Albert Dorfman and the Biosynthesis of Hyaluronic Acid
Year: 2005
Type: article
Abstract: The Biosynthesis of Hyaluronic Acid by Group A Streptococcus. I.Utilization of 1-C14-Glucose (Roseman, S., Moses, F. E., Ludowieg, J., and Dorfman, A. (1953) J. Biol. Chem. 203, 213-225) Albert Dorfman (1916-1982) was born and raised in Chicago. While in highschool, he became interested in science because of his older brother who wasstudying chemistry at the University of Illinois. After graduating, Dorfmanobtained a scholarship to the University of Chicago where he enrolled as achemistry major; however, during his senior year he switched to biochemistryand entered the University of Chicago School of Medicine. He eventually foundbiochemistry so appealing that he dropped out of medical school after 2 yearsto pursue graduate work. His thesis research was on the identification ofnicotinamide as a growth requirement for Shigella dysenteriae and thesynthesis of various nicotinic acid derivatives to correlate structure withbiological activity. Dorfman received his Ph.D. from the University of Chicago in 1939. Heremained at the University as a research associate and started to study therole of bacterial growth factors in metabolism. These studies led to Dorfman'sdevelopment of the technique of growing deficient cells to determine the roleof growth factors in metabolism. He also elucidated the roles of pantothenicacid in pyruvate metabolism and of biotin in aspartic acid biosynthesis. With the arrival of World War II and lack of an academic position, Dorfmanreturned to medical school and graduated in 1944. This experience rekindledhis interest in medicine, particularly pediatrics. An encounter with a childwith rheumatic fever also sparked an interest in the mechanism of action ofaspirin and would profoundly affect Dorfman's subsequent career. When Dorfman finished medical school he got an internship in internalmedicine at Beth Israel Hospital and then became a resident in pediatrics atthe University of Chicago. After completing his residency, he served 2 yearsin the U. S. Army where he was assigned to the Army Medical School and wasable to resume research in biochemistry. Around this time a study emergedclaiming that aspirin exerted its antirheumatic effect by inhibitinghyaluronidase. Dorfman promptly initiated studies on connective tissuepolysaccharides, an area of research he would pursue for the next 30 years. Hestarted by studying the biosynthesis of hyaluronic acid in group Astreptococci, which led to the development of quantitative methods for assaysof hyaluronidase, the discovery that chondroitin sulfate is a substrate fortesticular hyaluronidase, and the recognition that hyaluronidase is unusuallystable to heat and acid pH. After his 2 years in the army, Dorfman returned to the University ofChicago as an assistant professor of pediatrics and continued to study thebiosynthesis of hyaluronic acid. His goal was to determine the origins of the14 unique carbon atoms of the polysaccharide using specifically labeledprecursors. Dorfman embarked on this project with his postdoc, Saul Roseman,who was an author in a previous Journal of Biological Chemistry (JBC)Classic on Karl Paul Link (1.Classics JBC Campbell H.A. Link K.P. J. Biol. Chem. 1941; 138: 21-33Google ScholarStahmann M.A. Huebner C.F. Link K.P. J. Biol. Chem. 1941; 138: 513-527Abstract Full Text PDF Google ScholarOverman R.S. Stahmann M.A. Huebner C.F. Sullivan W.R. Spero L. Doherty D.G. Ikawa M. Graf L. Roseman S. Link K.P. J. Biol.Chem. 1944; 153 (http://www.jbc.org/cgi/content/full/280/8/e5): 5-24Abstract Full Text PDF Google Scholar)and will be featured in his own Classic in the future. Dorfman and Roseman,along with Julio Ludowieg and Frances Moses, synthesized[1-14C]glucose and incorporated it into medium upon which theycould grow streptococcus. They devised a method for isolating the radioactivehyaluronic acid from the streptococcus filtrate and then analyzed itscomponents. It became immediately evident that glucose was the major carbonprecursor of hyaluronic acid. The glucose was then converted to theglucosamine