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Function 1: Micelle Formation
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2010-F-MKH-cholesterol_formation_of_micelle.cdx

As shown above, only 1% of cholesterol is converted to steroidal hormones such as progesterone and estradiol.

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These features create the phospholipid bilayer that we see in the cell membrane. The polar phosphate heads make up the inside and outside of the bilayer, while the middle is composed of the nonpolar tail regions of the phospholipids.  

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2010-F-MKH-phospholipid_bilayer.cdx

The phospholipid bilayer works remarkably well, but because of its structure, it is impervious to many things the cell wishes to take in or to expel. It is thought that the cholesterol molecules inserted into the cell membrane help regulate the permeability of the bilayer and thus facilitate the transport of molecules through the membrane. However, the use of cholesterol in the membrane may become a problem when either not enough of it is present or too much of it is present. When there is not enough cholesterol in the membrane, not enough important molecules may be able to enter the cell. On the other hand, when there is too much cholesterol in the membrane, important molecules inside the cell can exit. In these cases, the controlled permeability provided by cholesterol has lost its effectiveness.

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There are two kinds of lipoproteins, specifically low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL delivers cholesterol from the liver to the cell membrane and after it dumps the cholesterol into the cell membrane, this empty lipoprotein returns back to the liver to pick up more cholesterol molecules.  High-density lipoprotein (HDL) also originates from the liver, but it picks up cholesterol from the cell membrane and returns it to the liver.  HDL is named accordingly because its membrane contains more proteins than LDL's membrane.  Since high levels of LDL can lead to serious health problems, the packaging of cholesterol in LDL is often referred to as "bad cholesterol." The LDL pathway is labeled in red (stop!) ,while the HDL ("good cholesterol") pathway is labeled in green (go!). In the end, there are not two kinds of cholesterol but rather two different micelle packagings of cholesterol.

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2010-F-MKH-cholesterol_transport.cdx

Your body needs cholesterol to regulate cell membrane permeability, and therefore needs both LDL and HDL, but too much LDL can be a bad thing. Your liver naturally produces about 1 gram of cholesterol per day, which is enough for normal biological function, but we can ingest much more than that. The increased levels of cholesterol lead to an increase of LDL production in the liver. The LDL deposits this excess cholesterol into the cell membranes, performing its normal function even if cholesterol levels are already too high.  High LDL levels can lead to health problems, such as a stroke:

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Cholesterol Biosynthesis

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2010-F-MKH-cholesterol_biosynthesis.cdx

Cholesterol biosynthesis proceeds as drawn above, a biological pathway beginning with Acetyl CoA that undergoes a series of reactions with different enzymes, cofactors, and substrates to produce cholesterol. How should we shut down cholesterol biosynthesis? In order to inhibit the biosynthesis of cholesterol you could attempt to stop the mechanism at any one of these steps, however if you inhibit the wrong step, there could be many adverse effects on the body. When selecting an inhibitor, you want to use a molecule that will inhibit the "committed step," or the first step in which the product will go on to only make cholesterol.  In this case the committed step is the reduction of HMG-CoA to mevalonate (meaning once mevalonate is produced, the only biological product will be cholesterol).  If you were to inhibit a later step in the synthesis, it may be hard to get rid of these later products. For example,  if you prevented the formation of lanosterol from squalene oxide, you would cause a build up of squalene oxide in your cells, which may result in toxic shock from squalene oxide overdose. If you were to stop the synthesis too soon, sometime during its initial steps, you could inhibit the production of hundreds of other biologically useful molecules that have the same first steps as the cholesterol biosynthesis. However, HMG-CoA is used for other functions in the body, so if you stop the biosynthesis at the reduction of HMG-CoA, it will not proceed to form cholesterol, but may go on to do other useful chemistry in the body.

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2011-Spring-LEG-malonate.cdx

The image above shows the mechanism of the committed step that we would like to inhibit. HMG-CoA is reduced by NADPH (looks like NADH) in HMG-CoA reductase. Electrons from the carbonyl bond are sent up onto the oxygen. One of the lone pairs of the now negatively charged oxygen will collapse down, reforming the double bond and eliminating the S-CoA substituent in the process. This conjugate addition and subsequent elimination normally goes on to produce mevalonate, and an inhibitor with structural similarities to HMG-CoA could work to prevent this step of cholesterol biosynthesis.
 

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Based on what we know about inhibitors of enzymes we can predict what the HMG-CoA enzyme would look like. Since the intermediate of the reductase is a tetrahedral intermediate very similar to that seen in aspartyl proteases we can employ a similar strategy to "fool" the enzyme. Secondary or tertiary alcohols have proved useful as aspartyl protease inhibitors. We can thus propose a potential inhibitor which simply replaces the carbonyl in the substrate with an alcohol group. This would create a molecule that would fit perfectly into the enzyme's specificity pocket but be non-processable as the alcohol will interact with the lysine residue but not be able to "collapse down" like the carbonyl.

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2011-Spring-LEG-probableinhibitor.cdx

Circled in green is the alcohol that has replaced the carbonyl of HMG-CoA. There are, however, problems with the above structure for use as a drug. The carboxyl group circled in red is highly polar. Due to this group this molecule will be unable to pass through the gastrointestinal tract and from there be circulated throughout the body. For this reason chemists had to come up with a creative strategy to mask this group during uptake and then unmask the group so the inhibitor can act on the reductase and reduce cholesterol biosynthesis.

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2010-S-PCS-reductase inhibition.cdx

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2010-S-PCS-intermediate structure.cdx

Mevastatin is drawn alongside the molecule it is mimicking in order to see the similarities in the two structures. The functionally critical elements of the structures are circled. (mevastatin on left) The large rings attached to the lactone functionality are also important in recognition by the enzyme. Looking back to the mechanism of HMG-CoA reductase we can see that NADPH is a critical cofactor in the reduction reaction. The two rings serve to mimic the structure of the NADPH cofactor, thus allowing for the inhibitor be better fitted to the enzyme's active site.

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Reversible inhibitors are very appealing to pharmaceutical companies and are useful for blocking cholesterol biosynthesis temporarily. Because reversible inhibitors only remain in the active site of the enzyme for a finite period of time, one must continuously take the drug to maintain effective inhibiting concentrations in the body, which leads to our next topic involving different types of statins.

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2009-F-YS-Statins-3.cdx

The Half Maximal Inhibition Concentration, or IC50 , is the concentration of inhibitor in a drug required for 50% inhibition of a biological process/part of a process. (in our case, the inhibition of the HMG-CoA Enzymes)

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