Summary of the Stadtman's Research
Vitamin B12 Biochemistry
Signs of vitamin B12 deficiency in humans include fatigue, nausea, and weight loss. It can lead to pernicious anemia and neurological disorders. Investigating the role of vitamin B12 in metabolic processes is an essential step for understanding these clinical symptoms.
In the 1950s and 60s, Thressa tackled two problems: how amino acids are broken down into smaller pieces in the absence of oxygen and how methane gas is produced by some bacteria living in oxygen-free conditions. She showed that vitamin B12 is required for several enzymes that functioned in these processes. Thressa and her co-workers discovered 5 of the 12 known vitamin B12-dependent enzymes.
Selenium, a chemical element, had long been known for its toxic effect before it was recognized in the 1950s as an important nutrient for animals. Numerous studies now relate dietary intake of selenium to reduction of cancer risk and prevention of a type of muscular dystrophy.
Thressa pioneered the field of selenium biochemistry, by identifying many selenium-containing proteins in cells and explaining the function of selenium in these proteins. She discovered in 1972 that selenium is required to synthesize an enzyme called glycine reductase. Several years later, she first identified selenocysteine, an amino acid that contains selenium as an essential component.
Fatty Acids Metabolism
The building blocks of fats are chain-like molecules called fatty acids, which are readily made in the body. By the late 1940s, biochemists had generally adopted a hypothesis that the capacity to make fatty acids is the unique property of specialized cellular systems, or particulate organelles. But Earl dispelled this hypothesis once and for all by demonstrating that enzymes extracted from certain bacteria can catalyze the synthesis of fatty acids in vitro, outside the living body.
Earl also showed that "Coenzyme A" (CoA) is involved in the synthesis of fatty acids as a carrier of the small molecular fragment called "acetyl." Among many coenzymes-molecules needed for the proper function of enzymes-CoA has most notable metabolic functions. Its derivative, "acetyl-CoA," is an essential substance involved not only in making fats, as Earl showed, but also in breaking down fats, carbohydrates, and proteins to generate energy in cells. In 1952, Earl successfully carried out the first "net synthesis" of acetyl-CoA in vitro, which means that he accomplished it by using only basic materials (acetyl phosphate and CoA) and the enzyme he had discovered (phosphotransacetylase). Overall, Earl's research helped establish the "energy-rich" nature of acetyl-CoA.
Cyclic Cascade Systems in Metabolic Regulation
Amino acids, the building blocks of protein, are generally provided in the diet, but some of them are also made in the body. How does an organism know that it is time to produce more amino acids, or stop making them?
In the 1960s and 70s, Earl and his co-workers discovered some mechanisms of controlling the production of amino acids. They examined glutamine synthetase, the enzyme that catalyzes the synthesis of an amino acid called glutamine. They showed that, in E. coli, its biosynthetic activity is regulated not only by glutamine, but also by other molecules that use glutamine as a nitrogen source. The regulation of glutamine synthetase is an example of cumulative feedback inhibition. Its activity is almost completely switched off when all final products are bound to the enzyme.
In addition, Earl and his co-workers discovered that glutamine synthetase can also be controlled by a process called cyclic cascade reversible covalent modification, which involves the attachment and detachment of certain molecules at specific positions of the enzyme. They showed that this regulatory process provides large signal amplification and fine tuning of the enzyme's activity.
Protein Oxidation and Aging
Our bodies use oxygen to burn nutrients for energy. Most of the oxygen we breathe is reduced to water in this energy-generating process, but some turns into oxygen free radicals or other forms of highly reactive molecules. They are "oxidizing agents" that can seriously damage cellular molecules, such as proteins and nucleic acids.
In the 1980s, Earl and his co-workers examined how damaged or inactivated proteins are removed from cells in a process called "protein turnover." Their study showed that oxidation of protein can trigger this removal process. Earl and his co-workers also discovered that the accumulation of damaged proteins is closely associated with the aging process and may play a role in age-related diseases such as Parkinson's disease.