Biochemical and Biophysical Research Communications 292, 1117–1120 (2002)

doi:10.1006/bbrc.2002.2031, available online at http://www.idealibrary.com on

Konrad Bloch—A Pioneer in Cholesterol and

Fatty Acid Biosynthesis
Dennis E. Vance* ,1 and Howard Goldfine†
*Department of Biochemistry and Canadian Institutes of Health Research Group on Molecular and Cell Biology of Lipids,
University of Alberta, Edmonton, Alberta T6G 2S2, Canada; and †Department of Microbiology,
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

EARLY YEARS

Konrad Emil Bloch was born in Neisse, Germany, on
January 21, 1912. His father’s name was Frederick
Bloch and progenitors had lived in this town in Upper
Silesia for 3 or 4 generations (1). Although Frederick
Bloch had a law degree, he took over the family busi-
ness of making draperies. In 1914, World War I began
and Frederick Bloch became an officer. The family
survived the war and the business continued. Konrad
Bloch obtained his schooling in Neisse, attending an
elementary school from the age of 6 to 9 and then high
school (humanistic gymnasium) for the next 9 years.
His interest in metallurgy led Bloch to attend Univer-
sity at the Technische Hochschule in Munich, Ger-
many. However, it was the organic chemistry lectures
of Hans Fischer that led Bloch into chemistry (2). In
Munich, Bloch also regularly attended the Munich
Chemical Society, where he was greatly influenced by
lectures by Richard Willstätter, Heinrich Wieland, and
Alfred Windaus.
In 1934, the Dean of the Technische Hochschule
informed Bloch that he was ineligible to continue be-
cause Professor Fischer would not have him as a grad-
uate student (2). This was not true, but simply the
beginning of the Nazi policy to eliminate Jews from
German society. In fact, Fischer wrote a letter of rec-
ommendation for Bloch that stated only, “Herr Bloch
ist gut” (1). Fischer arranged for Bloch to become a
research assistant at the Schweizerisches Höhenfors-
chung’s Institut in Davos. Bloch’s first assignment was
to determine if cholesterol was among the lipids of
human tubercle bacilli. Bloch’s experiment clearly
showed that cholesterol was absent, confirming an ear-
lier report from Erwin Chargaff. Bloch next investi-
gated, and found, phosphatidic acid in the tubercle
bacillus, which contradicted a report from R. J. Ander-
son at Yale University (2). About this time Bloch’s
permit in Switzerland was about to expire and Bloch
wrote to Anderson to see if he could join his laboratory.
Bloch subsequently received a letter from the Dean
1
To whom correspondence should be addressed. Fax: (780) 492-
3383. E-mail: dennis.vance@ualberta.ca.
indicating that he had been accepted as an assistant in
biological chemistry. However, a second letter from
Anderson indicated there was not a stipend associated
with the position. Nevertheless, Bloch moved to the
United States in part because his future wife, Lore,
whom he had met in Munich, had moved to America
(1). Bloch arrived in the United States in December
1936.
Anderson did not think that Bloch should come to
Yale because he believed Bloch might learn more from
Hans Clarke at Columbia University. Clarke was pre-
pared to give Bloch credit for his earlier work in Davos
toward a Ph.D. degree but required that he do some lab
work at Columbia, where he synthesized a series of
N-alkylcysteine derivatives (3). After obtaining his
Ph.D., Bloch became a postdoctoral fellow with Rudolf
Schoenheimer, who had joined Clarke’s department
and was introducing the use of stable isotopes to trace
metabolic pathways. Bloch stated in a later interview
that “Schoenheimer was first reluctant to hire me be-
cause he didn’t think my Ph.D. thesis was very impres-
sive” (1). This reservation must have been short-lived
because Bloch and Schoenheimer published a number
of papers on creatine metabolism in the Journal of
Biological Chemistry. During his time with Schoenhei-
mer, Bloch also started to work on the origin of the
oxygen atom in cholesterol, but without success (2). In
1941, tragically Schoenheimer committed suicide and
the work in his laboratory was divided among three
postdoctoral fellows, David Rittenberg, David Shemin,
and Konrad Bloch. Bloch ended up with the cholesterol
problem, Shemin with amino acid and heme metabo-
lism, and Rittenberg with protein synthesis and turn-
over (2). The division of projects occurred by drawing
lots (1, 2). The “luck of the draw” led Konrad Bloch into
lipid metabolism.
