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J. Biol. Chem., Vol. 281, Issue 6, 6, February 10, 2006
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Classics
The Complete Amino Acid Sequence of 
-Lactalbumin (Brew, K., Castellino, F. J., Vanaman, T. C., and Hill, R. L. (1970) J. Biol. Chem. 245, 4570–4582)
The Disulfide Bonds of Bovine -Lactalbumin (Vanaman, T. C., Brew, K., and Hill, R. L. (1970) J. Biol. Chem. 245, 4583–4590)
The Purification and Properties of the A Protein of Lactose Synthetase (Trayer, I. P., and Hill, R. L. (1971) J. Biol. Chem. 246, 6666–6675)
Robert L. Hill was born in Kansas City, Missouri in 1928. He earned a B.A. in chemistry in 1949 and a Ph.D. in biochemistry in 1954 from the University of Kansas. After receiving his Ph.D., he went to the University of Utah as a National Institutes of Health (NIH) postdoctoral fellow, where he worked with Emil L. Smith, who was featured in two Journal of Biological Chemistry (JBC) Classics (1, 2). Although Hill's Ph.D. thesis research concerned bacterial metabolism, his postdoctoral studies introduced him to protein and enzyme chemistry, research areas he pursued during his subsequent career. At Utah, he published papers on proteolytic enzymes and human hemoglobin and myoglobin. Hill remained at the University of Utah as a faculty member of the Department of Biochemistry until 1961. He then joined the faculty of the Department of Biochemistry at Duke University School of Medicine, where he remains today.
At Duke, Hill continued his work on human hemoglobins, including several abnormal variants, but soon turned his attention to the structure-function relationships of other proteins and enzymes, including human fibrinogen and other blood coagulation factors, immunoglobulins, egg white lysozyme, bacterial acyl carrier protein, and lactose synthase. In subsequent years he studied glycosyltransferases and worked in several areas of glycobiology. Hill's work on lactose synthase is the subject of the three JBC Classics reprinted here.
Lactose synthase consists of a catalytic galactosyltransferase in the endoplasmic reticulum of the mammary gland and a regulatory protein, -lactalbumin, secreted in milk. Without -lactalbumin, galactosyltransferase cannot synthesize lactose and instead catalyzes the attachment of galactose to N-acetylglucosamine units on glycoproteins. The presence of -lactalbumin changes the specificity of galactosyltransferase so that it can transfer galactose to glucose.
In the first JBC Classic, Hill, along with Keith Brew, Francis J. Castellino, and Thomas C. Vanaman, reports the complete amino acid sequence of bovine -lactalbumin. They deduced the sequence by characterizing the tryptic, chymotryptic, and peptic peptides of -lactalbumin cleaved with cyanogen bromide. Because the amino acid sequence of -lactalbumin is very similar to that of egg white lysozyme, Hill and his colleagues aligned the two sequences and found that 49 of the residues were identical and 23 were conservative replacements. Thus, they concluded that the three-dimensional structures of the two proteins were probably very similar (3) and that they most likely arose from a common ancestral gene.
Hill, Brew, and Vanaman confirmed this structural similarity in the second Classic in which they describe the locations of the four disulfide bonds in -lactalbumin. They found that the disulfide bonds are arranged in a manner similar to those in egg white lysozyme and proposed a three-dimensional structure for -lactalbumin based on the three-dimensional structure of lysozyme, as shown in Fig. 2. Later, Hill, Brew, and Vanaman showed how -lactalbumin serves as a regulatory protein for lactose synthase and permits the enzyme to synthesize lactose in the mammary gland.
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-lactalbumin attached covalently to Sepharose. In the presence of glucose, galactosyltransferase would bind to the column and could then be removed by omission of glucose from the elution buffer. Using this method, Hill and Trayer were able to purify galactosyltransferase from bovine milk about 12,000-fold. In 1969 Hill became the chairman of the Department of Biochemistry, and in 1974, the James B. Duke Professor. He served as chairman until 1993. He was President (1976) and Secretary (1972–1975) of the American Society of Biological Chemistry and was also on the Editorial Board (1965–1970, 1972–1977) and an Associate Editor (1988-present) of the JBC. Hill served on the FASEB Board (1972–1978), was General Secretary of the International Union of Biochemistry (1982–1991), and chair of the Organizing Committee of the 17th International Congress of Biochemistry and Molecular Biology in San Francisco in 1997. He was elected to the National Academy of Sciences in 1975, the Institute of Medicine in 1978, and the American Academy of Arts and Sciences in 1974. Hill received the Rose Award from the American Society for Biochemistry and Molecular Biology in 1991, the North Carolina Gold Medal (Science-1985), and the Karl Meyer Award from the Society for Glycobiology (2001).
Each of the coauthors on these Classic papers was a student or postdoctoral fellow in Hill's laboratory, and all have had productive, independent careers in biochemistry. Thomas Vanaman was a Ph.D. student who subsequently became Professor of Biochemistry and Chair at the University of Kentucky. The others were postdoctoral fellows. Keith Brew went to the University of Leeds (UK) before returning to the U. S. where he became Professor of Biochemistry at the University of Miami. He is now at Florida Atlantic University. Francis J. Castellino is currently Professor of Biochemistry at the University of Notre Dame, and Ian P. Trayer was Professor and Head of the School of Chemistry at the University of Birmingham (UK). Brew and Castellino served on the JBC editorial board. Vanaman also served on the JBC board and currently is an Associate Editor.
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-lactalbumin based on that of hen's egg-white lysozyme. J. Mol. Biol. 42, 65–86[CrossRef][Medline]
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