Hans Adolf Krebs

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German–British biochemist (1900–1981)

Krebs, the son of an ear, nose, and throat specialist, was born in Hildesheim, Germany, was educated at the universities of Göttingen, Freiburg, Munich, Berlin, and Hamburg, obtaining his MD in 1925. He taught at the Kaiser Wilhelm Institute, Berlin, and the University of Freiburg but in 1933, with the growth of the Nazi movement, decided to leave Germany. Consequently he moved to England, where from 1935 to 1954 he served as professor of biochemistry at Sheffield University; after 1945 he was appointed director of the Medical Research Council's Cell Metabolism Unit at Sheffield. In 1954 Krebs moved to Oxford to take the Whitley Chair of Biochemistry, a post he held until his retirement in 1967.

Krebs is best known for his discovery of the Krebs cycle (or tricarboxylic acid cycle) in 1937. This is a continuation of the work of Carl and Gerty Cori, who had shown how carbohydrates, such as glycogen, are broken down in the body to lactic acid; Krebs completed the process by working out how the lactic acid is metabolized to carbon dioxide and water. When he began this work little was known apart from the fact that the process involved the consumption of oxygen, which could be increased, according to Albert Szent-Györgyi, by the four-carbon compounds succinic acid, fumaric acid, malic acid, and oxaloacetic acid. Krebs himself showed in 1937 that the six-carbon citric acid is also involved in the cycle.

By studying the process in pigeon breast muscle Krebs was able to piece together the clues already collected into a coherent scheme. The three-carbon lactic acid is first broken down to a two-carbon molecule unfamiliar to Krebs; it was in fact later identified by Fritz Lipmann as coenzyme A. This then combines with the four-carbon oxaloacetic acid to form the six-carbon citric acid. The citric acid then undergoes a cycle of reactions to be converted to oxaloacetic acid once more. During this cycle two molecules of carbon dioxide are given up and hydrogen atoms are released; the hydrogen is then oxidized in the electron transport chain with the production of energy. Much of the detail of this aspect of the cycle was later filled in by Lipmann, with whom Krebs shared the 1953 Nobel Prize for physiology or medicine.

Krebs fully appreciated the significance of the cycle, pointing out the important fact that it is the common terminal pathway for the chemical breakdown of all foodstuffs.

In 1932, with K. Henselheit, Krebs was responsible for the introduction of another cycle. This was the urea cycle, whereby amino acids (the constituents of proteins) eliminate their nitrogen in the form of urea, which is excreted in urine. This left the remainder of the amino acid to give up its potential energy and participate in a variety of metabolic pathways.

(1900-1981) German-born biochemist; elucidated the pathways of urea synthesis (1932) and the citric acid cycle as the major pathway of intermediary metabolism (1937); performed first studies of requirements for vitamins A and C; Nobel Prize 1953.

The German-British biochemist Sir Hans Adolf Krebs (1900-1981) shared the Nobel Prize in Physiology orMedicine for his discovery of the citric, or tricarboxylic, acid cycle (Krebs cycle).

Hans A. Krebs, the son of Georg Krebs, an otolaryngologist, was born in Hildesheim, Germany, on April 25, 1900. He studied medicine at the universities of Göttingen, Freiburg im Breisgau, Munich, and Berlin, qualified in 1924, and in 1925 graduated as a doctor of medicine in the University of Hamburg. After a year's study of chemistry in Berlin, he was assistant to the biochemist Otto Warburg in Berlin-Dahlem from 1926 to 1930. Krebs then returned to university clinical work, first at Altona and then as assistant at the University Medical Clinic in Freiburg. In June of 1933 the Nazis terminated his appointment, and Sir Frederick Gowland Hopkins invited him to work, with a Rockefeller studentship, at the Biochemical Institute at Cambridge. In 1934 Krebs was appointed demonstrator of biochemistry at the University of Cambridge.

In 1935 Krebs went to the University of Sheffield as a lecturer in pharmacology. In 1938 he was appointed lecturer in biochemistry and director of the newly founded Institute of Biochemistry. In 1945 his appointment was upgraded to a professorship, and he was also director of a research unit of the Medical Research Council already established in his department. In 1954 he was appointed Whitley professor of biochemistry in the University of Oxford, and the Medical Research Council's research unit was transferred there. He was also elected a Fellow of Trinity College, Oxford.

The Ornithine Cycle

To keep organs and tissues alive for biochemical tests, they had been perfused with physiological salines as a substitute for blood. The results were often unsatisfactory. Early in his career Krebs devised the tissue-slice technique. The organ, rapidly removed after the death of the test animal, was cut into thin slices and kept in fresh saline for biochemical testing. He used this technique in his study of the synthesis of urea by the liver.

