Cholesterol synthesis

as we know cholesterol is a very important biological molecule for one thing we use cholesterol as a component of the cell membrane because cholesterol modulates the fluidity of the cell membrane in addition specialized tissues of the body can use cholesterol to help synthesize other important biological molecules for example we can use cholesterol to synthesize steroid hormones we can use cholesterol to synthesize bile acids to synthesize vitamin D and so forth now what I want to focus on is how the cells of the body can actually synthesize cholesterol from scratch now although cholesterol can be synthesized by essentially any tissue in the body the majority of the cholesterol actually comes from the liver the intestines the adrenal cortex and the reproductive organs such as the testes the ovaries and the placenta now regardless of the tissue type that synthesizes cholesterol cholesterol synthesis always occurs in a cytosol of the cell let's begin by talking about the greedy ins that are required to actually synthesize cholesterol within the cytosol so we have ingredients for cholesterol synthesis and when we talk about these different reactions keep these ingredients in mind so we know collapsed' was a 27 carbon molecule so that means we have to have a carbon source and the carbon atoms basically come from the same molecule it comes from acetate which is the same thing as acetyl coenzyme a and we'll see that shortly so the carbon source come from comes from acetate what about the energy source so many of these reactions actually require your energy and so the energy comes from either one of two places sometimes it comes from the hydrolysis of phosphate bonds and ATP other times it comes from the hydrolysis of high-energy thioether bonds in acetyl coenzyme a and then we also need reducing power many of these reactions are oxidation reduction reactions and so we need a source of electrons and so the using power the electrons actually come from an a/d pH and so we use the phosphate the pentose phosphate pathway the cells to help synthesize NADPH and this NADPH is important for synthesizing cholesterol if we don't have any NADPH in the cell we can't build any cholesterol so three major ingredients we need the carbon source so we typically use acetate in the form of acetyl coenzyme a the energy comes from the hydrolysis of either ATP or comes from acetyl coenzyme a and the reducing power comes from NADPH of the electrons come from NADPH so keep this in mind as we talk about all these different steps and cholesterol synthesis now obviously cholesterol synthesis is a very complicated process we have many different dividual reactions steps and so here we're only going to focus on the important steps the important reactions the first step is you take two acetyl coenzyme a molecules and you combine them to form another molecule so the enzyme that catalyzes this is thiolase and remember many of these enzymes are found in the cytosol and some of them are attached unto membranes but all of this happens in the cytosol of the cell so thiolase condenses to acetyl coenzyme a molecules each of them contain one two carbon atoms and so we form a molecule with four carbon atoms a c2 acetyl coenzyme a next we have a different enzyme HMG coenzyme a synthase that is present in the cytosol it adds another acetyl coenzyme a onto this four carbon molecule to now form a six carbon molecule known as h mg coenzyme a h mg coenzyme a stands for three hydroxyl three methyl glue Turrell coenzyme a and notice this is the same exact molecule that we use to help synthesize ketone bodies so I'm going to stop for a moment and talk about h mg coenzyme a days within our liver cells we actually have two different versions of HMG coenzyme a synthase we have two isozymes one version one isozyme is located in a cytoplasm of the cell and this is the version that's responsible for building cholesterol for building the HMG coenzyme a needed to build cholesterol the other isozyme the other the other version is located in the mitochondria and the mitochondrial HMG coenzyme a synthase is important in synthesizing ketone bodies so the cytosol of coenzyme a synthase HMG coenzyme a synthase is responsible for building cholesterol but the mitochondrial HMG coenzyme a synthase is responsible for building ketone bodies now once we build this six-carbon HMG coenzyme a the next step is an oxidation reduction reaction and it's catalyzed by the late delay the rate-limiting enzyme HMG coenzyme a reductase so HMG coenzyme a reductase is actually an enzyme that is present in the membrane of the endoplasmic reticulum but the functional component the functional domain of this reductase actually lies within the cytosol and so this reaction still takes place in the cytosol even though this enzyme is embedded in the membrane of the ER so this reductase uses the reduction of the reducing power of two NADPH molecules to form mevalonic acid so we go from a six carbon to a six carbon molecule and again this is the rate limiting step this is the step that is regulated by the cell for example if we have a lot of cholesterol within our cell there's a negative feedback loop that decreases the activity of HMG coenzyme a reductase thereby decreasing this step thereby decreasing the amount of cholesterol we can synthesize so again the next step is the rate limiting step that is catalyzed by the enzyme HMG coenzyme a reductase although the enzyme is found in membrane of the ER it's functional domain actually lies in the cytoplasm of the cell so this reaction occurs in the cytoplasm as do all these other reactions in cholesterol synthesis now this enzyme reduces it uses the reducing power of two NADPH molecules to help synthesize mevalonic acid now once we synthesize malonic acid then we have a bunch of kinase ha's that utilize two ATP molecules to attach two phosphate groups onto this carbon so we attach one two phosphate groups so we synthesize so we hydrolyze one two ATP molecules now we convert the mevalonic acid a six carbon molecule to a different six carbon molecule known as five pyrophosphate mevalonic acid