|Beta-d-glucose. Image by Rob Hooft, via Wikimedia. CC BY-SA 3.0|
Energy in animals and humans is stored in the body in the form of glycogen. Starch, a similar molecule but less branched, serves the same function in plants. Glycogen, discovered by Claude Bernard in 1856, is stored primarily in the liver (about 120 grams) and in muscle (about 400 grams), and to a lesser amount in the brain, kidneys, and red and white blood cells. Glycogen is a glucose polymer, consisting of as many as 120,000 glucose molecules linked together in a highly branched structure, appearing like a tree with its many branches pointing in all directions. In states of nutritional sufficiency, glycogen is synthesized from glucose by the cell.
Glucose is a cyclical molecule with its carbons conventionally numbered from 1 to 6 (Figure 1). It enters the cell as glucose-6-phosphate after being bound to phosphate in the presence of the enzyme hexokinase. Within the cell, under the influence of another enzyme called phosphoglucomutase, the phosphate molecule is shifted from position six to position one, becoming glucose-1-phosphate. This is then linked to another substance (UDP) that allows many glucose molecules to be linked and, under the influence of glycogen synthase and branching enzymes, to form the large glycogen molecule. This process of glycogen synthesis is called glycogenesis.
In states of nutritional deprivation and a drop in blood glucose levels, glycogen is broken down to glucose to maintain normal blood levels and provide for energy (glycogenolysis). Glycogen is therefore important in maintaining the blood glucose levels within strict limits. Glucose from the blood enters the cell under the influence of insulin and exits the cell under the influence of glucagon. Once inside cells glucose is broken down (oxidized) in several enzymatic steps (glycolysis and Krebs cycle) into carbon dioxide gas and water. The released energy is trapped in the form of an ATP molecule, which is the body’s universal currency of energy that makes possible the synthesis of all the proteins, lipids, complex carbohydrates, and vitamins required for life.
Many of these aspects of carbohydrate metabolism were discovered by the two Cori doctors, who worked and collaborated together in all their research. Gerty was born in Prague in 1896, daughter of the director of a sugar refinery. She received her name not as a diminutive but after a warship of the Austro-Hungarian navy, based in Trieste. She was taught at home until she was ten, then attended a lyceum for girls, graduating in 1912, but living first in the anti-Semitic Austro-Hungarian empire and after its breakup in its equally anti-Semitic successor state, Czechoslovakia. Being also a woman, she suffered from a double handicap, from being Jewish and because women were largely debarred from entering professions. But as she was extremely gifted, she graduated in medicine from the University of Prague in 1920.
Carl Cori was also born in the Austro-Hungarian empire, in Prague, from an old family that originated in Italy and had emigrated to Bohemia for political reasons. He was educated at a classical lyceum in Trieste, graduating in 1914. After leaving school he joined for some time a naval expedition studying the ecology of small uninhabited islands off the Dalmatian coast, then enrolled in the medical school in Prague. His studies were interrupted for two years by World War I and he served on the Italian front. Returning to Prague in 1918, he graduated two years later. He had met Gerty there, a fellow student, charming, intelligent, possessed of a sense of humor, and interested in science. In 1920 she converted from Judaism and in that year they were married.
When peace came, they worked for two years in Vienna and Graz, but life was hard there, even food being in short supply. Antisemitism was rampant, and opportunities for research limited. By 1922 the couple decided to move to the United States. Carl accepted an academic position in Buffalo, New York, and nine years later became Professor of Biochemistry at Washington University in St. Louis (1931). In those days, the United States was no more friendly to the idea of women entering careers in science then they were in the Old World. Gerty was employed as a laboratory assistant at one-tenth of Carl’s salary and later complained that she had nobody to help her wash the glassware. They also had to overcome myriads of other obstacles, rules, and prejudices, such as that married couples were not supposed to work together in the same place.
Their initial work was on the metabolism of glucose, the regulation of its concentration in the blood, and the effect of insulin and epinephrine on its handling by the body. They developed novel techniques to study this, and in 1929 described the events occurring in muscle during exercise. Under normal conditions, glucose in muscle cells is oxidized to pyruvate by glycolysis, a process that takes place in the cytoplasm. The pyruvate is then converted to acetyl coenzyme A as it enters the mitochondria and there is further oxidized to carbon dioxide and water in the Krebs cycle to generate ATP (energy). However, when demand for energy is high as in exercise or rapid activity, the energy is extracted prematurely from pyruvate by its conversion to lactate. The Coris showed that the massive amounts of lactate produced during anaerobic conditions such as severe exercise does not go to waste but are recycled in the liver to form glucose in a series of enzymatic reactions that became known as the Cori cycle.
In 1934 the Coris isolated from the liver the central molecule in glycogenesis, glucose-1-phosphate, which in their honor was later named Cori ester (an ester is formed when a hydroxyl group, like in glucose, combines with an acid, such as phosphate, to form glucose-1-phosphate). Cori ester plays a central role in both the formation and degradation of glycogen, one of the most important metabolic pathways in the human body. The Coris also identified the enzyme phosphorylase, which forms glucose-1-phosphate from glycogen, also phosphoglucomutase, which catalyzes the interconversion of glucose-1-phosphate and glucose-6-phosphate, and several other enzymes participating in glycogenolysis (the biological cleavage of glycogen to glucose), thus elucidating the sequence of the entire process by which glycogen is converted into glucose-1-phosphate and then by glycolysis into lactic acid in muscle. Later they carried out further work on enzymes participating in many other steps in carbohydrate metabolism.
For their achievements in elucidating the various mechanisms of glucose and glycogen metabolism, the Coris received many awards, notably the Nobel Prize in Physiology or Medicine in 1947. Dr. Gerty Cori was the first woman to be so honored. At the award ceremony she declared that “I believe the benefits of two civilizations—a European education followed by the freedom and opportunities of this country—have been essential to whatever contributions I have been able to make to science.” Later she also studied hereditable glycogen storage disease, identifying at least four forms, each related to a particular enzymatic defect. She continued her work until she died in 1957 from myelofibrosis, and Carl Cori carried on his research until his death in 1984 at age eighty-four. They were two remarkably productive and imaginative investigators, and they occupy a special place in the history of biochemistry.
|Gerty Theresa Radnitz Cori and her husband Carl Ferdinand Cori. Unidentified photographer. 1947. Smithsonian Institution Archives. Via Flickr.|
- Ochoa S and Kalckar HM. Gerty T. Cori, Science 1958;128:16 (July 4).
- Randle P. Carl Ferdinand Cori. Biographical Memoirs of Fellows of the Royal Society 1986; 32:66 (December).
GEORGE DUNEA, MD, Editor-in-Chief