Wednesday, June 11, 2008

Nobel Laureates: Stanford Moore and William Stein


The Nobel Prize in Chemistry 1972.

"for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active centre of the ribonuclease molecule"

Stanford Moore (1913 - 1983) and William Stein (1911 - 1980) were awarded the 1972 Nobel Prize in Chemistry for working out the role of amino acid side chains in the mechanism of catalysis by bovine ribonuclease A [see How Enzymes Work].

This is one of the most important achievements in biochemistry although it could hardly have been considered a breakthrough since the result was widely anticipated and predicted. Many other enzymes were being studied at the time and the award was, in a sense, a recognition of the general concept and not the particular contributions of Moore and Stein. Moore and Stein also developed the technique of automated amino acid analysis of proteins and peptides.

Moore and Stein shared their Nobel Prize with Christian Anfinsen.

The presentation speech was delivered by Professor Bo Malmström of the Royal Academy of Science.THEME: Nobel Laureates
Your Royal Highnesses, Ladies and Gentlemen,

The key substances of life are called enzymes. Everything we humans undertake - if we sit here enjoying the splendour of a Nobel ceremony, if we perform work, or even if we simply feel joy or sorrow - occurs by means of enzyme reactions. The phenomenon described as life is a network of coupled enzymatic processes. In chemical terminology the enzymes are catalysts, i.e. substances which accelerate chemical reactions without being consumed themselves. The concept of catalysis was introduced about 150 years ago by the great Swedish chemist Jöns Jacob Berzelius, who also, with astonishing intuition, suggested that the tissues of a living organism have catalytic activity. Around the turn of the century scientists started to associate this catalytic effect with specific substances, enzymes. This year's three Nobel Prize winners in Chemistry, Christian B. Anfinsen, Stanford Moore and William H. Stein, have performed fundamental studies with the enzyme ribonuclease making it possible for us now to approach the problem of enzymatic activity on a molecular level.

From a chemical point of view enzymes are proteins. These are built up of 20 different amino acids which are linked together into long chains. Despite the fact that proteins have only 20 building blocks, there are thousands of enzymes, each with its specific properties. This large degree of variation becomes possible because the number and sequence of the amino acids in the chain can be varied. Ribonuclease was the first enzyme for which the complete amino acid sequence was determined thanks to contributions from Anfinsen and from Moore and Stein.

Every living organism has its own characteristic pattern of enzymes. It can also produce a copy of itself, and this progeny has the same enzymes. An important question concerns the source of the information which has to be passed on from generation to generation for the enzyme pattern to be preserved. We know, thanks to contributions which have led to earlier Nobel Prize awards, that a specific molecule, called DNA, serves as the carrier of the traits of inheritance. These traits are expressed by DNA controlling the synthesis of enzymes. DNA accomplishes this by determining the sequence of the amino acids making up a particular protein molecule. An active enzyme does not, however, consist just of a long chain of amino acids linked together, but the chain is folded in space in a way which gives the molecule a globular form. What is the source of the information responsible for this specific folding of the peptide chain? It is this question in particular which has been the concern of Anfinsen's investigations. In a series of elegant experiments he showed that the necessary information is inherent in the linear sequence of amino acids in the peptide chain, so that no further genetic information than that found in DNA is necessary.

The contributions of Moore and Stein concern another fundamental question regarding ribonuclease, namely the basis for its catalytic activity. The reacting substances, the substrates, are bound to an enzyme in what is generally called its active site. In the complex so formed there is an interaction between enzyme and substrate leading to a changed reactivity of the substrate. Knowledge about the structure of an enzyme is of little help in understanding this interaction if it is not possible to find the active site and to determine the chemical groups in it. Moore and Stein discovered as an important principle that the active site contains amino acids with an anomalously high reactivity compared to the same amino acids in free form. This high reactivity is of direct importance for the catalytic activity of the enzyme, but Moore and Stein also found it possible to utilize it to label two amino acids in the active site by chemical modification. In this way the position of these amino acids in the long peptide chain could be unambigously determined. Through these investigations Moore and Stein were able to provide a detailed picture of the active site of ribonuclease long before the three-dimensional structure of the enzyme had been determined.

Dr. Anfinsen,

I have tried to explain your pioneering investigations showing that the linear sequence of amino acids in the enzyme ribonuclease determines the biologically active conformation of this enzyme. This finding has profound implications for our understanding of the way in which active enzyme molecules are formed in living cells.

Drs. Moore and Stein,

I have attempted to summarize your fundamental contributions to our understanding of the relationship between chemical structure and catalytic activity in the enzyme ribonuclease. In particular, I have stressed your studies leading to the localization of two specific histidine residues in the active site of the enzyme. It is for these pioneering experiments that the Royal Academy of Sciences has decided to award this year's Nobel Prize in Chemistry to you together with Dr. Anfinsen.

Drs. Anfinsen, Moore and Stein,

On behalf of the Royal Academy of Sciences I wish to convey to you our warmest congratulations, and I now ask you to receive your Prizes from the hands of His Royal Highness the Crown Prince.

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