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Subtilisin had exactly the same proton relay

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David Blow's work on the structure of a pancreatic enzyme
Manfred Eigen Scientist
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Some years ago, I think quite long... almost twenty years ago... there were the first three-dimensional structures of protein molecule. Well the first, of course, was Max Perutz with haemoglobin and John Kendrew with myoglobin and they got the Nobel Prize for that. But very soon other molecules were looked at using the X-ray diffraction method, which was pioneered in Cambridge in the school of Bragg. And among them there was David Blow, that time in Cambridge, who determined the structure of a pancreatic enzyme, so that's trypsin and chymotrypsin. A pancreatic enzyme is an enzyme which is used in metabolism of food and in this very special case it's a protein which... it's an enzyme which degrades protein molecules, so it hydrolyses a peptide bond. Now the wonderful result he got from it was not only that he could determine each atom in this three-dimensional structure within an angstrom or a fraction of an angstrom precise, what came out is a great insight into the catalytic mechanism. The catalytic mechanism was to be a proton relay, in other words there was a spatial conformation of three amino acids, one being a proton donor. That was serine, it has an OH group so, where the proton can dissociate it will do so in the basic range, so at neutral it will be still the OH group but if you go up with your pH it will be an O- and the proton will come over. At the other end there was an aspartate, that is the carboxylic group like in acetic acid, so that is the proton of that group dissociates already in the acetic range, that means two pH values below neutrality or even three... two to three pH values. That means under neutrality where the enzymes work you have always the de-protonated carboxylic group – COO-. And here the protonated hydroxyl group, and in between there was a histidine which has an imidazole ring and the imidazole ring has two nitrogens, one being protonated, the other not. So... and its pKa is at 7, at neutrality. So, at neutrality you have either the imidazole ring protonated, and you have two protons and a plus charge on, so the hydroxyl group can give off its proton to the imidazole and the other proton of the imidazole hops to the carboxylic group. That's a proton relay, you shuffle forth and back protons and then you can make a very efficient acid base catalysis, because it's a hydrolytic reaction. And that makes the splitting of the protein bond, wonderful mechanism was known and very satisfactory.

Nobel Prize winning German biophysical chemist, Manfred Eigen (1927-2019), was best known for his work on fast chemical reactions and his development of ways to accurately measure these reactions down to the nearest billionth of a second. He published over 100 papers with topics ranging from hydrogen bridges of nucleic acids to the storage of information in the central nervous system.

Listeners: Ruthild Winkler-Oswatitch

Ruthild Winkler-Oswatitsch is the eldest daughter of the Austrian physicist Klaus Osatitsch, an internationally renowned expert in gas dynamics, and his wife Hedwig Oswatitsch-Klabinus. She was born in the German university town of Göttingen where her father worked at the Kaiser Wilhelm Institute of Aerodynamics under Ludwig Prandtl. After World War II she was educated in Stockholm, Sweden, where her father was then a research scientist and lecturer at the Royal Institute of Technology.

In 1961 Ruthild Winkler-Oswatitsch enrolled in Chemistry at the Technical University of Vienna where she received her PhD in 1969 with a dissertation on "Fast complex reactions of alkali ions with biological membrane carriers". The experimental work for her thesis was carried out at the Max Planck Institute for Physical Chemistry in Göttingen under Manfred Eigen.

From 1971 to the present Ruthild Winkler-Oswatitsch has been working as a research scientist at the Max Planck Institute in Göttingen in the Department of Chemical Kinetics which is headed by Manfred Eigen. Her interest was first focused on an application of relaxation techniques to the study of fast biological reactions. Thereafter, she engaged in theoretical studies on molecular evolution and developed game models for representing the underlying chemical proceses. Together with Manfred Eigen she wrote the widely noted book, "Laws of the Game" (Alfred A. Knopf Inc. 1981 and Princeton University Press, 1993). Her more recent studies were concerned with comparative sequence analysis of nucleic acids in order to find out the age of the genetic code and the time course of the early evolution of life. For the last decade she has been successfully establishing industrial applications in the field of evolutionary biotechnology.

Tags: X-ray diffraction, protein molecules, haemoglobin, myoglobin, Nobel Prize, pancreatic enzyme, trypsin, chymotrypsin, serine, aspartate, acetic acid, catalytic mechanism, proton relay, imidazole ring, David Mervyn Blow, Max Ferdinand Perutz, John Cowdery Kendrew, William Lawrence Bragg

Duration: 3 minutes, 36 seconds

Date story recorded: July 1997

Date story went live: 24 January 2008