THE PATHWAY OF CHOLESTEROL BIOSYNTHESIS
The structure of cholesterol was solved in 1932 by
Heinrich Wieland and H. Dane (4). At that time, no

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Vol. 292, No. 5, 2002 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
clues in the structure led to reasonable predictions
about the biosynthetic pathway. Major insight came
from a paper published in 1937 by Sonderhoff and
Thomas (5) that arrived in the United States only in
1941 because of the war (2). This paper reported very
high incorporation of deuterium-labeled acetate into
the sterol fraction of yeast. Thus, Bloch and Rittenberg
fed deuterium-labeled acetate to rats and mice and
found substantial incorporation of label into choles-
terol and fatty acids (6, 7). Subsequent studies added to
the knowledge that acetate was a precursor of choles-
terol and that cholesterol was a precursor of bile acids
and steroid hormones.
In 1946, Bloch was enticed by a former graduate
student of Schoenheimer’s and a friend, Earl Evans, to
move to the Department of Biochemistry at the Uni-
versity of Chicago. In Chicago, in addition to studies on
cholesterol biosynthesis, Bloch worked on the biosyn-
thesis of glutathione as a model system for protein
biosynthesis. His work showed that amino acids, ATP,
and two specific enzymes were required for synthesis of
the tripeptide. From studies in other labs, it became
apparent that glutathione was not a good model of
protein synthesis and Bloch abandoned this line of
research.
For many years, the Bloch lab worked on the origin
of the 27 carbons of cholesterol in competition with the
laboratories of John Cornforth and George Popják.
Through the efforts of these labs, it was demonstrated
that all 27 carbons were specifically derived from ei-
ther the methyl or the carboxyl carbon of acetate (2, 8).
In 1934, the British chemist Sir Robert Robinson had
proposed that squalene might be folded into choles-
terol. It was only in 1952 that R. G. Langdon and Bloch
demonstrated that squalene was indeed a precursor of
cholesterol (9). Although Robinson had an important
insight, the proposed folding was not correct. The cor-
rect folding of squalene into lanosterol was predicted
by the organic chemist R. B. Woodward and Bloch in
1953 (10). The conversion of squalene to lanosterol
involves the migration of methyl groups (from C 8 to C 14
and from C 14 to C 13). The migration of the methyl
groups was described independently by Bloch’s lab (11)
and by Cornforth and Popják (12).
Missing links in the scheme between acetate and
squalene were 5-, 10-, and 15-carbon intermediates. An
important clue to the identity of these intermediates
came from studies in Merck, Sharp and Dohme labo-
ratories that resulted in the isolation of mevalonic acid
and the demonstration that it could substitute for ac-
etate in acetate-requiring strains of Lactobacillus aci-
dophilus (13). Subsequently, others showed mevalonic
acid to be a precursor of squalene and sterol (14).
Bloch’s group, Fyodor Lynen’s group in Germany, and
Cornforth and Popják in England were able to eluci-
date which isoprene phosphates were derived from me-
1118
valonate and were intermediates in the conversion of
acetate to squalene (15).
The final part of the puzzle was to determine the
pathway by which lanosterol was converted to choles-
terol. This conversion involves three demethylation re-
actions and hydrogenation of double bonds. Once again
Bloch’s laboratory was heavily involved in these stud-
ies (15). The key role Konrad Bloch played in elucidat-
ing the pathway for cholesterol biosynthesis was the
basis for the Nobel Prize in Physiology or Medicine that
was awarded to him and Lynen in 1964. In an inter-
view in 1993, Bloch was asked if he had expected to
receive the prize (1). He replied:
No. I think I can truthfully say that I thought someone with my
interests and my position had a finite chance, but no more. It
was not a thought that preoccupied me nor was it an incentive.
It came as a total surprise. I was fifty-two, and what I set out
to do was by no means complete. I think the award was for the
cumulative impact of research, not only on cholesterol biosyn-
thesis, but also fatty acid synthesis. That is what the citation
says.
