Frank H. Westheimer (1912–2007) Pioneering Chemist at the Interface with Biology
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NATURE|Vol 447|31 May 2007 NEWS & VIEWS OBITUARY Frank H. Westheimer (1912–2007) Pioneering chemist at the interface with biology. Today, we recognize that the complexities of using nuclear magnetic resonance (NMR) biology can be explained by understanding spectroscopy. But NMR wasn’t available the chemical and physical properties of at the time, so Westheimer’s analyses were the molecules, both large and small, that accomplished by ‘brute force’: the organic OFFICE NEWS UNIV. S. MITCHELL/HARVARD interact to mediate life’s processes. However, molecules were combusted to produce we should never forget the intellectual water, which was converted to hydrogen gas. foundation that allows us to approach The isotopic content of that gas was then difficult biological problems in this way. determined by mass spectrometry. Frank Westheimer, who died on 14 April at Westheimer also demonstrated that this the age of 95, demonstrated that chemists enzymatic hydrogen transfer is stereospecific have a unique advantage in deciphering — the active site distinguishes between two the key processes of biology. Westheimer chemically equivalent hydrogens in ethanol, used his insight to describe the workings transferring just one of them to the cofactor. of enzyme-catalysed reactions, providing Nowadays, it is understood that chemically in that area. One day, I realized that I had essential blueprints for future investigations equivalent hydrogen atoms in molecules can inadvertently crystallized a crucial enzyme, of the biochemical foundations of life. be differentiated in the chiral environment of so I asked Frank to come with me from his Westheimer was born in Baltimore, an enzyme active site. But Westheimer’s study office to the microscope in the laboratory. Maryland, on 15 January 1912. He graduated was the first demonstration of this effect, and Despite protestations that he was busy, he from Dartmouth College in 1932 and his results were unexpected. followed me, and I will never forget his smile received his PhD in chemistry from Harvard Shortly after moving to Harvard, when I told him what he was looking at. To a University in 1935. Following a postdoctoral Westheimer went on to investigate chemist, crystals are both measures of purity year at Columbia University, he joined the another important class of biochemical and objects of beauty. To Frank, crystals of chemistry department at the University of transformation: phosphoryl transfer a molecule as complex as an enzyme were a Chicago, where he worked for nearly 20 reactions. These are essential for many special joy. years. However, this period was interrupted biological processes, including the production Westheimer’s achievements extended by the Second World War, when he was and use of metabolic energy, the storage of beyond academia. In 1965, he chaired the a supervisor at the National Explosives genetic information, and signal transduction. US National Academy of Sciences Research Laboratory. In 1953, he returned The central chemical event in these processes Committee for the Survey of Chemistry. to Harvard, where he remained until his is the cleavage of bonds in phosphate ester This body issued the influential Westheimer retirement in 1983. He received the US molecules, which come in two varieties: Report, which recommended increases in National Medal of Science in 1986. monoesters (as found in the energy-storage US federal funding for the chemical sciences Westheimer began his career as a physical molecule ATP) and diesters (such as those and highlighted the importance of the organic chemist, and one of his most notable found in DNA). Westheimer established that emerging field of biochemistry. Westheimer achievements in this area was the invention the mechanisms of cleavage in phosphate also served as a science adviser to US President of molecular mechanics in the late 1940s. diesters and monoesters are not the same, Lyndon Johnson from 1967 to 1970. This is a mathematical approach in which so providing a crucial understanding of how I last saw Frank three years ago at his home the bending and stretching parameters of enzymes catalyse these diverse reactions. in Cambridge, Massachusetts. Even at 92, he molecules are used to predict the rates of With typical eclecticism, Westheimer was intensely interested in my science, just as chemical reactions. The manual calculation made another ground-breaking discovery in he had been when I was a graduate student. efforts required were considerable, but the 1960s by determining how enzyme active My plan was to give a private seminar about molecular mechanics (and its sibling, sites stabilize carbanions — unstable organic my most recent work, but I didn’t get far quantum mechanics) is now used routinely as anions that often occur as intermediates in before he was reminiscing about his career a computational method to predict the course enzyme-catalysed processes. Focusing on and how science had changed. As he observed of enzyme-catalysed reactions. the reaction mediated by the acetoacetate in my work, X-ray crystallography is now While at Chicago, Westheimer started decarboxylase enzyme, he showed that the used routinely to obtain enzyme structures, working in biochemistry; he was the first carbanion intermediate is stabilized by a providing once unimaginable information to apply the rigorous analysis of physical positively charged group (a β-iminium ion) for determining their modes of action. It was organic chemistry to enzymes. Because he that forms when the substrate reacts with humbling to recall that his pioneering work chose not to focus on a single problem, it is a lysine amino acid side chain in the active on alcohol dehydrogenase was achieved difficult to identify an area of biochemistry site. He also established the importance without even the benefit of NMR. But that Westheimer has not influenced. His of electrostatic effects in modulating the although experimental tools have changed, first breakthrough was in the early 1950s, reactivities of chemical groups in active sites. the intellectual guidelines established by when he used isotopic labelling to study the In the case of acetoacetate decarboxylase, the Westheimer for understanding the chemical oxidation of alcohol (ethanol) by the enzyme active-site environment decreases the basicity basis of biology will endure for ever. alcohol dehydrogenase. He discovered that a of the essential lysine residue, a necessary John A. Gerlt direct transfer of hydrogen occurs between effect if the enzyme is to work at neutral pH. John A. Gerlt is in the Departments of the substrate and the enzyme cofactor — a Westheimer continued to be intrigued Biochemistry and Chemistry, University of then surprising result that demonstrated by the cleavage of phosphate esters, and I Illinois, 600 South Mathews Avenue, Urbana, the power of his chemical approach. Today, joined his laboratory as a graduate student in Illinois 61801, USA. this study could be simply performed the early 1970s as part of his research effort e-mail: [email protected] 543.