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 of cholesterol. So now I wanna
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 cholesterol synthesis. 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
is 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.
Another name for the statins are lipitor which is the common
terms that's used commercially to sell these compounds.
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, isopentenyl pyrophosphate called IPP
and dimethylallyl 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 farnesyl-PPs together
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 that. 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 biosynthetic pathway 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 wanna 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.