FATTY ACID BIOSYNTHESIS
As indicated by the Nobel citation, Bloch had a long-
standing and parallel interest in fatty acid biosynthe-
sis. In a classic experiment, Bloch and Rittenberg dem-
onstrated in 1944 that fatty acids were formed from
acetate in animals (7). His interest in fatty acid metab-
olism was renewed when T. T. Chen and Bloch rein-
vestigated the origin of the oxygen atom of cholesterol
and demonstrated (15 years after Bloch first attempted
this experiment with Schoenheimer) that it originated
from O 2 (2). This result stimulated his interest in “ox-
ygen as an essential biosynthetic reagent, and led me
to investigate some consequences for aerobic versus
anaerobic patterns of metabolism” (2). In 1960, Bloom-
field and Bloch demonstrated the oxygen-dependent
desaturation of long-chain acyl-CoA derivatives in a
yeast extract (16). The requirement for NADH was also
shown and later Schroepfer and Bloch showed that the
removal of the two hydrogens of stearic acid to yield
oleic acid was stereospecific (17).
These findings led Bloch to think about the mecha-
nism of unsaturated fatty acid synthesis in anaerobic
organisms that could not use an oxygen-dependent
mechanism. In a series of studies, Bloch’s laboratory
showed that anaerobic and other bacteria produced
unsaturated fatty acids by a novel pathway, not used
by eukaryotic organisms, in which the double bond was
introduced during the process of chain elongation (18).
These studies explained the presence of the 18-carbon
11-cis-vaccenic acid in bacteria, instead of oleic acid,
found in eukaryotes, that has the double bond in the ⌬ 9
position. Bloch and co-workers isolated the enzyme
required for this step, ␤-hydroxydecanoyl thioester de-
hydrase, and found that the reaction required a heat-
Vol. 292, No. 5, 2002 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
stable protein (19) with properties similar to those of a
protein shown by Roy Vagelos and co-workers to be
required for fatty acid synthesis in Clostridium
kluyveri (20). The two groups met at the 1961 meeting
of the Federation of American Societies for Experimen-
tal Biology in Atlantic City and agreed “not to compete
but to pursue their separate objectives that had led to
the chance discovery of acyl-carrier protein. Roy’s lab-
oratory was primarily interested in the mechanism of
chain elongation, while we wanted to know how unsat-
urated fatty acids are formed anaerobically” (2). Sub-
sequent studies demonstrated the key role for
␤-hydroxydecanoyl thioester dehydrase in the biosyn-
thesis of unsaturated fatty acids in E. coli.
Work on the mechanism of unsaturated fatty acid
synthesis in bacteria led to the development of an
acetylenic substrate that was converted to an allene by
the dehydrase. This allene rapidly reacted with, and
inactivated, the dehydrase (2). This acetylenic “sui-
cide” substrate of the dehydrase opened a major area of
research on the use of “suicide” substrates in enzymol-
ogy and pharmacology. Bloch considered the name
“suicide” to be a misnomer since “this anthropomorpho-
logical term connotes a deliberate act on the part of the
enzyme, but this is not strictly the case. Dehydrase
falls prey to trickery because it fails to distinguish
between the C ␣ protons of the acetylenic and olefinic
substrates, an error that seals its fate” (2). He thought
suicide inhibition should be more correctly called
mechanism-based enzyme inactivation.
Bloch’s thinking and interests were also colored by a
deep curiosity in evolutionary mechanisms (see the
article by Harold White (20a) in this issue). Thus,
Bloch initiated studies in the late 1960s on the enzy-
matic synthesis of fatty acids in mycobacteria, which,
like eukaryotic organisms, possess a very large, multi-
functional fatty acid synthetase in which seven enzy-
matic activities of fatty acid synthesis reside in a single
polypeptide chain (21). The active form of the syn-
thetase is a dimer of this polypeptide. In E. coli and
most other bacteria, the individual enzymes of fatty
acid synthesis reside on separate polypeptides. In the
course of these studies, a heat-stable factor that stim-
ulated the reaction many-fold was identified (22). Sub-
sequently, this factor was shown to be a polysaccharide
containing 3-O-methylmannose (23). The polysaccha-
ride binds long-chain C 22 and C 24 fatty acids uniquely
made by the mycobacterial fatty acid synthetase and
relieves feedback inhibition of the enzyme by the fatty
acid product (21, 23–25).
EVOLUTION AND THE STRUCTURE
OF CHOLESTEROL
Bloch’s evolutionary interest brought him back to
cholesterol as a major focus in the late 1970s: why had
1119
the structure of cholesterol evolved as such? The im-
mediate product of squalene cyclization is lanosterol.
Is there an important evolutionary advantage for
lanosterol to undergo the many subsequent reactions
to yield cholesterol? What was the driving force for the
formation of cholesterol once the presence of oxygen
permitted the biosynthesis of lanosterol (26)? Subse-
quent work emanating from Bloch’s lab showed that
indeed, in several instances, cholesterol would function
whereas lanosterol could not replace cholesterol (27).
