metabolism - marist college · axel hugo theodor theorell, ... in frog muscle the lactic acid...
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Metabolism
OTTO FRITZ MEYERHOF AND ARCHIBALD VIVIAN HILL, 1922
OTTO HEINRICH WARBURG, 1931
ALBERT SZENT-GYORGYI VON NAGYRAPOLT, 1937
CARL PETER HENRIK DAM, 1943
EDWARD ADELBERT DOISY, 1943
CARL FERDINAND CORI AND GETTY THERESA GORI NÉE RADNITZ, 1947
SIR HANS ADOLF KREBS, 1953
FRITZ ALBERT LIPMANN, 1953
AXEL HUGO THEODOR THEORELL, 1955
KONRAD BLOCH AND FEODOR LYNEN, 1964
MICHAEL S. BROWN AND JOSEPH L. GOLDSTEIN, 1985
Otto Fritz Meyerhof, 1922 “For his discovery of the
fixed relationship between the consumption of
oxygen and the metabolism of lactic acid in the
muscle.”
• Born April 12, 1884, in Hannover, Germany.
• Studied medicine at Freiburg, Berlin, Strasbourg, and Heidelberg.
• Graduated from Heidelburg and devoted himself for a time to psychology
and philosophy.
• At Heidelberg he met Otto Warburg [ 1931] and became more and more
interested in cell physiology.
• In 1923 he was offered a Professorship of Biochemistry in the United States,
but in 1924 accepted an offer by the Kaiser Wilhelm Gesellschaft to join
the group working at Berlin-Dahlem.
• In 1938 conditions became too difficult for him and he left Germany for
the Institut de Biologie Physico-chimique at Paris.
• In June, 1940 the Nazis invaded France. Meyerhof fled from Paris. With the help of the Unitarian Service
Committee he reached Spain and in October 1940, the United States, where the post of Research Professor
of Physiological Chemistry had been created for him by the University of Pennsylvania and the Rockefeller
Foundation.
• In 1944 he suffered a heart attack; another one ended his life in 1951
Some history of muscle metabolism In 1867 Ludimar Hermann found that muscle can contract in the absence of oxygen. He thought that
muscle contained the hypothetical "inogen" whose molecules had the excess oxygen that was used
for the liberation of energy during muscular activity.
In 1906-1907 Fletcher and Hopkins proved that when muscle contracts under anaerobic conditions,
lactic acid accumulates in it, and that when oxygen is supplied the lactic acid disappears
In 1920 Meyerhof showed that in anaerobic conditions the lactic acid was derived from glycogen in
the muscle and that the amount of lactic acid formed was proportional to the activity of the muscle.
in 1926 Meyerhof showed that a muscle extract, prepared with an ice-cold solution, contained the
enzyme system for glycolysis.
In 1934, five years after the discovery of ATP, Meyerhof and his coworkers showed the sequence of
chemical events in muscular contraction. They concluded that the essential event is the
dephosphorylation of ATP and that both creatine phosphate breakdown and lactic acid production
are necessary for the rapid resynthesis of ATP.
Glycolysis
Meyerhof prepared an extract of
muscle which could carry out all the
steps of glycolysis with added
glycogen and hexose-diphosphate
in the presence of hexokinase
derived from yeast. He showed that
in frog muscle the lactic acid formed is reconverted to carbohydrate in the presence
of oxygen. Meyerhof was able to reconstruct in vitro the main steps of the reactions
leading from glycogen to lactic acid. He introduced the term glycolysis to describe the
anaerobic degradation of glycogen to lactic acid and showed the cyclic nature of
energy transformations in living cells.
Otto Heinrich Warburg, 1931, “for his discovery of
the nature and mode of action of the respiratory
enzyme”
Otto Warburg (1883 –1970)
studied chemistry under Emil Fischer [1902], and earned his Doctor of Chemistry in
Berlin in 1906.
earned the degree of Doctor of Medicine in Heidelberg in 1911
served as an officer in the elite cavalry regiment during the First World War, and was
awarded the Iron Cross (1st Class) for bravery.