It was known that urea is produced in a liver undergoing autolysis, and in 1904 it was shown that the autolysis produces the amino acid arginine, which is acted on catalytically by the enzyme arginase to produce urea. In 1932 Krebs found that, when an amino acid is added to liver, ammonia is liberated and is converted approximately quantitatively into urea. All the amino acids tested gave this result except two. When ornithine was added, the urea production was 10 times the expected amount, and arginine also gave an excess yield of urea. He therefore suggested that ornithine reacted with added ammonia and carbon dioxide to form arginine. Under the action of arginase, the arginine was broken down to urea and ornithine. If ammonia was omitted, there was no appreciable formation of urea. Further, ornithine was not observed to disappear while, with added ammonia, the synthesis of urea was in progress. Krebs therefore concluded that the ornithine acted as a catalyst. Many other substances were tested, but the only one that acted like ornithine was citrulline, and he suggested that citrulline formed a stage midway between ornithine and arginine. His ornithine cycle is still regarded as a sound explanation of the synthesis of urea in the body.

The Citric Acid Cycle

Krebs then turned to the intermediary oxidation of carbohydrates. In 1935 Albert von Szent-Györgyi elucidated the sequence of oxidations of the C₄-dicarboxylic acids as follows:

succinic acid→fumaric acid→malic acid→maoxaloacetic acid

He also showed that these reactions were at least in part catalytic. This was later proved, but the manner of action remained unknown. In 1936 C. Martius and F. Knoop showed that in biological material citrate yields alphaketoglutarate on oxidation. They further suggested that the intermediate products were cis -aconitic acid, isocitric acid, and oxalosuccinic acid. It was already known that alpha-ketoglutarate forms succinate. In 1937, when Krebs started his work, the following sequence of reactions was therefore known:

citric acid→cis -aconitic acid→iso-citric acid→oxalosuccinic acid→alpha-ketoglutamic acid→succinic acid→fumaric acid→malic acid→oxaloacetic acid

Krebs and W. A. Johnson found that citrate was not only rapidly broken down in muscle but was also readily formed provided that oxaloacetate was added. The assumption was that some of the oxaloacetate was broken down to pyruvate or acetate and that the formation of citrate was due to a combination of the remaining oxaloacetate with pyruvate or acetate. But pyruvate or acetate could be derived from carbohydrate. In 1937 Krebs conceived the whole process as a cycle in which an undefined derivative of pyruvate, resulting from the breakdown of carbohydrate, condensed with oxaloacetate to form citric acid. The citric acid then passed through the changes noted above until oxaloacetic acid was regenerated, and the cycle was repeated. The full cycle is therefore as follows:

citric acid→cis -aconitic acid→iso-citric acid→oxalosuccinic acid→alpha-ketoglutamic acid→succinic acid→fumaric acid→malic acid→oxaloacetic acid+pyruvic acid→citric acid

Since Krebs originally described this cycle, he and others did further work on it. In 1950 Fritz Lipmann showed that the derivative of pyruvic acid that combines with oxaloacetate to form citrate is acetyl-coenzyme A and that this coenzyme is also active at two other points in the cycle. It was shown that acetyl-coenzyme A, in addition to its formation from carbohydrate, is also formed from fatty acids and many amino acids. The Krebs cycle is therefore a most important concept of biochemistry. Krebs shared with Lipmann the Nobel Prize in Physiology or Medicine in 1953.

Among Krebs's other important contributions to biochemistry were his studies of the synthesis of glutamine in brain tissue under the influence of the enzyme glutaminase (1935), the passage of ions across cell membranes (1950), and the effect of primitive intrinsic regulating mechanisms in controlling the metabolism of metazoan cells (1957).

Later Life

In 1967 Krebs, having reached Oxford's mandatory retirement age of 67, retired from his Oxford chair and from his fellowship. He refused to stop researching, however. He was thereupon appointed a research scientist in the Nuffield Department of Clinical Medicine at Oxford and was elected a Supernumerary Fellow of St. Cross College. He was also appointed a visiting professor at the Royal Free Hospital School of Medicine in the University of London. Krebs died at Oxford in 1981 at the age of 81.

Krebs received many honors in addition to his Nobel Prize. In 1947 he was elected a Fellow of the Royal Society, and he was awarded its Royal (1954) and Copley (1961) Medals. He delivered its Croonian Lecture in 1963. He was a member of many foreign scientific societies, and he held honorary doctorates from 14 universities. He received the Gold Medal of the Royal Society of Medicine in 1965, and he was knighted in 1958.

Further Reading

There is a biography of Krebs in Nobel Lectures, Physiology or Medicine, 1942-1962 (1964), which also contains his Nobel Lecture. The Krebs cycle is discussed in all textbooks of biochemistry, such as A. White, P. Handler, and E. L. Smith, Principles of Biochemistry (3d ed. 1964), and E. Baldwin, Dynamic Aspects of Biochemistry (4th ed. 1963). A thorough two-volume chronicle of Krebs's life and work is Frederic Lawrence Holmes, Hans Krebs: Architect of Intermediary Metabolism (1993).

For other persons of the same name, see Hans Krebs.