For example, yeast is a sterol auxotroph when grown
anaerobically. Cholesterol will satisfy this sterol re-
quirement whereas lanosterol will not. Insects do not
have the ability to make sterols and require dietary
cholesterol. Lanosterol will not substitute for choles-
terol (27). The interactions of sterols with phospholip-
ids also showed that cholesterol was superior to lanos-
terol. Investigations into the leaking of glucose from
phosphatidylcholine vesicles demonstrated that cho-
lesterol, but not lanosterol, impeded this process (27).
The microviscosity of phosphatidylcholine vesicles was
four times higher with cholesterol than with lanosterol.
Moreover, the partially demethylated intermediates
were intermediate in their ability to substitute for cho-
lesterol. These and other studies led Bloch to conclude
in an article published in 1983 (27):
A sterol that fits and interacts effectively with the phospholipid
partner will alter the physical state of the membrane more
than a molecule that is poorly accommodated. Lanosterol, the
earliest intermediate in the sterol pathway fits least and cho-
lesterol, the end product, fits best. The fitness of partially
demethylated intermediates lies in between. This has been
shown by appropriate measurements both with artificial and
natural membranes. We therefore conclude that the temporal
sequence of steps nature has chosen for the sterol pathway
evolved in time in response to selection pressures. Improve-
ment of function was the driving force.
KONRAD BLOCH AFTER RETIREMENT
The last experimentally based papers from Bloch’s
lab were published in the early 1980s. He closed his lab
at this time. He did not have to write any more grant
applications! He had an office at Harvard and routinely
went there each day. His scholarly interests continued
during what he referred to as his permanent sabbatical
(28). Writing an autobiography did not appeal to him.
Instead he wrote a series of essays on topics he had
tucked in the back of his mind (28). This collection of
articles was published in 1994 by Yale University
Press in a book titled Blondes in Venetian Paintings:
The Nine-Banded Armadillo and Other Essays in Bio-
chemistry.
During a 1993 interview (1) he said, “I was struck by
the fact that many women painted notably by Titian,
Tintoretto, and Veronese, obviously from the upper
classes, had blonde hair. If you meet a blonde in north-
ern Italy, she is most likely a tourist from Scandinavia
Vol. 292, No. 5, 2002 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
or Germany, or a peroxide blonde. It struck me that in
the same paintings, the hair of the males is invariably
very dark, in fact black. I put all these clues together,
and concluded that the ladies in question must have
known about bleaching hair centuries before hydrogen
peroxide was discovered in 1812.” Further research led
to the first essay in his book (28).
Konrad Bloch died on October 15, 2000, at the age of
88. His contributions as a scientist, scholar, and a
human being were enormous. He was one of the lead-
ing scientific figures of the 20th century. Moreover, as
the accompanying articles in this volume testify, he
was also a beloved mentor, teacher, colleague, and
friend.
REFERENCES
1. Konrad Bloch, interview by James J. Bohning at Harvard Uni-
versity, 22 March 1993 (Philadelphia: Chemical Heritage Foun-
dation Oral History Transcript 109).
2. Bloch, K. (1987) Summing up. Annu. Rev. Biochem. 56, 1–19.
3. Bloch, K., and Clarke, H. T. (1938) N-Methylcysteine and deriv-
atives. J. Biol. Chem. 125, 275–287.
4. Bloch, K. (1982) The structure of cholesterol and of the bile acids.
Trends Biochem. Sci. 7, 334 –336.
5. Sonderhoff, R., and Thomas, H. (1937) Enzymic dehydrogenation
of trideuteroacetic acid. Liebeg’s Ann. Chem. 530, 195–213.
6. Bloch, K., and Rittenberg, D. (1942) On the utilization of acetic
acid for cholesterol formation. J. Biol. Chem. 145, 625– 636.
7. Bloch, K., and Rittenberg, D. (1944) The utilization of acetic acid
for fatty acid synthesis. J. Biol. Chem. 154, 311–312.
8. Cornforth, J. W., Hunter, G. D., and Popják, G. (1953) Studies of
cholesterol biosynthesis. 1. A new chemical degradation of cho-
lesterol. 2. Distribution of acetate carbon in the ring structure.
Biochem. J. 54, 590 –597 and 597– 601.
