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JAMES K. GRANT
limiting and may thus be a possible site of control of the whole biosynthetic process by hormones or other factors (18).
Steps between mevalonic acid and squalene are not yet clear. The
symmetry of the squalene molecule (IX) suggests that it might be
formed by a head-to-head union of two Ci 5 intermediates, such as
farnesenic acid (19) (VIII), but satisfactory evidence that this substance is an intermediate is lacking. In a general approach to the problem of intermediates in the biosynthesis of animal and plant sterols by
Tschesche and Korte (20) a hypothetical Ci 0 -hydroxy acid is visualized
as condensing with a variety of compounds to give steroids of varying
carbon content.
Mevalonic acid-5-pyrophosphate (VI) and a AMsopentenyl pyrophosphate (VII) have been isolated from yeast and may be intermediates (21).
There has been much discussion on the way in which the squalene
chain folds and undergoes cyclization (22). The accepted folded structure is shown at (IX) and it seems likely that this undergoes cyclization in one enzymically catalyzed step to give lanosterol (X). This
substance, found in yeast and wool fat, was formerly regarded as a
triterpene since, like squalene, it has 30 carbon atoms. It is now known
to possess the steroid tetracyclic structure and thus forms a structural
link between the triterpenes and the steroids. It may be noted that the
proposed scheme of cyclization (Fig. la,b) involves a shift of methyl
groups, a rather unusual type of biochemical reaction. Another wellestablished example of this type of biochemical intramolecular rearrangement is the transformation of p-hydroxyphenylpyruvic acid to
homogentisic acid. The enzyme which catalyzes the cyclization of
squalene has been called squalene-oxidocyclase I since it may be the
first to be discovered of a series of enzymes, of general biosynthetic
significance, involved in the cyclization of a variety of triterpenes.
Squalene-oxidocyclase I shows features in common with a group of
enzymes including nonspecific liver hydroxylase, phenolase, kynurenine
hydroxylase, steroid 11/3 "hydroxylase," and possibly other steroid "hydroxylases" described by Mason as "mixed-function oxidases" (23). It
has been shown in experiments with O
18 that reactions catalyzed by
these enzymes involve molecular oxygen and not oxygen derived from
water, many have been shown to require the presence of a heavy metal,
and all the presence of a reducing agent, usually reduced triphosphopyridine nucleotide.
Possible intermediates between lanosterol and cholesterol are 4,4'dimethylcholestadien-3/?-ol (XI) (24) and 4a-methylcholestenol (XII)
(25) isolated from rat tissues, zymosterol (XIII) a yeast sterol also
JAMES K. GRANT
limiting and may thus be a possible site of control of the whole biosynthetic process by hormones or other factors (18).
Steps between mevalonic acid and squalene are not yet clear. The
symmetry of the squalene molecule (IX) suggests that it might be
formed by a head-to-head union of two Ci 5 intermediates, such as
farnesenic acid (19) (VIII), but satisfactory evidence that this substance is an intermediate is lacking. In a general approach to the problem of intermediates in the biosynthesis of animal and plant sterols by
Tschesche and Korte (20) a hypothetical Ci 0 -hydroxy acid is visualized
as condensing with a variety of compounds to give steroids of varying
carbon content.
Mevalonic acid-5-pyrophosphate (VI) and a AMsopentenyl pyrophosphate (VII) have been isolated from yeast and may be intermediates (21).
There has been much discussion on the way in which the squalene
chain folds and undergoes cyclization (22). The accepted folded structure is shown at (IX) and it seems likely that this undergoes cyclization in one enzymically catalyzed step to give lanosterol (X). This
substance, found in yeast and wool fat, was formerly regarded as a
triterpene since, like squalene, it has 30 carbon atoms. It is now known
to possess the steroid tetracyclic structure and thus forms a structural
link between the triterpenes and the steroids. It may be noted that the
proposed scheme of cyclization (Fig. la,b) involves a shift of methyl
groups, a rather unusual type of biochemical reaction. Another wellestablished example of this type of biochemical intramolecular rearrangement is the transformation of p-hydroxyphenylpyruvic acid to
homogentisic acid. The enzyme which catalyzes the cyclization of
squalene has been called squalene-oxidocyclase I since it may be the
first to be discovered of a series of enzymes, of general biosynthetic
significance, involved in the cyclization of a variety of triterpenes.
Squalene-oxidocyclase I shows features in common with a group of
enzymes including nonspecific liver hydroxylase, phenolase, kynurenine
hydroxylase, steroid 11/3 "hydroxylase," and possibly other steroid "hydroxylases" described by Mason as "mixed-function oxidases" (23). It
has been shown in experiments with O
18 that reactions catalyzed by
these enzymes involve molecular oxygen and not oxygen derived from
water, many have been shown to require the presence of a heavy metal,
and all the presence of a reducing agent, usually reduced triphosphopyridine nucleotide.
Possible intermediates between lanosterol and cholesterol are 4,4'dimethylcholestadien-3/?-ol (XI) (24) and 4a-methylcholestenol (XII)
(25) isolated from rat tissues, zymosterol (XIII) a yeast sterol also