Chapter 26: The Biosynthesis of Membrane Lipids and Steroids
The chapter describes the synthesis of steroids, bile salts, and other im portantlipids.
In order to understand the structure and properties of lipids and the central role of acetyl CoA in the metabolism of the cell, you should review the earlier chapters.
The text describes the synthesis of cholesterol from acetyl CoA.
The regulation of a key enzyme in the biosynthetic pathway as well as other modes of regulation of cholesterol metabolism is outlined.
Cholesterol is used to make bile salts and steroid hormones.
The cholesterol and triacylglycerols are transported by lipoproteins to peripheral tissues.
Cholesterol is moved from the colon to the body's bile duct.
The mechanisms by which the lipoproteins deliver lipids to cells are discussed next.
The text describes the synthesis of steroid hormones from cholesterol and introduces a variety of isoprenoid lipids that are derived from isopentenyl pyrophosphate.
You should be able to complete the objectives once you have mastered this chapter.
List the functions of triacylglycerols.
There are activated sugars and acidic sugars.
There are examples of how sphingolipids confer diversity.
Give the key intermediates and list the major stages.
O2 is involved in the formation of cholesterol.
List the sources of cholesterol.
Approaches used to reduce cholesterol.
The major synthetic precursors or intermediates are listed in the right column.
The characteristic structural compo nents or properties can be found in the right column.
Match the lipids in the left column with the activated precursors in the right column.
List the intermediates in the synthesis of cholesterol in their proper sequence from the following compounds.
For the synthesis of cholesterol in the left column, choose the appropriate characteristics from the right column.
Aerobically growing yeast cells incorporate sterols into their membranes.
The conversion of 3-hydroxy-3-methylglutaryl CoA to mevalonate is the key step in cholesterol synthesis.
Match the components in the right column with the lipopro teins in the left column.
They should be placed in their proper order.
There are exons in the genes for the LDL receptor.
The binding of LDL to its receptor is prevented by the functionally deficient apoprotein B-100, which is why it is produced normally in a patient.
The characteristics in the right col umn distinguish them from one another, so match the steroid hormones in the left column.
The principle form of cholesterol can be named.
The answers are incorrect because neither neutral fats nor free fatty acids are found in the membranes.
The primary route is the reduction of dihydroxyacetonephosphate.
phosphatidyl serine can also be formed through an exchange reaction.
A process that is otherwise highly exergonic is the mation ofphosphate ester bonds in phosphoglycerides, which can be accomplished by the use of CDP-diacylglycerol and the CDP-alcohols.
The energy is supplied to form these compounds.
The synthesis of carbohydrates is similar to the use of UDP-sugars.
Two high-energy bonds are directly consumed in these reactions.
The net reaction is driven farther to the right by the hydrolyzed pyrophosphate.
Three high-energy bonds would be consumed to regenerate the two substances.
A2 cleaves the R2 chain to release the fatty acid, C cleaves the phophodiester bond to produce the R3-phosphate, and D cleaves the phosphodiester bond to produce.
The phosphatidyl ethanolamine would have cleaved the ester bond to yield the R1-contining fatty acid.
Inositol 4, 5-bisphosphate, inositol 1, 4, 5-trisphosphate, and diacylglycerol are the second messengers of Phospholipase C.
The ganglio side GM2 will accumulate in the lysosomes of the patients.
The GalNAc is deficient in these people.
All the compounds are intermediates in the synthesis of cholesterol except for cholyl CoA, which is a catabolic derivative of cholesterol and a precursor of bile salts.
The correct sequence is d, c, a, f, b, g.
squalene is a key intermediate in the synthesis of cholesterol and related sterols.
squalene 2,3-epoxide is converted to lanosterol.
The conversion of squalene to 2,3-epoxide is catalyzed by a monooxygenase.
yeast cells can't make sterols because they don't have enough oxygen to make a monooxygenase reaction.
A, b, c, d, f. circulating LDL is the main source of cholesterol for cells outside the body.
