REVIEWS 100 Years “Schlussel-Schloss-Prinzip” : What Made Emil Fischer Use this Analogy?** Frieder W. Lichtenthaler* Emil Fischer’s famous lock-and-key structive reasoning and the thought pat- others--he rather expounded on the analogy (Schliissel-Schloss-Prinzip) for terns underlying the fundamental in- scope of the lock-and-key picture: ‘‘I am the specifity of enzyme action has pro- sight. Accordingly, this account at- far from placing this hypothesis side by vided successive generations of scientists tempts to trace how Fischer was led to side to the established theories of our with a mental picture of molecular the lock-and-key analogy, based on the science, and readily admit. that it can recognition processes, and thus has state of knowledge and the views pre- only be thoroughly tested, when we are shaped to a marked degree the develop- vailing at the time. It reveals that Fi- able to isolate the enzymes in a pure ment not only of organic chemistry, but, scher, who had a pronounced tendency state and thus investigate their configu- through its extension to basic live pro- against any sort of theoretical specula- ration.” Others, most notably P. Ehrlich cesses, that of biology and medicine as tion, refrained from taking this meta- und F. Lillie, by introduction of the con- well. The hundredth anniversary of the phor any further, that is to the obvious cept of stereocomplementarity into first use of this most fertile metaphor extensions of what turns the key, and medicine and biology, induced the lock- provides a welcome opportunity not what kind of doors are then opened. Ex- and-key analogy to become something only for highlighting its paramount im- cept for a small refinement -the differ- of a dogma for explaining principal life portance, but for gaining an under- entiation of main key and special keys to processes. standing and appreciation of the cre- account for the fact that some yeasts can ative processes involved, of the con- ferment a larger number of hexoses than Id1 halte Lehr-e und Studium der historischm from oblivion, but for gaining an understanding and apprecia- Enttvicklung drr Wissenschafi fur zmenthrhrlich. tion of the creative processes involved, of the thought patterns Unsere Lehrhiicher versageri darin. underlying the fundamental insight, and the constructive rea- Richard Willstitter”’ soning that eventually led to it. A comprehension of these fac- tors appears to be required to get a true measure of the magni- Emil Fischer’s famous lock-and-key analogy for the specifity tude and significance of Fischer’s basic contribution. of enzyme action has provided successive generations of scien- Any attempt-after a 100 years-to trace what led Fischer to tists with their mental picture of molecular recognition pro- the lock-and-key analogy, must go back to the state of knowl- cesses, and. thus has shaped to a marked degree the develop- edge and the views pevailing at the time, that is around 1890, ment not only of organic chemistry, but, by extension to basic and to the scientific school from which Fischer emerged. In life processes, that of biology and medicine as well. 1871, he had entered the University of Bonn, where he attended Fischer’s seminal paper in which he first used the lock-and- lectures by A. Kekule and R. Clausius. yet, in the following year key metaphor appeared in Berichte d~rDeutschen Clirmischen transferred to the University of Strassburg to study with Adolf Gesrllschuft of 1894.[21Thus, a century has passed away since Baeyer, earning his doctorate with him in 1874 at the age of 22. and accordingly, this provides a unique opportunity to com- A year later. while working already independently in Baeyer’s memorate the 100th anniversary of this most fertile hypothe- laboratory, he accidentally discovered phenylhydra~ine‘~] sis-not only for historical purposes or for keeping pivotal facts which was to become the key reagent for his exploration of the sugars. when, ten years later, he finally applied it to the then [*I Prof. Dr. F. W. Lichtenthaler Institut fur Organische Chemie der Technischen Hochschule existing Petersenstrasse 22. D-64287 Darmstadt (FRG) The research school of Adolf Baeyer (1835-1917[51), from Telefax: lnt. code + (61511166674 which Fischer emerged -first in Strassburg, and then for [**I Based on a CommemoraLive Lecture presented at the European Research Conference “Supramolecular Chemistry: 100 Years Schloss-Schlusscl-Prin- 40 years after 1875 at the University of Munich-was ii major zip’.. Mainz. August 12, 1994. “forge” of talent. A group photograph[61 of 1878 (Fig. 1) 100 Years “Schlussel-Schloss-Prinzip” .REVIEWS Fig. 1. Photograph of the Baeyer group in early 1878 at the laboratory of the University of Munich (room for combustion analysis). wlth inscriptions from Fischer’s hand [6] attests to that almost literally: the unusually