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J. Biol. Chem., Vol. 282, Issue 21, 16, May 25, 2007
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Classics
The Simultaneous Determination of Partial Specific Volumes and Molecular Weights with Microgram Quantities
(Edelstein, S. J., and Schachman, H. K. (1967) J. Biol. Chem. 242, 306–311)
Cooperative Binding of the Bisubstrate Analog N-(Phosphonacetyl)-L-aspartate to Aspartate Transcarbamoylase and the Heterotropic Effects of ATP and CTP
(Newell, J. O., Markby, D. W., and Schachman, H. K. (1989) J. Biol. Chem. 264, 2476–2481)
Howard Kapnek Schachman was born in Philadelphia in 1918. As a high school student he was more interested in social and political issues than in science and planned on becoming a rabbi. Thus, he decided to pursue a liberal arts curriculum in college. However, a family friend urged him to think about his future employment, and as a result Schachman enrolled at the University of Pennsylvania as a chemical engineering major. A year later he transferred to the Massachusetts Institute of Technology where he got his B.S. in 1939. After graduating, Schachman found work at a small company but was not content in his job. Around this time he attended a lecture by Max Lauffer on the physical chemistry of the tobacco mosaic virus (TMV). Motivated by Lauffer's lecture style and his research, Schachman wrote him and discovered that Lauffer was looking for a technician. After an interview with Lauffer and Wendell Stanley, the head of the laboratory doing the research on TMV, Schachman abandoned his search for an industrial position as a chemical engineer (which included looking for openings by scanning the obituaries in Chemical and Engineering News) and became a technician in the Department of Animal and Plant Pathology at the Rockefeller Institute for Medical Research in Princeton, New Jersey.
At Rockefeller, Schachman's main job was to operate an air-driven ultracentrifuge for sedimentation velocity experiments requested by investigators. Because of the large number of experiments he was asked to perform, Schachman started thinking of better ways to calculate sedimentation coefficients from the raw data and to convert the observed values to standard conditions. This led to his construction of an alignment chart that simplified the procedure and minimized computational errors. Lauffer and Stanley thought the method should be published but discovered that a scientific paper by a technician was not acceptable at Rockefeller. It was decided that Lauffer would write the article and Schachman would be a coauthor. Much to their surprise, the coauthored paper was not approved by the Institute's administration. However, approval was granted for a paper with Schachman as sole author as long as it included an asterisk following his name, referring to a footnote reading, "Technical Assistant in the Laboratory of Plant Pathology." The paper appeared in the Journal of Biological Chemistry (JBC) in 1942 (1).
While working at Rockefeller, Schachman decided to attend graduate school and enrolled at Harvard University as a part-time student, taking courses in the summer. During his second summer at Harvard, Schachman got a message from Stanley saying that the laboratory had received a contract to work on an influenza vaccine and that Schachman had to return to
Rockefeller. As a result, Schachman became a part-time student at Princeton and earned his Ph.D. there in 1948.
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Schachman and Stuart Edelstein also came up with a method for the simultaneous measurement of partial specific volumes and molecular weights of proteins and other substances by sedimentation equilibrium experiments in H2O and D2O (or D 182O) solutions. This is the subject of the first JBC Classic reprinted here. To determine molecular weight by ultracentrifugation, the partial specific volume of the protein of interest must be known. However, in the mid-1960s, the standard procedures for determining partial specific volume required large amounts of protein. Schachman and Edelstein's sedimentation equilibrium method required only microgram quantities of protein and was based on the change produced in the equilibrium concentration distribution when the density of the solution is increased by the use of D2O (or D 182O). Using their method, they were able to determine the partial specific volumes and molecular weights of several proteins including ferredoxin, ribonuclease, myoglobin, 
-chymotrypsinogen, and bovine plasma albumin, as well as the small molecule adenosine.
In early 1964, John Gerhard approached Schachman about using the ultracentrifuge to answer questions about the subunit structure of aspartate transcarbamoylase (ATCase), the enzyme that catalyzes the first step in the pyrimidine biosynthetic pathway. This led to Schachman's career-long studies on ATCase and his discovery that the enzyme has distinct subunits for catalysis and regulation and that it undergoes global conformational changes upon ligand binding.
Substrate binding to the catalytic subunits of ATCase results in an equilibrium shift toward the R state, whereas binding of the inhibitor CTP to the regulatory subunits results in an equilibrium shift toward the T state. In contrast, when the activator ATP binds to the regulatory subunits, the equilibrium shifts toward the R state. Most investigations of the allosteric properties of ATCase were based on the sigmoidal dependence of enzyme activity on substrate concentration and the effects of CTP and ATP on the saturation curves. Interpretations of these effects, however, were complicated by an inability to distinguish between changes in substrate binding and catalytic turnover accompanying the allosteric transition. To eliminate this ambiguity, Schachman studied the binding of the bisubstrate analog N-(phosphonacetyl)-L-aspartate to ATCase in the absence and presence of ATP and CTP. This is the subject of the second JBC Classic reprinted here. The resulting saturation curves gave independent data for analyzing the allosteric properties of ATCase and allowed Schachman and his colleagues to relate measured conformational changes in the enzyme directly to the fractional occupancy of the active sites. A more complete overview of Schachman's research on aspartate transcarbamoylase can be found in his JBC Minireview (2).
Schachman was promoted to associate professor at Berkeley in 1954, and he became a full professor in 1959. He then served as Chairman of the Department of Molecular Biology and Director of the virus laboratory from 1969 to 1976. He remains at Berkeley as professor emeritus today.
Schachman has served the American Society for Biochemistry and Molecular Biology in numerous capacities including acting as President in 1987 and as Chairman of the Society's Public Affairs Advisory Committee for more than 10 years (1989–2000). He was also President of the Federation of American Societies for Experimental Biology in 1988. During that time Schachman traveled extensively to Bethesda and helped to formulate positions that he hoped represented the working scientist's point of view. Schachman also served for 6 years as an advisor to the Director of the National Institutes of Health (NIH), Harold Varmus, and as its Ombudsman in the Basic Sciences. More information about Schachman's involvement in public policy affecting science can be found in his JBC Reflections (3). For his efforts in public policy, FASEB honored Schachman in 1994 with their Public Service Award, and ASBMB established the Howard K. Schachman Public Service Award in 2001.
Schachman has received several other honors, including the E. H. Sargent and Co. Award for Chemical Instrumentation (1962), the John Scott Award of the City of Philadelphia (1964), the Warren Triennial Prize of the Massachusetts General Hospital (1965), the American Society of Biological Chemists Merck Award (1986), the Berkeley Citation for Distinguished Achievement and Notable Service (1993), the Alexander von Humboldt Award (1990), the American Society for Biochemistry and Molecular Biology Herbert A. Sober Award (1994), the Theodor Svedberg Award (1998), and the AAAS Scientific Freedom and Responsibility Award (2001). Schachman was elected to the American Academy of Arts and Sciences in 1966 and to the National Academy of Sciences in 1968. He was also elected as a Foreign Member of the Accademia Nazionale Dei Lincei in 1996.1
FOOTNOTES
1 Biographical information on Howard K. Schachman was taken from Ref. 4. 
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