Cholesterol released during the degradation of LDL suppresses the formation of new LDL receptors, which decreases the absorption of cholesterol by the cell.
A defect in apoprotein B-100 that prevents the binding of LDL to the cell surface re ceptor would result in stimulation of the synthesis of cholesterol and a decrease in the synthesis of cholesterol esters.
The consequences of such amutation may be similar to those seen in a family with hypercholesterolemia.
A, d, e 25.
Both polar and non polar re gions are contained in bile salts.
The ring system has a polar side chain that allows interactions with water.
The ring system can interact with nonpolar substances.
Unlike detergents like sodium dodecyl sulfate which are linear, bile salts are amphipathic.
The normal synthesis of cortisol and mineralocorticoids from progesterone will be disrupted by a deficiency of 21-Hydroxylase.
The cytochrome P450 dependent monooxygenases are present in the endoplasmic reticulum of the liver cells in mammals.
The hydroxylated derivatives are more water-soluble and have functional groups for the attachment of very polar substances, such as glucuronate, that allow them to be excreted in urine.
The action of the P450 system can convert potential cancer-causing compounds into cancer-causing derivatives.
The water-soluble bile salt is a major cholesterol breakdown product.
An infant has a number of health issues and has a retardation of development.
The urine has mevalonate in it.
5-phosphomevalonate is formed from a deficiency of mevalonate.
Give a brief explanation of your answer.
Most of the bile acids that are produced in the colon are returned to the liver.
bile acids are prevented from reabsorption by cholestyramine.
When rabbits were given cholestyramine, the hepatic absorption of 125I-labeled LDL was increased relative to normal, whereas the absorption of 131I-labeled LDL was unchanged.
Explain the relationship between the action of cholestyramine and the amount of cholesterol in the body.
The presence of apoprotein E in lipoproteins allows them to be taken up by hepatic cells.
Provide a brief explanation for each of the observations made by a person with a deficiency in apoprotein E synthesis.
Normal people have these particles in their bloodstream for a long time.
Increased rates of triacylglycerol breakdown can cause pregnant women to have elevated levels of ketone bodies in their blood.
Hopanoids are found in some plants.
A typical hopanoid is shown below.
The pathway used for cholesterol synthesis is similar to that used for hopanoids.
The biosynthetic pathway for hopane includes the formation of squalene, followed by more steps to form a C30 compound.
lanosterol is similar to hopane, but lacks the hydroxyl group.
The reaction does not require oxygen.
The formation of lanosterol from squalene is similar to this step.
A colleague has discovered a compound that is very powerful and will block the synthesis of mevalonate in the body.
The synthesis of lipoproteins is done in the liver.
Rats that are tained on a diet that is deficient in choline develop fat deposits.
fucose is one of the sugar residues found in ganglioside.
When GTP is available, fucose can be incorporated into the ganglioside.
A deficient phosphatidate phosphatase can cause the formation of diacylglycerol.
Desmolase is involved in the synthesis of pregnenol.
In Gaucher's disease, glucosylcerebrosides accumulate in bone-marrow cells.
Although the common galactosylceramides and their derivatives are found in the tissues of affected patients, there is no evidence of galactosylcerebrosides or ceramides accumulating.
The cells of the adrenal cortex have high concentrations of LDL.
The reaction occurs at a low rate at low concentrations of phospholipids in water.
The reaction rate increases when micelles are formed.
The activity of HMG CoA reductase has been reduced by Glucagon.
There are a number of ways that people with elevated levels of LDL can be treated.
Intake of cholesterol, ingestion of positively charged resins, and administration of lovastatin are included.
There are two established methods for dealing with hypercholesterolemia in patients.
The rationale for this procedure is based on the fact that 70% of the total body LDL receptors are in the liver.
There are a small group of patients who have undergone a transplant.
One patient became responsive to lovastatin after the transplant, and the rate of LDL turnover increased threefold.