wide hood in the the left Jacob Volhard (1834-1910), who was in charge of the background is certainly more reminiscent of a forge than of a analytical division in Baeyer’s institute, and whose successor laboratory. In the center Adolf Baeyer, wearing a prominent Fischer was to become in Munich a year later (1879), and at the hat; since several others also wear headgear, we may deduce that University of Erlangen in 1882. in the winter of 1878 the heating was deficient in that laboratory. Fischer, at Munich, pursued several classical organic research To the right of Baeyer the 25-year-old Emil Fischer, in a peaked topics : the phenylhydrazones of acetaldehyde, benzaldehyde. cap and strikingly self-confident three years after his Ph.D.; to and furfural were unequivocally characterized and structurally Frieder W Lichtenthaler, born 1932 in Heidelberg, studied chemistry at the Universitj. of Heidelberg from i952-1956 and received his doctorate there in i959 under E Cramer ,for research on enol phosphates. Thefollowing three years he spent as a postdoctoralfelloiti at the University of California, Berkeley, with Hermann 0. L. Fischer-the only of Emil Fischer’s sons who survived thefirst World War. He subsequently worked as an assistant at the Technische Hochschule Darmstadt, where he acquired his “Habilitation” in i963, was appointed associate professor in 1968, and was promoted to,fullprofessor in 1972. His research activities center on the generation of enantiopure building blocks from sugars, their utilization in the synthesis of’ oligosaccharides and complex non-carbohydrate natural products, the computer simulution of chemical and biological properties of sugars, and studies towardk the utilization of carbohy- drates as organic raw materials. Aii,qJii Clitwi Irir Ed Engl 1994, 33. 2364-2374 2365 REVIEWS F. W Lichtenthaler secured;"] over a number of years (1876-1880) hedid extensive "During the winter semester of 1876/1877 I again was in investigations on rosaniline dyes with his cousin Otto Fischer Strassburg, and there, through Dr. Albert Fitz, a wealthy (Fig. 1. far left. sitting).['] and in 1881 he started work on puri- winegrower from the Palatinate, was introduced to the book nes. investigating the structure of caffeine,lgl research that even- of Pasteur "Etudes sur la biere". that had just appeared. tually led to his classification of the purines. In 1882 at the age Therein, this ingenious researcher had laid down his experi- of 30, he moved from Munich to Erlangen, accepting the chair ences on the contamination of beer-yeast by other microor- of chemistry at that university, and there he was intensely occu- canisms and their harmful effect on the quality of the beer. pied with the conversion of phenylhydrazine into N-heterocy- When I reported on this to my father, he urged me to study cles,""] which led to the Fischer indole synthesis." 'I It was in this subject very thoroughly, which I gladly did since it inter- Erlangen in 1884, that is after having left Baeyer's sphere of ested me scientifically. A fine microscope was immediately influence for over two years, that he began his studies on sugars, acquired, and with the help of Dr. Fitz and the botanist Prof. by reaction of those that were known at the time (glucose. fruc- de Bary I made studies on moulds. sprouts, and yeasts. from tose, galactose, maltose. sucrose, and lactose) with phenylhy- which I later profited immensely in my investigations of the dra~ine.'~.21 The hydrazones and osazones obtained thereby sugars. For the time being, however. I had to make practical have not only rendered invaluable service for the identification use of this new knowledge. and isolation of the then existing sugars, but also have been Accordingly, I moved with my microscope to Dortmund for instrumental in the preparation of new ones. In 1888 Fischer several weeks, to train the workers of the brewery in the new had moved to the University of Wiirzburg by then -he discov- identification procedures. Presumably. I was the first chemist ered a new hexose in this way:"3] gentle oxidation of inannitol in Germany who attempted this, and have to admit, that I with nitric acid gave a mixture which could not be characterized was met with substantial distrust by the men. They made as such, but on exposure to phenylhydrazine afforded a crys- every effort to lead me astray with false statements on the talline phenylhydrazone, isomeric with the one generated from origin and the quality of the yeast under examination. They glucose (Fig. 2). By the became more serious-minded though after I could find out, acid hydrolysis of this with the help of the microscope, those yeast types that were mannitol product, an as yet un- spoiled. Yet. I did not succeed in instructing any of the men known hexose was ob- in the correct use of the microscope." IINO* 1 tained.