In 1918 was appointed professor at the Kaiser Wilhelm Institute for Biology in
Berlin.
In 1931 became director of the Kaiser Wilhelm Institute for Cell Physiology, (founded the previous year by
a donation of the Rockefeller Foundation.
was nominated for the award 46 times beginning in 1923 (13 of which were submitted in 1931)
Although his father was Jewish, the Nazis kept re-classifying Warburg to allow him to continue to work.
This may be because Hitler lived in fear of cancer and Warburg at that time was studying cancer.
After the war he tried to emigrate to America but was denied because of his tolerance of the Nazi
treatment of Jews.
Warburg’s research
Most of Warburg’s research was on cancer. He erroneously believed
that cancer was caused by a “disease of the mitochondria”
causing cancer cells to carry out anaerobic rather than aerobic
respiration. Unable to gain acceptance, he quoted Max Planck:
Science progresses not because scientists change their minds, but rather
because scientists attached to erroneous views die, and are replaced.
Warburg received the Nobel prize
for his work on “the respiratory
enzyme” which actually is a chain
of electron-transport enzymes
restoring the NADH produced in
glycolysis by donating the electron
to oxygen to form water.
Albert Szent-Györgyi von Nagyrapolt, 1937 “for his
discoveries in onnection with the biological combustion
processes, with special reference to vitamin C and the
catalysis of fumaric acid”
Born in Budapest, 1893
Entered Budapest Medical School in 1911; his studies were interrupted in 1914 by WWI. He spent two years in the trenches as a medic (received a medal of honor). After two years, discouraged and contemplating suicide, he shot himself in the arm (claiming it was enemy fire) and was discharged.
Received his MD in 1917, and married his first wife, Cornelia.
He was more interested in research than practicing. Hoping to obtain further scientific training, and escape the post-war chaos in Budapest, Szent-Györgyi took a research position in pharmacology in Pozsony, then a part of Hungary. When Pozsony became part of Czechoslovakia in September 1919, the Hungarians were ordered to
leave. After several months back in Budapest, Szent-Györgyi moved on to laboratories in Berlin, Hamburg, and Leiden, gaining experience in biochemistry.
Albert Szent-Györgyi In 1931, at the invitation of the Minister of Education, Szent-
Györgyi returned to Hungary to head the University of Szeged's department of medical chemistry.
He became increasingly involved in anti-fascist activities after 1935, and was part of Hungary's anti-Nazi underground during World War II. He spent much of 1944-45 hiding from the Gestapo*.
In 1941 he divorced Cornelia and married his second wife, Marta.
After the war, facing little scientific support under the Soviet regime, in 1947 he emigrated to the United States and settled in Woods Hole, Massachusetts.
During the 1960s and 1970s he spoke out against the Vietnam war and the growing threat of nuclear
weapons. He published many articles and several books addressing these topics, including The Crazy Ape (1970).
In 1963 Marta died of cancer
In 1965 he married his third wife, June (she was 25, he was 72) . They were divorced in 1968
In 1975 he married his fourth wife, Marcia
He died in 1986 at Woods Hole
Szent-Györgyi and vitamin C In 1911 Casimir Funk studied diseases which appeared to be caused
by dietary deficiencies. He named the factors missing in these
diseases ‘vitamines’ (vital amines). He proposed the existence of at
least four vitamins: one preventing beriberi; one preventing scurvy
(“antiscorbutic”); one preventing pellagra ;and one preventing rickets. They later became known as vitamins A, B, C, etc. C was the
vitamin whose absence causes scurvy.