Provide a rationale for each of the responses to an increase in the rate of transport.
3,4-dihydroxybutyl-1-phosphonate can be converted into diacylbutyl-1-phosphonate, an analogue of phosphatidate.
Give a brief explanation of your answer.
The figure is below.
The LDL-receptor complexes are internalized by the endocytosis.
The endosomes are fused with lysosomes, where cholesterol is lysosomal acid lipases.
The lysosomal enzymes don't affect the LDL receptor.
The conversion of free glycerol into glycerol 3-phosphate is done by the Glycerol kinase.
The activity of glycerol kinase in adipose tissue is low, despite the high levels of the enzyme in the body.
There is an inherited disorder of sphingomyelin breakdown.
White blood cells collected from a patient can easily be tested for this enzyme.
Both sphingomyelin and phosphocholine can be found in water and chloroform.
If you can get sphingomyelin labeled with 14C in any desired carbon atoms, you can design an experiment that will allow you to confirm a diagnosis of Niemann- Pick disease.
The formation of acetyl CoA in the cytosol is caused by the activity of the ATP-citrate lyase.
Acetyl CoA is used for the synthesis of HMG CoA, which gives rise to mevalonate for the synthesis of cholesterol.
If no other pathways can use mevalonate, its concentration in the liver will increase until it spills into the blood and then into the urine.
The rate of mevalonate will be stimulated because the activity of HMG CoA reductase is increased.
The amount of cholesterol in the cell is lowered by a depressed rate of cholesterol synthesis.
HMG CoA reductase activity increases when inhibition of its synthesis and activity by cholesterol is reduced.
One explanation is that cholestyramine stimulates the synthesis of more bile acids from cholesterol.
An increased demand for cholesterol stimulates the synthesis of LDL receptors, which takes up more cholesterol from the blood.
Mevinolin lowers the rate of cholesterol synthesis.
The requirement for cholesterol leads to an increase in the number of LDL receptors, which in turn can take up more LDL from the circulation.
The circulating levels of cholesterol and triacylglycerols are elevated because of these particles.
The rate of synthesis and export of VLDL particles is reduced when the hepatic tissue has an apo E deficiency.
LDL are reduced since VLDL are in circulation.
VLDLderived cholesterol repressed the synthesis of additional LDL receptors.
The levels of acetyl CoA and HMG CoA are also elevated because of the increased levels of acetoacetate.
Cholesterol synthesis is stimulated by an increase in the availability of certain substances.
squalene is a 30-carbon compound and is formed by IPP.
Six IPPs are needed for the synthesis of a molecule of squalene, which is in turn the precursor of hopane.
The required amount of mevalonic acid is six.
The synthesis of hopane from squalene probably preceded the synthesis of sterols.
The synthesis of mevalonate is required for the synthesis of a number of other important compounds, including ubiquinone, an important component of the electron transport chain.
Even if adequate cholesterol is available in the diet, the complete synthesis of mevalonate would be ill-advised.
Choline, a component of phosphatidyl choline, is an important component of the membranes and lipoproteins.
Chapter 26 could interfere with the synthesis and export of lipoproteins like VLDL, which is a carrier of triacylglycerols to peripheral tissues.
Triacylglycerols accumulate in the liver if they are not exported.
GDP-fucose appears to be the donor of fucose in this case.
You would expect to see reduced rates of synthesis of triacylglycerols, which use diacyl glycerols as acceptors of activated acyl groups.
phosphatidyl choline synthesis is dependent on the availability of diacylglycerols.
The increase in androgen production is caused by elevated levels of 17 a-hydroxyprogesterone.
The pathway from cholesterol to 17 a-hydroxyprogesterone includes a step that cleaves the bond between C-20 and C-22 in 20a, 22b dihydroxycholesterol to form pregnenolone.
The rate of androgen synthesis would be decreased by a deficiency of desmolase.
The normal feedback mechanism leads to increased ACTH production.
