Biochemistry's Fab Five

1. The mechanism of hormonal action remained a complete mystery for almost 50 years, because effects always disappeared when the target tissue was homogenized. In the early 1950s, Earl Sutherland reproduced the effect of a hormone in a cell homogenate for the first time (the stimulation of hepatic glycogenolysis by adrenaline) and showed that adrenaline exerted its effect by inducing the production of a dialyzable heat-stable factor.1 How the factor was identified a few years later as adenosine 3', 5'-cyclic monophosphate (cyclic AMP) is beautifully described in the book, Cyclic AMP, by G.A. Robison, R.W. Butcher, and Earl Sutherland (Academic Press, 1970). I regard the discovery of cyclic AMP, the first "second messenger," as one of the greatest biological discoveries of the 20th Century. Earl Sutherland was so far ahead of his time that his work was regarded with disbelief for a number of years.2. Nearly all aspects of cellular life are controlled by reversible phosphorylation of proteins, while abnormalities in phosphorylation are a cause or consequence of many diseases. About 30% of human proteins contain covalently bound phosphate and, to deal with this, the genome encodes more than 500 protein kinases and about 150 protein phosphatases. Protein kinases have recently become the second most studied group of drug targets after G protein-coupled receptors. Eddy Fischer and Ed Krebs won the 1992 Nobel Prize in Medicine for discovering the first example of phosphorylation nearly 40 years earlier.2 Yet, like many prescient discoveries, the work's general significance was not appreciated for many years. Even 15 years later, it was still thought of as a control mechanism specific to the regulation of one metabolic pathway, glycogen metabolism.3. Metabolic Interconversions of Enzymes was an influential series of occasional meetings held between 1969 and 1985. Remarkably, in the first few of these meetings, it was possible to cover quite comprehensively all the known posttranslational modifications involved in controlling enzyme activity. At the meeting held in Arad, Israel, I heard Avram Hershko describe the first example of ubiquitin-mediated proteolysis.3 It was a great talk but I doubt whether any of us imagined that it would turn out to be of such general significance. The discoveries in this area continue to amaze. Hundreds, if not thousands, of proteins are degraded by ubiquitin-mediated proteolysis, and ubiquitination and related modifications, such as sumoylation, are turning out to have many other roles in cell regulation.4. In 1966, Peyton Rous was awarded the Nobel Prize for his discovery of Rous Sarcoma virus many years earlier; RSV was the first example of a tumor-bearing virus. By the early 1970s, a single protein v-src, encoded by the RSV genome, was known to be responsible for cell transformation, but how it exerted this effect was unknown. Then, Ray Erikson demonstrated that v-src was a protein kinase that performs an enzymatic activity essential for transformation.4 I have selected this article, not only because it was a great paper, but also because it illustrates how unlucky you can sometimes be in science. In the paper, src was reported to phosphorylate itself at a threonine and not a serine residue (or residues), the separation of phosphothreonine from phosphoserine being carried out by the then-standard technique of high-voltage paper electrophoresis at pH 2. But at this pH, phosphothreonine does not separate from phosphotyrosine. Had Ray performed the separation at the slightly higher pH of 3.5, he, and not Tony Hunter, would have been the first to identify a protein tyrosine kinase.5. By the mid-1960s it was thought that the control of glycolysis had been completely solved, and the proposed mechanisms were established dogma in every undergraduate textbook of biochemistry. It was therefore quite mind-blowing when I heard Gery Hers report at a 1980 meeting on Metabolic Interconversions of Enzymes in Titisee, Germany, that a novel molecule, fructose 2,6 bisphosphate, was the key activator of glycolysis.5 It is a salutary lesson for all of us: Some of the most exciting and unexpected discoveries can be made in areas that everyone beleives to have been fully worked out long ago.Philip Cohen is director of the Medical Research Council's Protein Phosphorylation Unit at the University of Dundee, Scotland.

Biochemistry's Fab Five

Glycolysis revision, kinases, and the first "second messenger" star in these five favorite papers

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