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.

Muscle Metabolism

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.)

Coenzyme A

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.