NEW YORK — the complete chemical synthesis of an enzyme, which belongs to one of life's most important group of compounds, was reported by research teams at Merck & Co. and Rockefeller University.
Enzymes are proteins that are essential to life. They are the catalysts that trigger the hundreds of chemical reactions that go on inside every living cell. Without enzymes, a cell would be unable to take simple foodstuffs and convert them to the vitamins, hormones, fats and the myriad of other chemicals necessary for life.
The enzymes synthesized by the two groups, working separately in using different methods, is also the largest proteins scientists have yet put together starting with ordinary chemicals. Heretofore, only nature has been able to make such complex molecules.
The particular enzymes synthesized by the researchers is known as ribonuclease and is identical to ribonuclease produced by the pancreas gland of cattle. The enzyme is a particular importance to scientists but, in itself, probably is of little use in treatment of human disease or in solving practical problems.
However, the ability to synthesize an enzyme has some awesome implications. The same techniques used to make ribonuclease presumably can be used to make other enzymes and large proteins, such as hormones, which might be of use in treating human diseases. More important, the researchers said, synthesizing enzymes opens the way to solving ministry of how these proteins work.
"This is the first total synthesis of an enzyme, and we think it will open the way to other syntheses and a further understanding of the way in which these important biological catalysts work," Professor Robert B. Merrifield, one of the Rockefeller researchers, said at a press conference.
Practical Applications Unclear
"How this will be involved (in practical applications) isn't clear yet," noted Dr. Max Tischler, Merck's vice president for research. But, he added, it should provide much "of the knowledge needed to devise the next generation of therapeutic agents."
Medical researchers only recently have begun to explore the use of enzymes in treating disease. For example, Merck, and efforts on related to enzymes synthesis research, currently is producing a bacterial enzyme being tested in the treatment of a certain type of leukemia and an other enzyme that might have value in tooth decay.
Separate reports of the two teams announcing that seat are being published today in the Journal of the American Chemical Society. While it isn't unusual for two different groups of scientists to come up with a discovery about same time, it is rare for two groups to make an advance "of this magnitude" simultaneously, noted Maclyn McCarty, vice president of Rockefeller University.
The Merck team was headed by Robert G. Denkewalter, vice president of exploratory research for the Merck, Sharp & Dohme Laboratories division, and Ralph F. Hirshmann, director of peptide research for the division. The Rockefeller team was headed by Prof. Merrifield and Bernard Gutte, research associate.
The researchers' excitement stands partly from the fact that only a few years ago most chemists and biologist thought it would be impossible to make enzymes synthetically. In order for a cell to take such a food as sugar, for instance, and make all the chemicals it needs to live, the cell has to perform hundreds of chemical reactions, building up one substance, breaking down another.
One Enzyme, One Reaction
Each of these chemical reactions requires an enzyme to trigger it. Separate enzyme is needed for each reaction; an enzyme will trigger only one kind of reaction and on the other. As a result, a liver cell, which is an extremely active cell, may have as many as 1000 different enzymes.
Organic chemists, noted Mr. Denkewalter, long have been able to synthesize many cell-made chemicals, such as vitamins. However, to do this, the chemists has to use high temperatures and corrosive and poisonous chemicals in a long, laborious process.
By contrast, enzymes can trigger hundreds of chemical reactions a second because the reactions to be carried out at body temperature in a solution of water. "Still more remarkable," Mr. Denkewalter said, "is the fact the whole operation is integrated and automated. A cell can be described as a factory and the enzymes and the machines. But, these machines are automatically turned on and off as needed."
So far researchers have identified about 1000 enzymes out of what could be billions on billions. They have figured out what these enzymes do, with a look like headed some instances, have determined their molecular structure. However, still mysterious is how the enzymes work in such a seemingly marvelous way.
"If the (enzyme) molecule could be made in the laboratories and much could be learned about how it works," explained Prof. Merrifield.
Enzymes, like all other proteins, are long chains of "building-block" molecules called amino acids. To string together synthetically a chain of amino acids and exactly its natural sequence is extremely difficult.
The first time it was done, the chemists, Vincent du Vigneaud of Cornell University, was awarded a Nobel Prize. He synthesized a hormone consisting of 10 amino acids. More recently, chemists have made slightly bigger protein molecules, including one with 39 amino acids and insulin consisting of two chains with a total of 51 amino acids.
The ribonuclease made by the two research teams, is by far the largest; it consists of 124 amino acids. The two teams each take ribonuclease for their work because it was the first enzyme for which chemists have determined the sequence of the amino acids. Little is known about what the enzymes' job is supposed to be. It breaks down a key chemical called ribonucleic acid (hence the name, ribonuclease) and is produced by the pancreas. It is thought to be involved in the digestion of food.
To make it synthetically, each team using different methods. Basically, the Rockefeller researchers started with a microscopic plastic bead has an a "anchor" and then cooked each amino acid on, one by one, until the 124-unit chain was completed. The Merck team, by contrast, first made several fragments, each with several amino acids, and then began hooking the fragments together until they completed the chain.
Adapted to Large-scale Output
It should be possible to adapt the techniques to large-scale productions of other enzymes and large proteins, the researchers suggested. For instance, some hormones and enzymes currently being tried in human diseases have to be derived from human sources, Mr. Denkewalter noted. An enzyme called urokinase is being tested for dissolving blood clots; it has to be extracted in tiny amounts from human urine. Similarly, human growth hormone for treating potential towards has to be extracted from human pituitary glands. It might soon be possible to make these chemical synthetically.
It is likely that most drugs taken for an illness probably work with the help of enzyme-triggered reactions in the cell. Thus, understanding how enzymes work, particularly in relation to drugs, might lead to new medicines that wouldn't necessarily be enzymes.
There are a number of diseases that are caused by a defective enzyme. One type of mental retardation, for instance, occurs because the body lacks an enzyme capable of converting one amino acid into another one. Undoubtedly, new understanding of how enzymes function will throw some light on such diseases, though exactly which one is impossible to predict at this time, the researchers said.
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