Fritz Lipmann and the Discovery of Coenzyme A
Year: 2005
Type: article
Abstract: 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. Heearned an M.D. degree from the University of Berlin in 1924 but toward the endof his medical studies he began to doubt whether he really wanted to practicemedicine. A course in biochemistry and the opportunity to work in a laboratoryat the University of Amsterdam for 6 months convinced him to get a Ph.D. inbiochemistry. Thus, he joined Otto Meyerhof, author of a previous Journalof Biological Chemistry (JBC) Classic(1Meyerhof O. Junowicz-Kocholaty R. J. Biol. Chem. 1943; 149: 71-92Abstract Full Text PDF Google ScholarMeyerhof O. J. Biol. Chem. 1945; 157: 105-120Abstract Full Text PDF Google ScholarMeyerhof O. andOesper P. J. Biol. Chem. 1947; 170 (JBC Classics, http://www.jbc.org/cgi/content/full/280/4/e3): 1-22Abstract Full Text PDF Google Scholar), at the Kaiser WilhelmInstitute in Berlin in 1926 to do his thesis research on metabolic fluorideeffects. After completing his Ph.D. in 1929, Lipmann joined Albert Fischer'slaboratory where he worked on using metabolism as a method to measure cellgrowth. Fischer was getting ready to move to a new laboratory at theBiological Institute of the Carlsberg Foundation in Copenhagen and askedLipmann 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. Leveneat the Rockefeller Institute in New York. When he returned to Fischer's laboratory in Copenhagen, Lipmann becameinterested in the metabolism of fibroblasts, which prompted him to study thePasteur Effect (the inhibiting effect of oxygen on the process offermentation). This led to investigations into the mechanism of pyruvic acidoxidation because the pyruvic acid stage is where respiration branches offfrom fermentation. For these studies, Lipmann used a pyruvic acid oxidationenzyme from a certain strain of Lactobacillus delbrueckii. He noticedthat pyruvic acid oxidation was completely dependent on the presence ofinorganic phosphate. Suspecting an energy-rich intermediary, Lipmann addedradioactive phosphate and adenylic acid and found that pyruvate oxidationyielded ATP. He then deduced that acetyl phosphate was the missing link in thereaction chain and showed that a crude preparation of acetyl phosphate couldtransfer phosphate to adenylic acid. Several years later, Lipmann definitivelyidentified acetyl phosphate as the initial product of pyruvic acid oxidation(2Lipmann F. A phosphorylated oxidation productof pyruvic acid.J. Biol. Chem. 1940; 134: 463-464Abstract Full Text PDF Google Scholar,3Lipmann F. Enzymatic synthesis of acetylphosphate.J. Biol. Chem. 1944; 155: 55-70Abstract Full Text PDF Google Scholar). 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, anAmerican colleague he had met while working with Meyerhof. Burk had just beeninvited by Vincent du Vigneaud (who was featured in a previous JBC Classic(4du Vigneaud V. Cohn M. Chandler J.P. Schenck J.R. Simmonds S. J. Biol.Chem. 1941; 140: 625-641Abstract Full Text PDF Google Scholardu Vigneaud V. Melville D.B. Folkers K. Wolf D.E. Mozingo R. Keresztesy J.C. Harris S.A. J. Biol. Chem. 1942; 146: 475-485Abstract Full Text PDF Google Scholardu Vigneaud V. Ressler C. Trippett S. J. Biol. Chem. 1953; 205: 949-957Abstract Full Text PDF PubMed Google ScholarKatsoyannis P.G. du Vigneaud V. J. Biol. Chem. 1958; 233 (JBC Classics, (http://www.jbc.org/cgi/content/full/279/51/e11)): 1352-1354Abstract Full Text PDF PubMed Google Scholar)) to join his department atCornell Medical School. Burk agreed to take Lipmann on as his assistant, andin 1939 Lipmann moved to New York. During this time, Lipmann continued to think about the role of acetylphosphate in metabolism and the fact that it not only contained an energy-richphosphoryl radical but also an energy-rich acetyl. This prompted him to writea landmark paper about group potential and the transfer of acetyl andphosphoryl groups in which he proposed that acetyl phosphate acted as anacetyl donor in the biosynthesis of essential metabolites and that ATPfunctioned as a generalized energy carrier(5Lipmann F. Metabolic generation andutilization of phosphate bond energy.Adv. Enzymol. 