American Geneticist and Microbiologist
Charles Yanofsky's most significant contributions to genetics and biochemistry developed from his studies of the genetics and biochemistry of tryptophan synthetase. Yanofsky's pioneering investigation of tryptophan synthetase was the first to demonstrate than an enzyme could contain two dissimilar subunits. Eschericia coli tryptophan synthetase catalyzes the final two sequential reactions in the biosynthesis of tryptophan. Yanofsky's work on the relationship between the genes controlling the enzyme and the synthesis and regulation of the enzyme contributed to a more sophisticated version of the "one gene—one enzyme" concept advanced by George Beadle (1903-1989) and Edward Tatum (1909-1975).
Yanofsky was born in New York City. He received his B.S. degree, with a major in biochemistry, from the City College of New York in 1948. He earned his M.S. and Ph.D. degrees in microbiology from Yale University in 1950 and 1951, respectively. From 1944 to 1946, he served with the Armed Forces of the United States. After spending two years as a research assistant in microbiology (1951-1953), he became Assistant Professor of Microbiology at Western Reserve University Medical School (1954-1958). In 1958 he accepted a professorship in the Department of Biological Sciences at Stanford University. In 1967 he was appointed Herzstein Professor of Biology. He was elected to the American Academy of Arts and Sciences in 1964, and the National Academy of Sciences in 1966.
One of the first biosynthetic pathways to be thoroughly elucidated by biochemical and genetic analyses in Neurospora crassa was the one leading to the amino acid tryptophan. Further research with typtophan-requiring mutants of Eschericia coli and Salmonella typhimurium confirmed the findings in Neurospora. Stimulated by the work of Beadle and Tatum, Yanofsky's advisor at Yale, David Bonner, attempted to investigate the relationship between genes and enzymes by examining the enzymes of Neurospora that appeared to be defective or missing in specific mutants. By the 1950s members of Bonner's group had chosen enzymes in Neurospora or E. coli for further enzymatic and genetic analyses, hoping to reveal the structural relationship between gene and protein. Because of his previous research experience, Yanofsky chose tryptophan synthetase. Work with this complex enzyme would provide valuable insights into the structural relationship between genes and enzymes, including such specific aspects as suppression, reaction mechanisms, active sites, protein folding, and the variability of enzymes from different microbial species.
In 1954 Yanofsky and his colleagues unequivocally proved that tryptophan synthetase in Eschericia coli consisted of two separable protein subunits. Yanofsky's group also determined the relationship between the protein subunits and the series of reactions catalyzed by the intact protein, the ability of the subunits to aggregate, and the location of the active sits for substrates.
In the 1980s Yanofsky carried out a series of experiments that illuminated the phenomenon of attenuation in the control of bacterial operons concerned with the biosynthesis of amino acids. According to these experiments, the operons in the bacterial chromosome that are responsible for the biosynthesis of amino acids contain a site called the attenuator. The translation product of the initial segment of these operons is a peptide that is rich in the amino acid whose synthesis is controlled by that operon. When the supply of that amino acid was very low, translation at the relevant codons of the transcript was inhibited. This process allowed RNA polymerase to proceed through a site that would terminate transcription when the supply of the amino acid in question is high. Attenuation provided a new mechanism for the regulation of gene expression based on the selective reduction of the transcription of distal portions of an operon. Yanofsky explained that the existence of two mechanisms—the repression system and attenuation—for regulating transcription of the tryptophan operon might be explained in terms of the various metabolic reactions that are involved in the biosynthesis and utilization of tryptophan. According to Yanofsky, the combination of the two regulatory mechanisms allowed the bacterium to recognize and respond efficiently to both external and internal events. Studies of tryptophan synthetase were so fruitful that Yanofsky has called it a "charmed enzyme."
LOIS N. MAGNER