Sometime in the 1920s Szent-Gyorgyi began studying biological
oxidation and intracellular respiration. Given a Rockefeller fellowship
at Cambridge University in 1926, he spent several years working to
isolate a reducing substance found in citrus fruit, some vegetables,
and adrenal glands. He called it "hexuronic acid." Cambridge
awarded him a PhD for the work in 1927. After two years Szent-
Györgyi was able to isolate nearly one ounce of the substance, but
made no further progress in establishing its identity.
In the fall of 1931, an American post-doctoral fellow, Joseph Svirbely, joined Szent-Györgyi's research team. Svirbely had been working with C. G. King at the University of Pittsburgh, trying to isolate vitamin C. Szent-Györgyi gave him the remains of the hexuronic acid he had isolated and asked him to test it on guinea pigs with induced scurvy. Repeated trials proved that "hexuronic acid" was, in fact, vitamin C. Svirbelywrote to his former mentor in March, 1932, telling him what he had found, adding that he and Szent-Györgyi were submitting a report to Nature. On April 1, Science published an announcement by King that he had discovered vitamin C. King cited Szent-Györgyi's earlier work on hexuronic acid but gave him no credit for vitamin C. Szent-Györgyi and Svirbely sent off their own report to Nature, challenging King's priority in the discovery. A bitter controversy ensued. King, American scientists by and large supported King and vilified Szent-Györgyi as a plagiarist. Yet European and British scientists also knew of Szent-Györgyi's long history and accepted his prior claim, which eventually became accepted.
Szent-Györgyi spent the next several years "preaching vitamin C" (as he put it) all over Europe, suggesting that it might be valuable as a preventive or cure for the common cold and other illnesses. He attempted to interest some of the British biochemists in running some clinical trials, but they considered the idea crankish and refused to consider it. Vitamin C proved disappointing as a miracle cure, however, and Szent-Györgyi eventually got back to his basic research in other areas.
Szent-Györgyi and vitamin C
Returning to his earlier work in the biochemistry of plant respiration, Szent-Györgyiinvestigated respiration in muscle tissue. It was known that fumaric, malic, and succinic acids played some role in respiration, but scientists assumed that they were consumed in the process. When Szent-Györgyi added small amounts of these to active muscles, he found that far more oxygen was consumed than would be needed to oxidize them. Thus the acids were not being consumed as fuels. In fact, each of them stimulated the oxidation of a carbohydrate present in the tissue cells. Szent-Györgyi proposed that carbohydrate fuel was providing electrons to reduce a dicarboxylic acid, oxaloacetic acid to malic acid which in turn reduced fumaric acid to succinic acid which then transferred its hydrogen to cytochromes. By 1937, Szent-Györgyi had identified the process as a cycle and was close to elaborating all of the steps that generate ATP. Unfortunately Szent-Györgyi's focus on malate and oxaloacetate was an error, and Hans Krebs* soon found that the key link was citric acid. Thus "Szent-Györgyi's cycle" became the “citric acid cycle” or Krebs cycle (Nobel, 1953)
Szent-Györgyi and the TCA cycle
*whom Szent-Gyorgy had helped escape the Nazis in the 1930s
In 1940, Szent-Györgyi offered all of his Nobel prize money to Finland (The Hungarian Volunteers had travelled to fight for the Finns after the Soviet invasion of Finland in 1939.)
In 1947 he established the Institute for Muscle Research at the Marine Biological Laboratory in Woods Hole, Massachusetts
He received the Lasker Award in 1954.
In 1955, he became a naturalized citizen of the United States and became a member of the National Academy of Sciences in 1956.
In the late 1950s, Szent-Györgyi developed a research interest in cancer and developed ideas on applying the theories of quantum mechanics to the biology of cancer. Attorney Franklin Salisbury contacted him and later helped him establish a private nonprofit organization, the National Foundation for Cancer Research.
He died in Woods Hole, Massachusetts on October 22, 1986. He was honored with a Google Doodle September 16, 2011, 118 years after his birth.
Szent-Györgyi later life
Carl Peter Henrik Dam, 1943 “for
the discovery of vitamin K”
Dam was born (1895) and died (1976) in Copenhagen.
