Now going back to our original pathway
where we had the production of HMG-CoA,
I noted that HMG-CoA was a branch point
between synthesis of ketone bodies
and the production
So now I want to follow the
pathway that leads to cholesterol.
The step that converts
HMG-CoA to mevalonate
is probably the most important step
in the synthesis of cholesterol.
And it's important because
the enzyme HMG-CoA reductase
is a regulated enzyme in
In fact, it's the only regulated
enzyme in cholesterol synthesis.
This enzyme is
interestingly inhibited by
the by product of its
pathway that is cholesterol.
So cholesterol can feedback
and when cholesterol accumulation gets
too high will turn off this enzyme
and it will turn off the pathway that
leads to the synthesis of cholesterol.
Now that's important; because,
the synthesis of cholesterol
requires a lot of energy.
It requires many steps.
And if the body is making too much
cholesterol and doesn't need it
there is no reason to waste energy
and making additional cholesterol.
So this enzyme plays
a critical role.
Well we all know, of
course, that our cholesterol
isn't always maintained at
the levels it needs to be
and there are some complicated
reasons why that's the case.
But this enzyme is also useful
from a medical perspective;
because, this enzyme is the target
for cholesterol lowering drugs.
So we have probably all heard
of what are called statins
and these are molecules
that resemble HMG-CoA.
So they are competitive
inhibitors of this enzyme.
And as a result when
this enzyme is inhibited,
again, the entire cholesterol
pathway itself is inhibited.
Well this mevalonate is converted
into the 5 carbon precursors
called isoprenoids that are used to
assemble the cholesterol molecule.
These 5 carbon molecules are made
by decarboxylating mevalonate.
You may remember that
mevalonate had 6 carbons in it.
But the isoprenoid
molecules used to assemble
to make cholesterol
only have 5 carbons.
And these are the molecules you
see on the top of the screen,
pyrophosphate called IPP
pyrophosphate called DMAPP.
These two molecules are what we describe
as the building blocks of cholesterol
that go together to make larger
molecules as we shall see.
Now in this first step of the
process we see IPP and DMAPP
that are joined together to
make a 10 carbon molecule.
So each IPP and
DMAPP has 5 carbons.
The 10 carbon molecules that's produced is
called geranyl-PP or geranyl pyrophosphate.
Addition of another IPP
causes production of a 15 carbon
molecules called farnesyl pyrophosphate.
And joining two of those
creates a 30 carbon
molecule call squalene.
Squalene is the last
of what we described
as the linear intermediates in
the synthesis of cholesterol.
Squalene bonds can be rotated
around, and around and around
to create a circular structure
that looks like this.
Now there is couple of steps involved
in that but I won't go through.
But the first cyclic intermediate is
the first thing that starts to look like
cholesterol in the
and this molecule is
known as the lanosterol.
So the lanosterol is
the first molecule
that's produced that
looks like cholesterol.
But before we talk about that
I want to remind you that
everything that you have seen on the
screen here was produced as a result
of carbons that all
came from acetyl-CoA.
So very large complicated molecules
have very very simple roots.
This is the root of
what we call anabolism.