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On Glutathione. II. A Thermostable Oxidation-Reduction System (Hopkins, F. G., and Dixon, M. (1922) J. Biol. Chem. 54, 527–563) Sir Frederick Gowland Hopkins (1861–1947) was born in East Sussex, Great Britain. He founded the Department of Biochemistry at the University of Cambridge in 1914. In 1920, the estate of Sir William Dunn provided funds for the establishment of a School of Biochemistry, a Chair of Biochemistry, and a new building for the Department at Cambridge. The Sir William Dunn Institute of Biochemistry was opened in 1924, and Hopkins was the first Sir William Dunn Chair (subsequent occupants of the Dunn Chair at Cambridge were A. C. Chibnall, Sir Frank Young, Sir Hans Kornberg, and, at present, Tom L. Blundell). Hopkins focused his own research on “accessory food factors,” later termed vitamins, and his interests shaped the directions of research in this distinguished department. Among the many contributions Hopkins made is the discovery and characterization of glutathione that is described in this Journal of Biological Chemistry (JBC) Classic Paper. It had been recognized that glutathione underwent reversible oxidation-reduction, which involved a disulfide linkage between two molecules of GSH in GSSG. In this paper, Hopkins cites the discovery of “coferment” of alcoholic fermentation by Harden, Young, and Meyerhof for his discovery of the factors necessary for respiratory oxidations as well as for the method of simple extraction of tissues with water to identify the factors necessary for a biochemical process. After studying chopped muscle tissue extracted with water, Hopkins concluded that “When a tissue is washed until it has lost its power to reduce methylene blue, the subsequent addition of glutathione to a buffer solution in which the tissue residue is suspended restores reducing power.” By using boiled tissue, he demonstrated that the system was heat-stable and is non-enzymatic. Although the discovery of glutathione certainly ranks among the major discoveries in biochemistry, Hopkins is unfortunately remembered for his error regarding the structure of glutathione, which he had concluded was a dipeptide of glutamic acid and cysteine. The structure of glutathione was controversial for several years. In 1927, Hunter and Eagles described a product, isolated using the same procedure employed by Hopkins, that had significantly less sulfur per mass than Hopkins had reported and was possibly a tripeptide (1Hunter G. Eagles B.A. J. Biol. Chem. 1927; 72: 133Abstract Full Text PDF Google Scholar). After seeing a preprint version of the Hunter and Eagles paper provided by the Editors of JBC with permission of the authors, Hopkins responded that their preparation of glutathione was impure and reasserted that glutathione was a dipeptide (2Hopkins F.G. J. Biol. Chem. 1927; 72: 185Abstract Full Text PDF Google Scholar). In 1929, after developing a new procedure for preparing crystalline glutathione, Hopkins recognized that“ Hunter and Eagles were right in doubting that the substance is a simple dipeptide of glutamic acid and cysteine....” (3Hopkins F.G. J. Biol. Chem. 1929; 84: 269Abstract Full Text PDF Google Scholar). He then showed that glutathione is indeed a tripeptide of glutamic acid, glycine, and cysteine. Although he did not determine the precise structure, he suggested it was Glu-Cys-Gly. (The structure of glutathione is, in fact,γ -l-glutamyl-l-cysteinylglycine). In reference to the mistake, Hopkins wrote that “The grave discomfort involved in making an admission of previous error is mitigated by the circumstances that I am now able to describe a method, not without special interest in itself, which with ease and rapidity separates from yeast and red blood cells a pure crystalline thiol compound with a.... tripeptide structure” (3Hopkins F.G. J. Biol. Chem. 1929; 84: 269Abstract Full Text PDF Google Scholar). His error on the structure of glutathione has not been forgotten many decades later. Hopkins is more appropriately remembered, however, as a giant of biochemistry. He was knighted in 1925 and received the Nobel Prize in Physiology or Medicine in 1929. In 1936, a young undergraduate student, Max Perutz, left his native Vienna, with the rise in anti-Semitism, and moved to Cambridge. He was attracted to Hopkins's department and Hopkins's work on vitamins and enzymes. Perutz worked with John Desmond Bernal in the Cavendish Laboratory and began his historic crystallographic analysis of the structure of hemoglobin.
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