John Cornforth (1917–2013) Nobel-Prizewinning Chemist Who Tracked How Enzymes Build Cholesterol

OBITUARY COMMENT John Cornforth (1917–2013) Nobel-prizewinning chemist who tracked how enzymes build cholesterol. ife depends on the geometric War, the radioisotope carbon-14 intricacies of enzymatic reac- became available for basic research, tions. Even when molecules providing a way to establish the bio- Lare exact mirror images of each other, logical building blocks of larger enzymes treat the ‘left-handed’ and molecules. Other researchers had BETTMANN/CORBIS ‘right-handed’ versions differently. already begun to figure out the origin John Cornforth identified which of a of certain carbon atoms in a side chain series of mirror images interact with of the cholesterol molecule by using the enzymes that carry out the natural radioactively labelled acetate, a small synthesis of cholesterol. This work, for organic compound containing only which he shared the 1975 Nobel Prize two carbon atoms. Cornforth took on in Chemistry, laid the foundations the more demanding experimental for many studies of how cells build work required to establish the origin organic compounds. of each of the carbon atoms in choles- Cornforth, who died on 8 December terol’s four conjoined molecular rings. 2013, was born in Sydney, Australia, in He identified 14 steps in the early 1917. By the time he was ten, the first stages of the natural formation of signs of his oncoming deafness had cholesterol. In each of these steps, the become apparent. As a boy, he built intermediate products could be trans- his own rudimentary laboratory at formed in one of two ways. His design home. And, encouraged by a school for labelling experiments defined a teacher, he entered the University of single pathway out of the 16,384 (214) Sydney at the age of 16 to read chem- possibilities. istry, a subject in which he thought his In another series of experiments, deafness would be less of a handicap. on acetic acid, Cornforth labelled the Although unable to hear the lectures, hydrogen atoms around a carbon, his thorough study of the scientific literature multi-ringed organic compounds that replacing the hydrogens with the isotopes enabled him to graduate in 1937 with a first- includes cortisone, estrone and testosterone. deuterium and tritium such that each had a class honours degree and a university prize. This effort eventually bore fruit in the first distinct position around carbon. These clas- Boyhood rambles in the bush inspired total synthesis of an androgenic hormone, sic experiments opened up the possibility of Cornforth’s interest in natural products, and reported in 1953 (H. M. E. Cardwell et al. exploring a wide range of enzyme reactions, he began graduate studies at the University J. Chem. Soc. 361–384; 1953). including fatty-acid biosynthesis. of Sydney. A number of his early papers were In 1942, as part of the joint US–UK war In 1975, the same year that he won the on the constituents of Australian plants, such effort, the couple joined the team working Nobel prize for decoding the stereochem- as the caustic vine (Sarcostemma australe). on the structure of the antibiotic penicillin. istry of biosynthetic reactions, Cornforth His lifelong nickname, Kappa, arose from Cornforth made a number of important accepted a Royal Society research professor- chemists’ habit at the time of engraving contributions, including identifying and ship at the University of Sussex, UK. There, their glassware: his initials (JC) resembled synthesizing penicillamine, a key degrada- he began an extremely ambitious project to the Greek letter. tion product of penicillin. This work stimu- craft a compound that could act as an ana- Cornforth’s deafness led to an intense lated Cornforth’s investigations into the class logue for hydratase, the enzyme that adds loneliness that was alleviated by the com- of compounds known as oxazolones, includ- water to another molecule. panionship in the laboratory. The skills ing a type of chemical rearrangement that He was knighted in 1977 and made a he developed in his home lab, of building now bears his name. Companion of the Order of Australia in and repairing experimental apparatus, had In 1946, the Cornforths moved to the 1991. Kappa lectured undergraduates and many benefits. One was meeting the talented Medical Research Council National Insti- supervised student projects until he was chemist, Rita Harradence, who asked him to tute for Medical Research in London. Here, well into his 80s, often enhancing conver- repair a flask. In 1941, she became his wife. Cornforth continued his work on steroid sations with an aptly worded limerick. His Throughout his career she acted both as an and oxazolone chemistry and began a very kindness, generosity and humour were interpreter and a collaborator; they authored fruitful collaboration with the medical bio- appreciated by all with whom he came into more than 40 papers together. chemist George Popják, which continued contact. ■ In 1939, Cornforth and Harradence were when they became co-directors in 1962 awarded scholarships for doctoral studies of Shell Research’s newly set up Milstead Jim Hanson is professor emeritus of under Robert Robinson, an organic chemist Laboratory of Chemical Enzymology in chemistry at the University of Sussex, at the University of Oxford, UK, who won Sittingbourne, UK. Brighton, UK. He worked in the same the 1947 Nobel Prize in Chemistry. They Like many chemists, Cornforth was laboratory as John Cornforth for three began work on the synthesis of steroids, a intrigued by how natural products are decades. biologically important class of complex, formed. In the years after the Second World e-mail: [email protected] 6 FEBRUARY 2014 | VOL 506 | NATURE | 35 © 2014 Macmillan Publishers Limited. All rights reserved.

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