1975

Enzyme Stereochemistry

Frank H. Westheimer (1912–2007), John Cornforth (1917–2013), Hermann Eggerer (1927–2006), Duilio Arigoni (b. 1928)

One of the many remarkable things about enzymes is their extraordinary sensitivity toward chirality (left- and right-handedness). If they use chiral substrates, they tend to show great selectivity for one form over the other, and if they start from a nonchiral molecule but generate chiral products, they generally make only one form of those as well. The amino acids that make up an enzyme all have chiral centers (except for the simplest one, glycine), giving them plenty of opportunity to have discriminating active sites and binding pockets.

Australian-British chemist Sir John Cornforth played a large role in discovering just how selective these reactions were by using one of the physical organic–chemist’s most powerful techniques: labeling with isotopes (two or more of the same element with different atomic masses). Switching a specific hydrogen atom in a structure with a deuterium (or a radioactive tritium) and tracking where it ends up after a reaction, or watching for rate differences due to kinetic isotope effects, can illuminate reaction mechanisms like no other technique. Cornforth and his collaborators, including German biochemist Hermann Eggerer, synthesized labeled forms of the substrates for various enzymes—often no small problem in itself—and were able to determine biosynthetic pathways by tracking where the labels ended up. Cornforth’s lab developed the stereochemical details of cholesterol’s synthesis from the starting material used by cells for all the steroids, a compound called mevalonic acid, which has six hydrogens that can be tracked. All six of them were eventually (and painstakingly) labeled in various combinations, and in 1975, Cornforth received the Nobel Prize in Chemistry for this work.

American chemist Frank H. Westheimer, Swiss chemist Duilio Arigoni, and many others also applied Cornforth’s techniques, and, in general, the more enzyme mechanisms were investigated, the more impressive they looked. Organic chemists are still catching up and trying to engineer enzymes to their own specifications.

Strawberry wine fermentation, which involves the use of enzymes in yeast to convert carbohydrates into carbon dioxide and alcohol.