|Earl then sought
to examine the role of acetyl phosphate in the synthesis
of the four-carbon fatty acid, butyric acid; that is,
to determine how this intermediate transfers its acetyl
part to another form of by the reaction of acetyl phosphate
coenzyme A, might be
an intermediate in fatty acid metabolism. An opportunity
to test this hypothesis came in 1949 when Earl spent several
months in Fritz Lipmann's laboratory as a postdoctoral
fellow. There, Earl and G. D. Novelli showed decisively
that CoA is indeed required in the reaction catalyzed
by phosphotransacetylase, the enzyme he had isolated.
Acetyl phosphate + CoA Acetyl-CoA
Among the many coenzymes, CoA has the
most notable metabolic functions. Its derivative, "acetyl
CoA ," is an essential substance involved
not only in making fatty acids, as Earl showed, but
also in breaking down fatty acids, carbohydrates, and
proteins to generate energy in cells. In 1952, Earl
successfully carried out the first "net synthesis" of
acetyl CoA in vitro : he accomplished this
synthesis by using only basic materials (acetyl phosphate
and CoA) and the enzyme he had discovered (phosphotransacetylase).
Overall, Earl's research helped establish the "energy-rich"
nature of acetyl CoA.
Roy Vagelos, Earl's first
postdoctoral fellow with an M.D., carried out important
studies that further elucidated fatty acid metabolism.
He demonstrated that, unlike the synthesis of short-chain
fatty acids in bacteria where acetyl CoA is a key intermediate,
the synthesis of long-chain fatty acid acids is catalyzed
by an enzyme complex in which methylmalonyl CoA is the
source of active acetate.