Steroids and Bile Acids: Mevalonate Pathway II

by Kevin Ahern, PhD

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    00:02 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.

    00:13 So now I want to follow the pathway that leads to cholesterol.

    00:17 The step that converts HMG-CoA to mevalonate is probably the most important step in the synthesis of cholesterol.

    00:24 And it's important because the enzyme HMG-CoA reductase is a regulated enzyme in cholesterol synthesis.

    00:32 In fact, it's the only regulated enzyme in cholesterol synthesis.

    00:36 This enzyme is interestingly inhibited by the by product of its pathway that is cholesterol.

    00:44 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.

    00:56 Now that's important; because, the synthesis of cholesterol requires a lot of energy.

    01:01 It requires many steps.

    01:02 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.

    01:10 So this enzyme plays a critical role.

    01:13 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.

    01:22 But this enzyme is also useful from a medical perspective; because, this enzyme is the target for cholesterol lowering drugs.

    01:31 So we have probably all heard of what are called statins and these are molecules that resemble HMG-CoA.

    01:41 So they are competitive inhibitors of this enzyme.

    01:44 And as a result when this enzyme is inhibited, again, the entire cholesterol pathway itself is inhibited.

    01:51 Well this mevalonate is converted into the 5 carbon precursors called isoprenoids that are used to assemble the cholesterol molecule.

    02:05 These 5 carbon molecules are made by decarboxylating mevalonate.

    02:09 You may remember that mevalonate had 6 carbons in it.

    02:13 But the isoprenoid molecules used to assemble to make cholesterol only have 5 carbons.

    02:18 And these are the molecules you see on the top of the screen, isopentenyl pyrophosphate called IPP and dimethylallyl pyrophosphate called DMAPP.

    02:28 These two molecules are what we describe as the building blocks of cholesterol that go together to make larger molecules as we shall see.

    02:37 Now in this first step of the process we see IPP and DMAPP that are joined together to make a 10 carbon molecule.

    02:44 So each IPP and DMAPP has 5 carbons.

    02:49 The 10 carbon molecules that's produced is called geranyl-PP or geranyl pyrophosphate.

    02:55 Addition of another IPP causes production of a 15 carbon molecules called farnesyl pyrophosphate.

    03:03 And joining two of those farnesyl-PPs together creates a 30 carbon molecule call squalene.

    03:10 Squalene is the last of what we described as the linear intermediates in the synthesis of cholesterol.

    03:16 Squalene bonds can be rotated around, and around and around to create a circular structure that looks like this.

    03:23 Now there is couple of steps involved in that but I won't go through.

    03:26 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.

    03:37 So the lanosterol is the first molecule that's produced that looks like cholesterol.

    03:40 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.

    03:50 So very large complicated molecules have very very simple roots.

    03:55 This is the root of what we call anabolism.

    About the Lecture

    The lecture Steroids and Bile Acids: Mevalonate Pathway II by Kevin Ahern, PhD is from the course Lipid Metabolism.

    Included Quiz Questions

    1. Lanosterol
    2. Squalene
    3. Farnesyl pyrophosphate
    4. Geranyl pyrophosphate
    5. Dimethylallyl pyrophosphate
    1. Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are produced from HMG-CoA by the action of the enzyme HMG-CoA reductase in the presence of lanosterol.
    2. The conversion of HMG-CoA to mevalonate is mediated by an enzyme called HMG-CoA reductase.
    3. Cholesterol regulates the production of HMG-CoA enzyme through feedback inhibition.
    4. HMG-CoA reductase enzyme plays a very important role in the regulation of cholesterol synthesis in the body.
    5. Statin drugs act as competitive inhibitors of HMG-CoA reductase, so it is useful as a cholesterol-lowering drug.

    Author of lecture Steroids and Bile Acids: Mevalonate Pathway II

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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