Elucidation of the Cholesterol Synthetic Pathway

Rudolph Schoenheimer is credited with the initial application of stable isotopes that inaugurated the study of metabolic pathways in which the cholesterol synthetic pathway was elucidated for over more than a 20-year period. Dr. Schoenheimer, born in Berlin as a Jew, was forced to emigrate Nazi Germany and was offered a position at Columbia University in New York in 1933. In the Department of Chemistry was Harold Urey, who discovered deuterium which led to his award of the Nobel Prize in 1934.

Schoenheimer attended a seminar by Urey and recognized the potential of an isotope of hydrogen to elucidate biochemical transformations. Utilizing deuterium as a tracer, Schoenheimer and his colleagues in 1937 were able to demonstrate that cholesterol was undergoing degradation at some rate and being resynthesized at a comparable rate to maintain a steady state. Konrad Bloch, another Jewish emigrant from Nazi Germany, joined Schoenheimer’s lab at Columbia and focused primarily on using isotopes to understand the cholesterol synthetic pathway.

Tragically, Schoenheimer committed suicide in 1941, but Bloch and his colleague David Rittenberg continued the isotope research in cholesterol metabolism. In 1942, they showed that acetate contributes in a major way to both the side chain and ring structures of cholesterol.

Moving to the University of Chicago, he was able to demonstrate in 1950 that all the individual 27 carbon atoms in cholesterol were derived from acetate. Over the next few years, Blochin in collaboration with R. Langdon discovered that acetate over many steps first makes squalene and then converts it to cholesterol in rats.

The exact steps by which three acetate units gave rise to a six-carbon intermediate followed by the loss of one carbon to generate a five-carbon isopentenyl precursor remained elusive. The breakthrough came through the discovery at Merck of mevalonic acid while looking for a nutritive substitute for acetate. Following this discovery, the pathway to mevalonate via acetoacetate and hydroxymethylglutarylCoA (HMGCoA) was quickly demonstrated by Feodor Lynen working independently from Bloch in Germany.

In 1964, Bloch and Lynen were jointly awarded the Nobel Prize in Medicine for the mechanism of cholesterol synthesis. Lynen died at age 68 in 1979. During a routine medical check, Lynen was found to have an abdominal aortic aneurysm at a time when he was asymptomatic. Following medical advice, he underwent surgical resection of the aneurysm. However, he died 6 weeks later following complications. Bloch went on to also discover that bile and estrogen were made from cholesterol, which led to the recognition that all steroids are made from cholesterol.

He died at age 88 in 2000 of congestive heart failure. Many of the intermediates in cholesterol synthesis and their complex stereochemistry were elucidated by John Cornforth and Popjak in the MRC in the UK. Cornforth received the Nobel Prize for his brilliant work on stereochemistry.