipmann joined Albert Fischer's laboratory where he worked on using metabolism as a method to measure cell growth. Fischer was getting ready to move to a new laboratory at the Biological Institute of the Carlsberg Foundation in Copenhagen and asked Lipmann to accompany him there, which he did in 1932. Between 1931 and 1932, Lipmann spent time as a Rockefeller Fellow in the laboratory of P. A. Levene at the Rockefeller Institute in New York.

When he returned to Fischer's laboratory in Copenhagen, Lipmann became interested in the metabolism of fibroblasts, which prompted him to study the Pasteur Effect (the inhibiting effect of oxygen on the process of fermentation). This led to investigations into the mechanism of pyruvic acid oxidation because the pyruvic acid stage is where respiration branches off from fermentation. For these studies, Lipmann used a pyruvic acid oxidation enzyme from a certain strain of Lactobacillus delbrueckii. He noticed that pyruvic acid oxidation was completely dependent on the presence of inorganic phosphate. Suspecting an energy-rich intermediary, Lipmann added radioactive phosphate and adenylic acid and found that pyruvate oxidation yielded ATP. He then deduced that acetyl phosphate was the missing link in the reaction chain and showed that a crude preparation of acetyl phosphate could transfer phosphate to adenylic acid. Several years later, Lipmann definitively identified acetyl phosphate as the initial product of pyruvic acid oxidation (2, 3).

Toward the end of 1938, Hitler's fascism was slowly expanding into Denmark, and Lipmann decided it was time to leave. He got in touch with Dean Burk, an American colleague he had met while working with Meyerhof. Burk had just been invited by Vincent du Vigneaud (who was featured in a previous JBC Classic (4)) to join his department at Cornell Medical School. Burk agreed to take Lipmann on as his assistant, and in 1939 Lipmann moved to New York.

During this time, Lipmann continued to think about the role of acetyl phosphate in metabolism and the fact that it not only contained an energy-rich phosphoryl radical but also an energy-rich acetyl. This prompted him to write a landmark paper about group potential and the transfer of acetyl and phosphoryl groups in which he proposed that acetyl phosphate acted as an acetyl donor in the biosynthesis of essential metabolites and that ATP functioned as a generalized energy carrier (5). In this essay he also introduced the term “energy-rich phosphate bond” and the squiggle to denote this distinction (∼P).

In 1941 Lipmann moved to Boston to join the research staff of the Massachusetts General Hospital. There, he set out to study acetyl transfer in animals and to confirm that acetyl phosphate represented active acetate. This work is the subject of the JBC Classic reprinted here. Lipmann worked out an easy method to prepare acetyl phosphate (6) and was able to isolate a potent acetylation system from pigeon liver extract with which he studied the acetylation of the amino group of the drug sulfonamide. Unexpectedly, Lipmann found that acetyl phosphate was a poor acetyl donor in his enzyme system. Adenyl phosphate, on the other hand, was able to acetylate sulfanilamide. Thus, although Lipmann was able to show that energy transfer between respiration and acetylation occurred by way of phosphate bonds, he was unable to prove the involvement of acetyl phosphate.

Despite Lipmann's initial disappointment with the above experiment, his decision to study acetylation would eventually prove fruitful. From the above studies, he noticed the requirement for a heat-stable factor that disappeared from the enzyme extracts on aging or dialysis. Because the cofactor was present in boiled extracts of all organs and could not be replaced by any other known cofactor, Lipmann suspected that he was dealing with a new coenzyme. Eventually, he was able to purify the coenzyme from pork liver and found it to be active in choline acetylation with dialyzed brain extracts (7). He named the factor coenzyme A (CoA), in which “A” stood for “activation of acetate.”

Lipmann subsequently showed that CoA is composed of adenosine 5′-phosphate pantothenic acid and a sulfhydryl moiety and that acetyl-CoA is involved in the acetylation of choline, in the synthesis of citrate and acetoacetate, and in pyruvate and fatty acid metabolism. His work on the coenzyme was eventually recognized in 1953 when he shared the Nobel Prize in Physiology or Medicine with Hans Adolf Krebs “for his discovery of co-enzyme A and its importance for intermediary metabolism.” (Krebs was awarded the Prize “for his discovery of the citric acid cycle.”)

In 1949 Lipmann became Professor of Biological Chemistry at Harvard Medical School. He remained at Harvard until 1957, when he was appointed a Member and Professor of the Rockefeller Institute, New York. He became a Professor Emeritus at Rockefeller in 1970. Lipmann's initial work on CoA led him to investigate the general use of group activation by way of phosphorylation as a common intermediary reaction in biosynthesis. His later research included demonstrating that carbamyl phosphate is a carbamyl donor, exploring the function of ATP in sulfate activation, and investigating the biological mechanisms of peptide and protein synthesis.

In addition to receiving the Nobel Prize, Lipmann was awarded many other honors. In 1966 President Johnson presented him with the National Medal of Science for his original discoveries of molecular mechanisms and his fundamental contributions to the conceptual structure of modern biochemistry. He also received the American Society of European Chemists' Carl Neuberg Medal and the American Society for Nutritional Sciences' Mead Johnson Award and was elected to the National Academy of Sciences in 1950.¹