Cholesterol Biosynthesis PDF

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Cholesterol Biosynthesis Cholesterol is an amphipathic molecule that plays a critical role in membrane fluidity as well a precursor of biosynthesis of biological molecules having numerous functions including formation of steroid hormones, bile salts/acids, and ubiquinone to name a few. Cholesterol is characterized as having rigidity due to a fused four-ring structure, an aliphatic tail, and a hydrophilic -OH group that can further be esterified to form a cholesterol-ester. The biosynthesis of cholesterol occurs in the cytosol of liver cells. AcetylCoA exported from the mitochondrial matrix in the form of citrate serves as a substrate for cholesterol biosynthesis. Two molecules of acetyl CoA condense to acetoacetyl-CoA in a reaction catalyzed by thiolase, that is the reverse of the last step of beta oxidization. Thiolase utilizes an acid-base mechanism to allow for activation of nucleophilic attacks with the reaction driven by the release of CoA.

The next step is catalyzed to allow for acetoacetyl-CoA to be converted to β-hydroxy-β-methylglutarylCoA (HMG-CoA) by the enzyme HMG-CoA synthase. These two steps are catalyzed by the same enzymes show in ketone body biosynthesis. The pathway for cholesterol biosynthesis occurs in the cytosol as compared to the biosynthesis of ketone bodies which happens within the mitochondria. Thus, it’s the third step that is unique to cholesterol biosynthesis where HMG-CoA is converted to mevalonate by the enzyme HMGCoA reductase. This is the committed step for the cholesterol biosynthetic pathway and thus a drug target for treating high cholesterol. HMG-CoA reductase is regulated by three mechanisms: (1) phosphorylation by cAMPdependent kinase that inactivates the enzyme under low energy conditions, (2) degradation of the enzyme based on response to high cholesterol levels, and (3)

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epigenetic impacts whereby gene expression producing mRNA can be utilized in response to low cholesterol levels. Mevalonate is a molecule that contains energy in the form of carboxyl group, and the next two successive reactions add phosphates to mevalonate to produce 5-pyrophosphomevalonate which can undergo decarboxylation and hydrolysis of pyrophosphate. These reactions are catalyzed by mevalonate-5-phosphotransferase and phosphomevalonate kinase, respectively.

Now the high energy 5-pyrophosphomevalonate is utilized to drive biosynthesis of the 5C unit isoprene. First a decarboxylation event is catalyzed by pyrophophomevalonate decarboxylase using hydrolysis of ATP drives long chain of otherwise unfavorable e- transfers. The formation of isopentenyl pyrophosphate is isomerized to produce dimethylallyl pyrophosphate – each being 5C units. These two 5C units are condensed via release of PPi to produce geranyl pyrophosphate (10C) in a reaction catalyzed by prenyltransferase. A second reaction catalyzed by prenyltransferase combines geranyl pyrophosphosphate (10C) and isopentyl pyrophosphate (5C) to produce farnesyl-pyrophosphate (15C). Squalene synthase, a NADPH dependent enzyme, catalyzes the condensation of two farnesyl pyrophosphates to produce squalene (30C). Squalene oxidase catalyzes addition of an epoxide ring that when cleaved leads to a series of electron transfers to produce lanosterol. Though there are 20 additional reactions required to fully produce cholesterol, lanosterol structurally has many similarities to cholesterol.

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In response to high cholesterol, HMG Co-A reductase is not only regulated, but the number of LDL receptors is diminished in response to high cholesterol in cells. The consequence of the loss of LDL receptors is two-fold: (1) levels of LDL (and VLDL) rise in the blood stream and (2) the uptake of LDL in extrahepatic cells decreases, leading to a decrease in HDL. Thought of as the good cholesterol, HDL levels are lowered, thus the excretion pathway for excess cholesterol is minimized via the decrease in HDL conversion to bile acids in the liver. Diminished levels of HDL coupled with increased levels of VLDL/LDL lead to a buildup of cholesterols that lead to pro-inflammatory response, leading to calcification of plaques in arteries and blood vessel damage; collectively this is termed atherosclerosis.

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