Dam's key experiment involved feeding a cholesterol-free diet to chickens. The chickens began hemorrhaging and bleeding uncontrollably after a few weeks. These defects could not be restored by adding purified cholesterol to the diet. A second compound apparently had been extracted along with the cholesterol. Dam called this compound the “coagulation vitamin”. It received the letter K because the initial discoveries were reported in a German journal, in which it was designated as “Koagulationsvitamin”.
He was on a lecture tour of Canada and the United States under the auspices of the
American Scandinavian Foundation in 1940-1941 when German troops occupied of Denmark
in April, 1940. He was able to carry out research in Woods Hole Marine Biological Laboratories
during the summer and autumn of 1941, and at the University of Rochester, N.Y., between
1942-1945 as a Senior Research Associate.
He returned to Denmark in 1946 There his main research subjects were vitamin K, vitamin E, fats, cholesterol, and, nutritional studies in relation to gall-stone formation.
Vitamin K
Vitamin K refers to a group of structurally similar,
fat-soluble vitamins the human body needs for
complete synthesis of certain proteins that are
required for blood coagulation, and also
certain proteins that the body uses to control
binding of calcium in bone and other tissues.
The vitamin K-related modification of the
proteins allows them to bind calcium ions,
which they cannot do otherwise. Without
vitamin K, blood coagulation is seriously
impaired, and uncontrolled bleeding occurs.
Low levels of vitamin K also weaken bones and
promote calcification of arteries and other soft
tissues.In the same ceremony as Dam’s in 1943
Edward Adelbert Doisy jointly received the
Nobel Prize for working out the chemical
nature of vitamin K.
Carl Ferdinand Cori and Gerty Theresa Cori née
Radnitz, 1947 “for their discovery of the course of
the catalytic conversion of glycogen”
Gerty Theresa Cori (1896 –1957) was a Czech-
American biochemist who became the first woman
to be awarded the Nobel Prize in Physiology or
Medicine. She was the third woman and first
American woman to win a Nobel Prize in science.
The Cori Cycle
Hans Adolf Krebs, 1953 “for
his discovery of the citric
acid cycle” born 1900 in Hildesheim, Germany
studied under Warburg (1931) for four years in Berlin (1930-34)
In 1932 he worked out the basic chemical reactions of urea cycle, which established his scientific reputation.
In 1933 the Nazi Party rose to power and Germany decreed the removal of all non-Aryans and
anti-Nazis from professional occupations. Krebs was dismissed. The University of Cambridge invited him to work in the Department of Biochemistry. He accepted the offer and settled in Cambridge (with financial support from the Rockefeller Foundation). Thoughrestricted to bring only his personal belongings, he took the manometer developed by Warburg specifically for the measurement ofoxygen consumption in thin slices of tissues. In 1935 he moved to the University of Sheffield (double the salary); In 1944, the British
Medical Research Council established the MRC Unit for Cell Metabolism Research at Sheffield, and Krebs was appointed as the Director. He continued research and took his MRC unit to the Nuffield Department of Clinical Medicine at the Radcliffe Infirmary, Oxford. From there he published over 100 research papers.
His son John (Sir John Krebs, and later Baron Krebs) became a renowned ornithologist, Professor at the University of Oxford, Principal of Jesus College, Oxford, and Member of the British House of Lords.
Krebs died on 22 November 1981 in Oxford.
Krebs and the Krebs Cycle
At the University of Sheffield, Krebs investigated cellular respiration (consumption of oxygen to produce energy from glucose) using Warburg’s manometer to detect oxygen consumption. (Back in Germany he had suggested this method to Warburg, but Warburg had flatly rejected the idea.) Using the manometer he tested putative intermediates via increased oxygen consumption in the pigeon breast muscle. Succinate, fumarate, and malate proved to have a strong influence. In 1937 German biochemists Franz Koop and Carl Martinus had demonstrated a series of reactions using citrate that produced oxaloacetate. Krebs realized his chemicals could be the missing intermediates for such reaction. After four months of experimental works to fill the gap, Krebs succeeded in establishing the sequence of the chemical cycle, which he called the "citric acid cycle".