now the the entire point of adding these two phosphate groups is we want to make this molecule into a very hydrophilic molecule we want to be able to dissolve it in the cytoplasm of the cell that's the entire point of adding these negatively charged phosphate groups to basically make it more water-soluble and so in the next two steps we have these kinases that hydrolyze ATP s to add two phosphate groups to that mevalonic acid thus forming the five pyrophosphate mevalonic acid the next step is a decarboxylation step so we actually remove a carbon molecule a carbon atom in the form of carbon dioxide and this also utilizes an ATP so we transformed the five pyrophosphate mevalonic acid into isopentenyl pyrophosphate which is a five carbon molecule and that makes sense because here we have six carbons we utilize an ATP we hydrolyze it that removes carbon dioxide so now we have a five carbon molecule isopentyl pipi so I pp so to form IPP we need one two three carbon sorry one two three ATP molecule so let's keep track of these ATP molecule so so far we've used three ATP molecules to form a single ip3 a single IPP isopentenyl pyrophosphate next we have an enzyme known as isomerase which basically converts it to a different isomer so we form three three dimethylallyl pyrophosphate which also is DPP so this is IPP and this is DPP now once we form DPP the next step is catalyzed by transferase enzyme a different enzyme and what this enzyme does is it takes an IPP molecule and it attaches it onto a DPP molecule so we essentially want to combine these two molecules now this molecule to form it requires three ATP's to form this molecule also requires three ATP's so if we combine these two molecules so far we've used six ATP molecules so we have six ATP molecules used so far and now we form a ten carbon molecule why well because this is five carbons this is five carbons we combine them via this transferase reaction to form a geranyl pyrophosphate attend carbon molecule and notice we still have these phosphate groups and these phosphate groups are important because they keep these relatively hydrophobic molecules dissolved within a cytosol because these two phosphate groups have a lot of negative charge next we have another transferase enzyme that adds yet another IPP molecule to this to form a 15 carbon intermediate known as farnesyl pyrophosphate and so we need another ip3 so that we know that means we need to use another 3 ATP molecule so so far we've used nine ATP molecules because we've combined an IPP a DPP and another IPP and so we have this foreignness cell pyrophosphate again I'm gonna emphasize that it carries these two phosphate groups which gives it enough negative charge to keep it dissolve by self in a cytosol now once we form the farnesyl pyrophosphate the fpp we have an enzyme known as squalene synthase and what squelen synthase does is it takes two FP PS and it combines them so if it takes nine ATP's to form one farnesyl then we have to use nine more ATP's to form a second for initial pyrophosphate so that we can combine them via this reaction and so now we've used nine times two so we've used 18 ATP's so it requires 18 ATP's to actually form squealing via the activity of this enzyme so squalene synthase utilizes NADPH that's where the reduction power comes into play and now we remove all of those phosphate groups so two phosphate groups came from one for initial pyrophosphate the second to Peyer the second two phosphate groups came from that second foreign a superior phosphate and so now we form the squealing molecule that does not contain any phosphate groups and that makes squalene very hydrophobic in fact it's so hydrophobic that it can't dissolve in the cytosol by itself and so squalene actually requires an intracellular sterile carrier protein in fact all the molecules or the all the intermediates from this molecule forward actually require an intracellular carrier protein to remain dissolved within the cytoplasm as opposed to here we have these phosphate groups that help dissolve these molecules now once we form squalene via the activity of squalene synthase squalene is then converted to land knows the role and knows the role is a 30 carbon so this is a 30 carbon because we multiply 15 by 2 so 30 carbon and then here we have another 30 carbon but the but the but the differences between this and this is that now here we have a bunch of cyclic structures here we have no cyclic structures but here we form cyclic structures via the activity of squalene mono oxygenase so squalene mono oxygenase also uses the reducing power of NADPH but it also uses the oxidizing power of oxygen so we have to use a diatomic oxygen to help form those cyclic structures in mono stirol' so squalene synthase uses NADPH to combine to fpp molecules to form a 30 carbon molecule accord squalene but squalene has no cyclic structures and has no rings so now we use squalene mono oxygenase which utilizes NADPH and oxygen to help form those cyclic structures and once we form the lunesta role then we eventually converted into cholesterol via a multi-step reaction that is catalyzed by many different types of enzymes in fact we have as many as 18 plus different enzymes which are utilized by the cell to convert learn as the role in to cholesterol so notice that lanessa role has 30 carbon atoms but cholesterol eventually has 27 carbon atoms and so in this process we have to remove some of those carbon atoms we also have to redo some of those double bonds and we have to place carbon place the carbon double bonds in different locations and so forth but ultimately we converted into cholesterol so we actually don't know the specifics of all of these reactions and so that's why you probably don't have to know these reactions but know that there are different types of enzymes involved in the conversion of lanessa role into cholesterol

Channel: AK LECTURES

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Keywords: cholesterol synthesis, cholesterol biosynthesis, synthesis of cholesterol, cholesterol, HMG CoA reductase

Id: VaG0R-aYmk8

Length: 15min 14sec (914 seconds)

Published: Fri Jun 21 2019