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J. Biol. Chem., Vol. 280, Issue 10, 7, March 11, 2005
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Classics
On the Utilization of Acetic Acid for Cholesterol Formation (Bloch, K., and Rittenberg, D. (1942) J. Biol. Chem. 145, 625-636)
The Utilization of Acetic Acid for the Synthesis of Fatty Acids (Rittenberg, D., and Bloch, K. (1945) J. Biol. Chem. 160, 417-424)
The Biological Conversion of Cholesterol to Pregnanediol (Bloch, K. (1945) J. Biol. Chem. 157, 661-666)
Konrad Emil Bloch (1912-2000) was born in Neisse, eastern Germany (now Nysa in Poland). Growing up he was more interested in engineering and natural sciences than chemistry, but an organic chemistry course taught by future Nobel laureate Hans Fischer at the Technische Hochschule in Munich provided a turning point. Bloch said of Fischer's class, "As he presented it, the subject matter was fascinating, the organization superb, and the delivery monotonous" (1). Despite Fischer's monotone delivery, Bloch was influenced enough to become a chemistry student in his laboratory.1
In early 1934, Bloch was told by Nazi authorities, in line with new racial laws, that he could no longer study at the Technische Hochschule. Fischer managed to arrange for Bloch to work at the Schweizerisches Höhenforschung's Institut in Davos. There, he studied the lipids of human tubercle bacilli and was able to show that a previous report of the presence of cholesterol in this organism was erroneous. This was Bloch's first encounter with cholesterol, a subject in which he would eventually play a great role.
In 1936, with the help of R. J. Anderson at Yale University, Bloch immigrated to the United States and started working with Hans Clarke at the College of Physicians and Surgeons (P & S), Columbia University. He received his Ph.D. a year and one-half later, after completing a relatively straightforward piece of research on amino acid chemistry, and was then invited by Rudolf Schoenheimer to join his group.
Also in Schoenheimer's laboratory at this time was a scientist named David Rittenberg who had done his graduate work on deuterium with Harold Urey. Shortly after receiving his degree, Rittenberg approached Schoenheimer with the prospect of using deuterium as a biological tracer. This resulted in the publication of several seminal papers authored by Rittenberg and Schoenheimer on the use of deuterium to study metabolism, which was the subject of a previous Journal of Biological Chemistry (JBC) Classic (2).
Schoenheimer was eager for Bloch to apply the isotope tracer method to study the biosynthesis of cholesterol and had him start by investigating whether the hydroxyl oxygen in cholesterol came from water or oxygen. Unfortunately, Bloch was unable to solve this first problem because no method existed at that time for the mass spectrometric analysis of stably bound oxygen in complex organic compounds. Eventually, in 1956, Bloch's student T. T. Tchen would show that molecular oxygen is the source of the hydroxyl oxygen (3).
Schoenheimer died in 1941, and his laboratory's research projects were divided up among its members. Bloch inherited lipids, and Rittenberg acquired protein synthesis. Although he was still working on the cholesterol oxygen problem at that time, Bloch's attention was quickly diverted with the publication of a paper by R. Sonderhoff and H. Thomas, which reported that "The nonsaponifiable fraction of yeast grown in a medium supplemented with deuterated acetate had a deuterium content so high that a direct conversion of acetic acid to sterols has to be postulated" (4). Schoenheimer and Rittenberg had also done experiments with D2O that indicated that animal cholesterol is synthesized from small molecules (5). Combining their areas of expertise, Rittenberg and Bloch did the next obvious experiment: they fed labeled acetates to rats and mice. As reported in the first JBC Classic reprinted here, they found that a substantial amount of deuterium was incorporated into cholesterol. However, their results did not tell them how many of the 27 sterol carbon atoms were supplied by acetic acid. The definitive answer came 10 years later when Bloch used an acetateless mutant of Neurospora crassa to show that the mutant's sterol derived all its carbon atoms from exogenous acetate (6).
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Eventually Rittenberg became director of the isotope laboratory at P & S in 1941 and remained there until he retired. His research with isotope tracers encompassed a wide variety of subjects, including the study of hippuric acid metabolism, the dynamics of red blood cell survival in patients with blood abnormalities, the development of a method to assay amino acids in protein hydrolysates, and investigations into the synthesis of porphyrin, which will be the subject of a future JBC Classic. Rittenberg's many contributions to the isotope tracer technique were recognized when he was awarded the Eli Lilly Award in Biological Chemistry from the American Chemical Society and also with his election to the National Academy of Sciences in 1953.2
In addition to using isotopes to study the biosynthesis of cholesterol, Bloch also used the tracers to examine the precursor role of cholesterol in bile acids and steroid hormones. In the final JBC Classic reprinted here, Bloch demonstrates that cholesterol is converted into progesterone. However, Bloch encountered several logistical problems when starting this experiment. First, labeled cholesterol was unavailable commercially so he had to spend much of his time introducing deuterium into cholesterol by platinum-catalyzed exchange in heavy wateracetic acid mixtures. Second, the only practical source for isolating the progesterone metabolite pregnanediol in sufficient quantity was from human pregnancy urine, and his request to the P & S department of obstetrics and gynecology for permission to administer labeled cholesterol to one of its patients was denied. Bloch eventually managed to obtain his pregnanediol due to a "willingness to cooperate at home" (1) and proved that progesterone was indeed synthesized from cholesterol.
In 1946 Bloch moved to the Department of Biochemistry at the University of Chicago and then to Harvard University in 1954. He continued to study fatty acids and cholesterol as well as the enzymatic synthesis of the tripeptide glutathione. Eventually, through the combined efforts of Bloch, John Cornforth, and George Popják, the origin of each of the 27 individual carbon atoms of cholesterol (from the methyl or carboxyl group of acetate) was established. Bloch also aided in the identification of several important landmarks in the series of more than 30 reactions in the biosynthesis of cholesterol, including the cyclization of squalene to lanosterol. His work on fatty acids and cholesterol was eventually rewarded when he shared the 1964 Nobel Prize in Physiology or Medicine with Feodor Lynen "for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism."
The elucidation of the pathway from acetic acid to cholesterol was not only a tremendous achievement for biochemistry but also of great importance to medicine. Knowledge of the biosynthetic pathway for cholesterol eventually aided in the discovery of statins, drugs that interfere with cholesterol synthesis, which are now widely used to treat high cholesterol.
FOOTNOTES
1 All biographical information on Konrad Bloch was taken from Refs.
1,
7,
8, and
9. 
2 All biographical information on David Rittenberg was taken from Ref.
10.
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