3. LIPIDS: STEROID METABOLISM
165
enriched with heavy water. It was subsequently shown (5) that acetate
may be a major source of the carbon atoms of cholesterol, and when
degradation studies revealed the origin of each carbon atom of cholesterol (II) derived biosynthetically from isotopically labeled acetate, it
was possible to conclude that the entire cholesterol molecule may be
constructed from acetate as the sole source of carbon (3a). This work
was done with rat liver. Conclusive proof, however, is still lacking that
acetate is the sole primary unit for cholesterol biosynthesis in mammalian tissues. It has been shown that this is very probably so for the
closely related compound ergosterol (III) synthesized by Neurospora
crassa (6). A mutant strain of this organism requiring acetate as a
growth factor was used.
As might be expected, coenzyme A is necessary for the synthesis of
cholesterol from acetate.
The distribution pattern of acetate carbons in the isooctyl side chain
of cholesterol as revealed by the degradation studies suggested the
possibility that cholesterol might be derived from isoprenoid precursors
(7). This idea was supported by the isolation of labeled squalene (IX)
derived from C
14 -acetate from rat liver and its subsequent transformation by mouse liver into labeled cholesterol (8). The C 30 triterpenoid
hydrocarbon squalene had previously been found in the livers of
elasmobranch fishes (9) and is now known to be widely distributed,
occurring among other places in the sebum of animals (10). As early
as 1926 a biochemical relationship between squalene and cholesterol
was suggested and supporting evidence was obtained from experiments
in which it was shown that there was an increase in the cholesterol of
the livers of rats fed squalene (11), but the matter was not pursued
further at the time.
The search for the acetate product which condenses was influenced
by work in other fields. Thus Bonner and Arreguin (12) found that
acetate or the branched-chain compound β,β-dimethylacrylate stimulates formation of the polyisoprenoid, rubber, in guayule plants. They
suggested that three acetate molecules condense with loss of a carbon
atom to form an isoprenoid "building unit," such as dimethylacrylate,
which may condense to form rubber. In addition to dimethylacrylate a
number of C 5 and C 6 branched-chain acids, which may be synthesized
from acetate by plants, have been considered to be cholesterol precursors (13). However, the efficiency with which they are converted
to cholesterol by liver preparations is low and it was difficult to decide
which, if any, was an intermediate. A significant advance was made in
1956 with the isolation of mevalonic acid (β,δ-dihydroxy-ß-methyrvaleric
acid, V) from "brewers' solubles," a product of alcoholic fermentation
165
enriched with heavy water. It was subsequently shown (5) that acetate
may be a major source of the carbon atoms of cholesterol, and when
degradation studies revealed the origin of each carbon atom of cholesterol (II) derived biosynthetically from isotopically labeled acetate, it
was possible to conclude that the entire cholesterol molecule may be
constructed from acetate as the sole source of carbon (3a). This work
was done with rat liver. Conclusive proof, however, is still lacking that
acetate is the sole primary unit for cholesterol biosynthesis in mammalian tissues. It has been shown that this is very probably so for the
closely related compound ergosterol (III) synthesized by Neurospora
crassa (6). A mutant strain of this organism requiring acetate as a
growth factor was used.
As might be expected, coenzyme A is necessary for the synthesis of
cholesterol from acetate.
The distribution pattern of acetate carbons in the isooctyl side chain
of cholesterol as revealed by the degradation studies suggested the
possibility that cholesterol might be derived from isoprenoid precursors
(7). This idea was supported by the isolation of labeled squalene (IX)
derived from C
14 -acetate from rat liver and its subsequent transformation by mouse liver into labeled cholesterol (8). The C 30 triterpenoid
hydrocarbon squalene had previously been found in the livers of
elasmobranch fishes (9) and is now known to be widely distributed,
occurring among other places in the sebum of animals (10). As early
as 1926 a biochemical relationship between squalene and cholesterol
was suggested and supporting evidence was obtained from experiments
in which it was shown that there was an increase in the cholesterol of
the livers of rats fed squalene (11), but the matter was not pursued
further at the time.
The search for the acetate product which condenses was influenced
by work in other fields. Thus Bonner and Arreguin (12) found that
acetate or the branched-chain compound β,β-dimethylacrylate stimulates formation of the polyisoprenoid, rubber, in guayule plants. They
suggested that three acetate molecules condense with loss of a carbon
atom to form an isoprenoid "building unit," such as dimethylacrylate,
which may condense to form rubber. In addition to dimethylacrylate a
number of C 5 and C 6 branched-chain acids, which may be synthesized
from acetate by plants, have been considered to be cholesterol precursors (13). However, the efficiency with which they are converted
to cholesterol by liver preparations is low and it was difficult to decide
which, if any, was an intermediate. A significant advance was made in
1956 with the isolation of mevalonic acid (β,δ-dihydroxy-ß-methyrvaleric
acid, V) from "brewers' solubles," a product of alcoholic fermentation