Krebs wrote a short manuscript of the discovery to Nature on 10 June 1937. On 14 June he received a
rejection letter from the editor who expressed that the journal had "already sufficient letters to fill correspondence columns of NATURE for seven or eight weeks" and that Krebs was encouraged to "submit it for early publication to another periodical." Krebs immediately prepared a longer version titled "The Role of Citric Acid in Intermediate Metabolism in Animal Tissues" which he sent to the Dutch journal Enzymologia after two weeks and was published in two months.
The Citric Acid CycleGlycolysis
C6H12O6→6CO2+6H2O + Energy
Citric Acid Cycle, AKA Krebs’ Cycle;
Tricarboxyic Acid (TCA) Cycle
Fritz Albert Lipmann, 1953 “for his discovery of
co-enzyme A and its importance for
intermediary metabolism”
Lipmann was born in Königsberg, Germany, to a Jewish family.
Lipmann studied medicine In 1926 he joined Otto Meyerhof (1922) at the Kaiser Wilhelm Institute, Berlin, for his Ph.D. thesis. He followed Meyerhof to Heidelberg to the Kaiser Wilhelm Institute for Medical Research.
He left Germany in1939 for the United States, at Cornell University Medical College. In 1941 he joined the research staff of the Massachusetts General Hospital in Boston. In 1949 he became Professor of Biological Chemistry at Harvard Medical School. In1957 he moved to the Rockefeller University. He was awarded the National Medal of Science in 1966.
He died in New York in 1986. (His widow Freda died in 2008 aged 101.)
Axel Hugo Theodor Theorell, 1955 “for his
discoveries concerning the nature and mode
of action of oxidation enzymes”
Axel Theorel 1903-1982
In 1933 a Rockefeller Foundation fellowship
enabled him to go to Berlin-Dahlem to work with
the biochemist and cell physiologist Otto
Warburg (1931). There they worked on
Warburg’s “yellow enzyme”
Theorell was able to separate the yellow enzyme
into two components: a protein and a
coenzyme which he analyzed and found to be
Flavin mononucleotide (FMN).
This was the first discovery of coenzymes.
FMN
Konrad Bloch and Feodor Lynen, 1964, “for their
discoveries concerning the mechanism and regulation
of the cholesterol and fatty acid metabolism”
Konrad Bloch (1912-2000) was born in Neisse , in the German Empire's Prussian Province of Silesia. In 1934, due to the Nazi persecutions of Jews, he fled to Davos, Switzerland, before moving to the United States in 1936. There he enrolled at Columbia University, and received a
Ph.D in biochemistry in 1938. He taught at Columbia from 1939 to 1946. From there he went to the University of Chicago and then to Harvard University in 1954, a post he held until 1982.
Feodor Lynen (1911-1979) was born in Munich, Germany. He graduated from the Munich University in 1937 He remained in Germany throughout World War II. In 1954 he became director of the Max-Planck Institute
for Cellular Chemistry in Munich, a position which was created for him at the instigation of Otto Warburg and Otto Hahn.
Michael S. Brown and Joseph L.
Goldstein, 1985 “for their discoveries
concerning the regulation of cholesterol
metabolism”They discovered that human
cells have low-density
lipoprotein (LDL) receptors that
remove cholesterol from the
blood and that when LDL
receptors are not present in
sufficient numbers, individuals
develop hypercholesterolemia
and become at risk for
cholesterol related diseases.
Their collaboration (40 years,
since 1972) is the longest in the
history of this prize.
In addition to explaining the underlying pathology of
hypercholesterolemia, their work uncovered a fundamental
aspect of cell biology - Receptor-mediated endocytosis.