9. Langdon, R. G., and Bloch, K. (1952) Biosynthesis of squalene
and cholesterol. J. Am. Chem. Soc. 74, 1869.
10. Woodward, R. B., and Bloch, K. (1953) The cyclization of
squalene in cholesterol synthesis. J. Am. Chem. Soc. 75, 2023–
2024.
11. Maudgal, R. K., Tchen, T. T., and Bloch, K. (1958) 1,2-Methyl
shifts in the cyclization of squalene to cholesterol. J. Am. Chem.
Soc. 80, 2589.
12. Cornforth, J. W., Cornforth, R. H., Pelter, M. G., Horning, G.,
and Popják, G. (1959) Rearrangement of methyl groups in the
enzymic cyclization of squalene to lanosterol. Tetrahedron 5,
311–339.
13. Wolf, D. E., Hofmann, C. H., Aldrich, P. E., Skeggs, H. R.,
1120
Wright, L. D., and Folkers, K. (1956) ␤-Hydroxy-␤-methyl-␦-
valerolactone (divalonic acid), a new biological factor. J. Am.
Chem. Soc. 78, 4499.
14. Tavormina, P. A., Gibbs, M. H., and Huff, J. W. (1956) The
utilization of ␤-hydroxy-␤-methyl-␦-valerolactone in cholesterol
biosynthesis. J. Am. Chem. Soc. 78, 4498 – 4499.
15. Bloch, K. (1965) The biological synthesis of cholesterol. Science
150, 19 –28.
16. Bloomfield, D. K., and Bloch, K. (1960) The formation of delta-
9-unsaturated fatty acids. J. Biol. Chem. 236, 337–345.
17. Schroepfer, G. J., and Bloch, K. (1963) Enzymatic stereospecific-
ity in the dehydrogenation of stearic acid to oleic acid. J. Am.
Chem. Soc. 85, 3310.
18. Bloch, K. (1969) Enzymatic synthesis of mono-unsaturated fatty
acids. Acc. Chem. Res. 2, 193–202.
19. Lennarz, W. J., Light, R. J., and Bloch, K. (1962) A fatty acid
synthetase from E. coli. Proc. Natl. Acad. Sci. USA 48, 840 – 846.
20. Goldman, P., Alberts, A. W., and Vagelos, P. R. (1961) Require-
ment for a malonyl-CoA–CO 2 exchange reaction in long-chain
but not short-chain fatty acid synthesis in Clostridium kluyveri.
Biochem. Biophys. Res. Commun. 5, 280 –285.
20a.White, H. (2002) Konrad Bloch, evolution, and the RNA world.
Biochem. Biophys. Res. Commun. 292, 1267–1271.
21. Bloch, K., and Vance, D. E. (1977) Control mechanisms in the
synthesis of saturated fatty acids. Annu. Rev. Biochem. 46, 263–
298.
22. Brindley, D. N., Matsmura, S., and Bloch, K. (1969) Mycobacte-
rium phlei fatty acid synthetase—A bacterial multienzyme com-
plex. Nature 224, 666 – 669.
23. Ilton, M., Jevans, A. W., McCarthy, E. D., Vance, D., White,
H. B., and Bloch, K. (1971) Fatty acid synthetase activity in
Mycobacteria phlei: Regulation by polysaccharides. Proc. Natl.
Acad. Sci. USA 68, 87–91.
24. Vance, D. E., Mitsuhashi, O., and Bloch, K. (1973) Purification
and properties of the fatty acid synthetase from Mycobacterium
phlei. J. Biol. Chem. 248, 2303–2309.
25. Knoche, H., Esders, T. W., Koths, K., and Bloch, K. (1973)
Palmityl-CoA inhibition of fatty acid synthesis—Relief by bovine
serum albumin and mycobacterial polysaccharides. J. Biol.
Chem. 248, 2317–2322.
26. Bloch, K. (1976) On the evolution of a biosynthetic pathway in
reflections on biochemistry (Kornberg, A., Horecker, B. L., Cor-
nudella, L., and Oro, J., Eds.), pp. 143–150, Pergamon Press,
Oxford.
27. Bloch, K. (1983) Sterol structure and membrane function. CRC
Crit. Rev. Biochem. 14, 47–92.
28. Bloch, K. (1994) Blondes in Venetian Paintings, the Nine-
Banded Armadillo, and Other Essays in Biochemistry, Yale
Univ. Press, New Haven, CT.