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
Fatty Acids Metabolism
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.
Cyclic Cascade Systems
in Metabolic Regulation
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.
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.
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.