1941; 1: 99-162Google Scholar). In this essay he alsointroduced the term “energy-rich phosphate bond” and the squiggleto denote this distinction (∼P). In 1941 Lipmann moved to Boston to join the research staff of theMassachusetts General Hospital. There, he set out to study acetyl transfer inanimals and to confirm that acetyl phosphate represented active acetate. Thiswork is the subject of the JBC Classic reprinted here. Lipmann worked out aneasy method to prepare acetyl phosphate(6Lipmann F. Tuttle L.C. Acetylphosphate: chemistry, determination, and synthesis.J. Biol.Chem. 1944; 153: 571-582Abstract Full Text PDF Google Scholar) and was able to isolate apotent acetylation system from pigeon liver extract with which he studied theacetylation of the amino group of the drug sulfonamide. Unexpectedly, Lipmannfound 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 betweenrespiration and acetylation occurred by way of phosphate bonds, he was unableto prove the involvement of acetyl phosphate. Despite Lipmann's initial disappointment with the above experiment, hisdecision to study acetylation would eventually prove fruitful. From the abovestudies, he noticed the requirement for a heat-stable factor that disappearedfrom the enzyme extracts on aging or dialysis. Because the cofactor waspresent in boiled extracts of all organs and could not be replaced by anyother known cofactor, Lipmann suspected that he was dealing with a newcoenzyme. Eventually, he was able to purify the coenzyme from pork liver andfound it to be active in choline acetylation with dialyzed brain extracts(7Lipmann F. Kaplan N.O. A common factorin the enzymatic acetylation of sulfanilamide and of choline.J.Biol. Chem. 1946; 162: 743-744Abstract Full Text PDF Google Scholar). He named the factorcoenzyme A (CoA), in which “A” stood for “activation ofacetate.” Lipmann subsequently showed that CoA is composed of adenosine5′-phosphate pantothenic acid and a sulfhydryl moiety and thatacetyl-CoA is involved in the acetylation of choline, in the synthesis ofcitrate and acetoacetate, and in pyruvate and fatty acid metabolism. His workon the coenzyme was eventually recognized in 1953 when he shared the NobelPrize in Physiology or Medicine with Hans Adolf Krebs “for his discoveryof co-enzyme A and its importance for intermediary metabolism.” (Krebswas awarded the Prize “for his discovery of the citric acidcycle.”) In 1949 Lipmann became Professor of Biological Chemistry at Harvard MedicalSchool. He remained at Harvard until 1957, when he was appointed a Member andProfessor of the Rockefeller Institute, New York. He became a ProfessorEmeritus at Rockefeller in 1970. Lipmann's initial work on CoA led him toinvestigate the general use of group activation by way of phosphorylation as acommon intermediary reaction in biosynthesis. His later research includeddemonstrating that carbamyl phosphate is a carbamyl donor, exploring thefunction of ATP in sulfate activation, and investigating the biologicalmechanisms of peptide and protein synthesis. In addition to receiving the Nobel Prize, Lipmann was awarded many otherhonors. In 1966 President Johnson presented him with the National Medal ofScience for his original discoveries of molecular mechanisms and hisfundamental contributions to the conceptual structure of modern biochemistry.He also received the American Society of European Chemists' Carl Neuberg Medaland the American Society for Nutritional Sciences' Mead Johnson Award and waselected to the National Academy of Sciences in1950. 1All biographical information on Fritz Lipmann was taken from Refs.8Lipmann F. Development of theacetylation problem: a personal account.Nobel Lecture. 1953; (December 11,1953)Google Scholar and9Lipmann F. A long life in times of greatupheaval.Annu. Rev. Biochem. 1984; 53: 1-33Crossref PubMed Google Scholar. 1All biographical information on Fritz Lipmann was taken from Refs.8Lipmann F. Development of theacetylation problem: a personal account.Nobel Lecture. 1953; (December 11,1953)Google Scholar and9Lipmann F. A long life in times of greatupheaval.Annu. Rev. Biochem. 1984; 53: 1-33Crossref PubMed Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: History and Philosophy of Science
Field: Arts and Humanities
Domain: Social Sciences
Open Access status: hybrid
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