Hans Adolf Krebs
Born	25 August 1900(1900-08-25) Hildesheim, Germany
Died	22 November 1981 (aged 81) Oxford, England
Citizenship	United Kingdom
Nationality	Germany
Fields	Internal medicine, biochemistry
Institutions	Kaiser Wilhelm Institute for Biology University of Hamburg Cambridge University University of Sheffield University of Oxford
Alma mater	University of Göttingen University of Freiburg University of Berlin University of Hamburg
Known for	discovery of the urea cycle and the citric acid cycle
Notable awards	Nobel Prize in Physiology or Medicine (1953)

Sir Hans Adolf Krebs (25 August 1900 – 22 November 1981) was a German born British physician and biochemist. Krebs is best known for his identification of two important metabolic cycles: the urea cycle and the citric acid cycle. The latter, the key sequence of metabolic chemical reactions that produces energy in cells, is also known as the Krebs cycle and earned him a Nobel Prize in 1953.

Contents 1 Biography 1.1 Early years 1.2 Career 1.3 Personal life 2 See also 3 References 4 External links

Biography

Early years

Krebs was born in Hildesheim, Germany, to Georg Krebs, an ear, nose, and throat surgeon, and Alma Davidson . He went to school in Hildesheim and studied medicine at the University of Göttingen and at the University of Freiburg from 1918–1923. He earned his Ph.D. at the University of Hamburg in 1925, then studied chemistry in Berlin for one year, where he later became an assistant of Otto Warburg at the Kaiser Wilhelm Institute for Biology until 1930.

Career

Krebs joined the German army in 1932, and was appointed to the 13th mechanized infantry division regardless of his Jewish faith. Krebs returned to clinical medicine at the municipal hospital of Altona and then at the medical clinic of the University of Freiburg, where he conducted research and discovered the urea cycle. Because he was Jewish, he was barred from practicing medicine in Germany and he emigrated to England in 1933. He was invited to Cambridge, where he worked in the biochemistry department under Sir Frederick Gowland Hopkins (1861–1947). Krebs became professor of biochemistry at the University of Sheffield in 1945. Krebs' area of interest was intermediary metabolism. He identified the urea cycle in 1932, and the citric acid cycle in 1937 at the University of Sheffield. He moved to Oxford as Professor of Biochemistry in 1954 and after his retirement continued work at the Radcliffe Infirmary, Oxford until his death. He was a fellow of Trinity College.

In 1953 he received the Nobel Prize in Physiology for his "discovery of the citric acid cycle." He was knighted in 1958.

He was elected Honorary Fellow of Girton College, Cambridge University in 1979.

Personal life

Krebs was married in 1938 to Margaret Cicely Fieldhouse with whom he had three children: sons, John (later Baron Krebs, an ornithologist and member of the House of Lords) and Paul, and daughter, Helen. Krebs died in Oxford, England in 1981.

See also

• Fritz Albert Lipmann

References

• Weber, G (2001). "Sir Hans A. Krebs Centenary Lecture: cancer and clinical targeting". Adv. Enzyme Regul. 41: 1–29. doi:10.1016/S0065-2571(00)00026-1. PMID 11417529. 
• Stubbs, M; Gibbons G (September 2000). "Hans Adolf Krebs (1900-1981)...his life and times". IUBMB Life 50 (3): 163–6. doi:10.1080/152165400300001462. PMID 11142342. 
• Raju, T N (May 1999). "The Nobel chronicles. 1953: Hans Adolf Krebs (1900-81) and Fritz Albert Lipmann (1899-1986)". Lancet 353 (9164): 1628. doi:10.1016/S0140-6736(05)75758-5. PMID 10334294. 
• Sri Kantha, S: The question of nepotism in the award of Nobel prizes; a critique of the view of Hans Krebs. Medical Hypotheses, 1991; 34: 28-32.

External links

• Biography
• 1953 Nobel Prize in Physiology or Medicine

v • d • e Nobel Laureates in Physiology or Medicine Max Theiler (1951) · Selman Waksman (1952) · Hans Krebs / Fritz Lipmann (1953) · John Enders / Thomas Weller / Frederick Robbins (1954) · Hugo Theorell (1955) · André Cournand / Werner Forssmann / Dickinson W. Richards (1956) · Daniel Bovet (1957) · George Beadle / Edward Tatum / Joshua Lederberg (1958) · Severo Ochoa / Arthur Kornberg (1959) · Frank Burnet / Peter Medawar (1960) · Georg von Békésy (1961) · Francis Crick / James D. Watson / Maurice Wilkins (1962) · John Eccles / Alan Hodgkin / Andrew Huxley (1963) · Konrad Bloch / Feodor Lynen (1964) · François Jacob / André Lwoff / Jacques Monod (1965) · Francis Rous / Charles B. Huggins (1966) · Ragnar Granit / Haldan Hartline / George Wald (1967) · Robert W. Holley / Har Khorana / Marshall Nirenberg (1968) · Max Delbrück / Alfred Hershey / Salvador Luria (1969) · Bernard Katz / Ulf von Euler / Julius Axelrod (1970) · Earl Sutherland, Jr. (1971) · Gerald Edelman / Rodney Porter (1972) · Karl von Frisch / Konrad Lorenz / Nikolaas Tinbergen (1973) · Albert Claude / Christian de Duve / George Palade (1974) · David Baltimore / Renato Dulbecco / Howard Temin (1975) Complete roster · 1901–1925 · 1926–1950 · 1951–1975 · 1976–2000 · 2001–present

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