and glucuronic acid portions of the molecule without cleavage ofthe carbon chain. These results are presented in the JBC Classic reprintedhere, which is the first in a series of JBC papers Dorfman published on thebiosynthesis of hyaluronic acid by group A streptococcus. Dorfman and his colleagues subsequently synthesized[6-14C]glucose and [1-14C]acetic acid and used thosecompounds to establish that acetate is a precursor of the acetyl group ofN-acetylglucosamine and that glucosamine but notN-acetylglucosamine serves as a precursor of theN-acetylglucosamine residue in hyaluronic acid. These results werealso published in the JBC series(2.Roseman S. Ludowieg J. Moses F.E. Dorfman A. The biosynthesis of hyaluronic acid by group AStreptococcus. II. Origin of the glucuronic acid.J. Biol.Chem. 1954; 206: 665-669Abstract Full Text PDF PubMed Google Scholar,3.Dorfman A. Roseman S. Moses F.E. Ludowieg J. Mayeda M. The biosynthesis of hyaluronic acid by group AStreptococcus. III. Origin of the N-acetylglucosamine moiety..J. Biol. Chem. 1955; 212: 583-592Abstract Full Text PDF PubMed Google Scholar). The discovery of uridine nucleotide sugars by Luis Leloir, as reported in aprevious JBC Classic (4.Classics JBC Caputto R. Leloir L.F. Cardini C.E. Paladini A.C. J. Biol. Chem. 1950; 184: 333-350PubMed Google ScholarCabib E. Leloir L.F. Cardini C.E. J. Biol. Chem. 1953; 203: 1055-1070Abstract Full Text PDF PubMed Google ScholarCabib E. Leloir L.F. J. Biol.Chem. 1954; 206 (http://www.jbc.org/cgi/content/full/280/19/e16): 779-790Abstract Full Text PDF PubMed Google Scholar),suggested to Dorfman that these compounds might be intermediates inpolysaccharide synthesis. Together with J. A. Cifonelli, Dorfman establishedthat streptococci contain two uridine nucleotide sugars,UDP-N-acetylglucosamine and UDP-glucuronic acid, which are requisitefor the biosynthesis of hyaluronic acid(5.Cifonelli J.A. Dorfman A. Thebiosynthesis of hyaluronic acid by group A Streptococcus. V. The uridinenucleotides of group A Streptococcus.J. Biol. Chem. 1957; 228: 547-557Abstract Full Text PDF PubMed Google Scholar). Using labeled nucleotides,they were able to demonstrate the synthesis of hyaluronic acid in a cell-freepreparation of streptococci. This was published as the final paper inDorfman's hyaluronic acid series in the JBC(6.Markovitz A. Cifonelli J.A. Dorfman A. The biosynthesis of hyaluronic acid by group AStreptococcus. VI. Biosynthesis from uridine nucleotides in cell-freeextracts.J. Biol. Chem. 1959; 234: 2343-2350Abstract Full Text PDF PubMed Google Scholar). In addition to his work on hyaluronic acid, Dorfman also contributedsignificantly to understanding the biosynthesis of other glycosaminoglycans.As well, he discovered the cause of Hurler's syndrome, a genetic disease thataffects bones and cartilage and results in mental retardation. He deduced thatthe condition results from elevated levels of dermatan sulfate and heparinsulfate due to a defect in α-l-iduronidase, an enzyme neededfor the normal catabolism of the two glycosaminoglycans. In 1967 Dorfman became the Richard T. Crane Distinguished Service Professorof Pediatrics and Biochemistry and acted as Chairman of the Department ofPediatrics from 1962 to 1972. He also served as Director of the La RabidaUniversity of Chicago Institute (1957-1972) and Director of the Joseph P.Kennedy, Jr. Mental Retardation Research Center (1967-1982). In addition tohis research activities, Dorfman was President of the Society for Glycobiology(1975) and President of the Pediatric Society (1979). His contributions toscience were recognized with his election to the National Academy of Sciencesin 1973. 1All biographical information on Albert Dorfman was taken from Ref.7.Schwartz N.B. Rodén L. Biographical Memoir of Albert Dorfman. 72. NationalAcademy of Sciences, Washington, D. C.1997: 70-87Google Scholar. 1All biographical information on Albert Dorfman was taken from Ref.7.Schwartz N.B. Rodén L. Biographical Memoir of Albert Dorfman. 72. NationalAcademy of Sciences, Washington, D. C.1997: 70-87Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1572652045