BMB 401 Biochemistry 401 Lecture 29 Today we re going to talk about cholesterol We re going to talk about the function of cholesterol first and then the synthesis the regulation and some cholesterol derivatives and this will include the function and the synthesis of these derivatives So let s get started Cholesterol is a steroid consisting of four rings and a hydrophobic tail It is a very planar molecule and hydrophobic It functions as a membrane lipid to modulate membrane fluidity and it s also found in lipid rafts It is a precursor for synthesis of steroid hormones of bile salts and also of vitamin D Now cholesterol can be transported in lipoproteins and can be stored in the cell but to do so we re going to hide the polar hydroxyl because that is the only polar group in the whole molecule and we re going to hide that by adding a fatty acid through esterification We re going to make an ester linkage between the fatty acid and cholesterol to make a cholesterol ester This is going to increase the hydrophobicity of cholesterol and allow it to pack even tighter into a smaller area for storage in the cell or for transport In membranes the polar hydroxyl group is important It s oriented towards the aqueous environment and interacts with polar head groups of membrane lipids and water molecules There are two sources of cholesterol dietary cholesterol and endogenous cholesterol Dietary cholesterol is ingested in the foods that we eat It s packaged into transport micelles and this happens in the intestines These micelles are also called chylomicrons Endogenous cholesterol on the other hand is synthesized de novo It is packaged up in the liver into transport units called very low density lipoprotein particles that include both lipid and protein and we ll talk about both of these later on in more detail Here we see a brief overview of the steps involved in cholesterol synthesis There are five important steps Step one is a condensation of three activated acetyl units to form the six carbon molecule HMG CoA Step number two is the reduction of HMG CoA to form mevalonate Step number three is decarboxylation to the five carbon activated isoprenyl unit isopentenyl pyrophosphate Step four is the condensation of six activated isoprenes both isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate to eventually form the 30 carbon unit 1 BMB 401 squalene This happens first through the formation of geranyl pyrophosphate 5 5 10 and geranyl pyrophosphate has 10 carbons We re then going to add another five carbons to geranyl pyrophosphate to yield farnesyl pyrophosphate Farnesyl pyrophosphate contains 15 carbons Then comes the condensation of two molecules of farnesyl pyrophosphate to form squalene 15 15 30 Finally step number five is a cyclization of squalene to form lanosterol and then modification in several steps to form the mature cholesterol We re going to look at these one by one in more detail The first reaction that occurs in cholesterol synthesis is a condensation reaction between the four carbon molecule acetoacetyl CoA and the two carbon molecule acetyl CoA This results in the production of 3 hydroxy 3 methyl glutaryl CoA HMG C A and release of CoA Now we ve seen HMG CoA before in the mitochondrion It s also an intermediate in ketone body synthesis and so here we see two isozymes of HMG CoA synthase one in the cytoplasm that functions in the synthesis of cholesterol and one of the mitochondrion that s involved in ketone body synthesis Now in the cytosol 3 hydroxy 3 methyl glutaryl CoA is an intermediate in cholesterol synthesis and is going to be reduced in a series of reactions to yield mevalonate and the electron carrier in this case is any NADPH So what we re left with are two molecules of NADP coenzyme A and the sixcarbon intermediate mevalonate Now in the mitochondrion as we said 3hydroxy 3 methyl glutaryl CoA is an intermediate in the synthesis of ketone bodies and it s used to make acetyl CoA and acetoacetate you ll recall that acetoacetate is actually ketone body And so let s go back to the synthesis of mevalonate in cholesterol synthesis in the cytosol In going from 3 hydroxy 3methyl glutaryl CoA to mevalonate there are two reduction reactions one to produce an aldehyde and the second to produce an alcohol The enzyme that carries out these reductions is HMG CoA reductase and this name makes sense This is actually an integral membrane protein that carries out a cytosolic reaction but the protein itself is anchored to the outside face of the endoplasmic reticulum HMG CoA reductase catalyzes the rate limiting step in cholesterol synthesis It s the slowest step in the pathway and therefore it s highly regulated Now the next step that we re going to see is going to use three molecules of ATP which is really expensive and so it s a good idea to make sure that you really want to make mevalonate 2 BMB 401 The synthesis of mevalonate represents the rate limiting step in cholesterol synthesis and therefore the enzyme that catalyzes this reaction HMG CoA reductase is highly regulated Here we see figure of one monomer of the tetrameric enzyme HMG CoA reductase In eukaryotes this is an integral membrane protein that s bound to the outer face of the endoplasmic reticulum This represents one of the most highly regulated enzymes in the human body And so from the six carbon intermediate mevalonate we re going to produce the five carbon activated isoprene unit 3 isopentenyl pyrophosphate To do this were going to use three molecules of ATP The final step is going to release carbon dioxide to go from a six carbon unit to a five carbon unit One molecule of inorganic phosphate is also going to be released You do not need to know all of the intermediates between mevalonate and 3 isopentenyl pyrophosphate You do need to know the starting reactants which are the six carbon mevalonate and three molecules of ATP You also need to know the final products which are the five carbon 3 isopentenyl pyrophosphate carbon dioxide and one molecule of inorganic phosphate Now that we have 3 isopentenyl pyrophosphate what can we do with this This is a very important intermediate it turns out These are some of the derivatives that can be made from 3 isopentenyl pyrophosphate they include cholesterol of course but also steroid hormones bile salts and vitamins D A E K which you should recognize as being all of the lipid soluble vitamins also the quinone electron carriers ubiquinol that when all and all calls you
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