The defect involves ganglioside breakdown rather than ganglioside synthesis because glucosylcerebrosides accumulate but galactosylcerebrosides do not.
The cells of the adrenal cortex use cholesterol to synthesise a number of steroid hormones.
It is necessary for additional cholesterol to be obtained from plasma lipoproteins because these cells can themselves synthesise cholesterol.
cortical cells are able to take up cholesterol with a high concentration of LDL.
In the cell, most of the time, a phospholipase will encounter something that is part of an aggregate.
The local concentrations of the conjugates should be higher than if they were individually free in solution.
The presence of glucagon is a sign that triacylglycerol catabolism is needed.
One would expect biosynthetic reactions to be suppressed under such conditions.
Low energy charge means highAMP levels that would lead to thephosphorylation of HMG CoA reductase.
The compound that stimulates bile salt reabsorption from the gut stimulates the synthesis of bile acids from cholesterol in the liver and decreases concentrations of sterol in the cells.
Mevinolin reduces the rate of cholesterol synthesis, which can increase the absorption of LDL from the bloodstream.
Reducing circulating levels of cholesterol could be done with any of these treatments.
The inability of such people to internalize significant amounts of LDL means that the circulating levels of that lipoprotein are elevated in the blood.
The absence of LDL receptors means that cholesterol doesn't enter the cell to suppress de novo synthesis.
It would not prevent formation of LDL and other lipoproteins from cell turnover of cholesterol if you restricted your diet.
The bile sequestrants of bile salts wouldn't increase the amount of LDL in the circulation.
Mevinolin will suppress cholesterol synthesis, but it won't be compensated for by the circulation.
Homozygotes with two nonfunctional receptor genes are resistant to some compounds.
None of these measures have an effect on reducing circulating LDL levels in these patients.
VLDL and IDL are considered to be precursors of LDL, so that total cholesterol concentration in the blood would be lowered by apheresis.
The method can reduce cholesterol levels by 70%.
The effects of long-term apheresis are problematic, and treatment must be repeated about every two weeks.
A response to lovastatin shows that functional LDL receptors can be used to accelerate absorption in response to diminished de novo cholesterol synthesis.
It's important to note that liver transplant operations are dangerous in FH homozygotes who have advanced atherosclerosis.
There is interest in gene therapy designed to target a normal LDL gene to liver cells of FH homozygotes because of the fact that normal liver cells can contribute functional LDL receptors.
Less LDL particles will be able to enter the cell, resulting in a decrease in the entry of cholesterol.
The formation of diacylglycerol is the start of the conversion of phosphatidate to a triacylglycerol.
The formation of CDP-diacylglycerol involves the formation of an anhydride bond between the phosphatidic acid and cytidylic acid.
The synthesis of normal substrates would not be impaired since the phosphonate is not cleaved in this reaction.
A reduction in free cholesterol release from the lysosome leads to an increase in the production of cholesterol-lowering drugs.
Increased rate of LDL entry and accelerated cholesterol synthesis lead to an increase in cholesterol concentrations in the cell.
The cell can eventually be destroyed by cholesteryl esters and triglycerides.
The disease can be fatal within a year after birth.
The trip takes about 10 minutes.
The 115-kd glycoprotein would need to be synthesised at a much faster and wasteful rate if the lysosomal enzymes were to be destroyed.
In mammals, free glycerol is produced when triglycerides are converted to free fatty acids and glycerol by lipases.
Lipolysis occurs when there is a low level of sugar in the air.
The low activity of glycerol kinase in adipocytes prevents unnecessary resynthesis of triacylglycerols from free fatty acids and phosphatidic acid.
It is more likely that triacylglycerol synthesis will occur when there are high levels of sugar.
glycerol 3-phosphate can be synthesised by adipocytes.
Unless a suitable carbon source is available, adipocytes are unable to synthesise triglycerides.
White cells from the blood of a person suspected of having a sphingomyeli nase deficiency are cultured in a solution labeled with 14C in the methyl groups of the phosphocholine moiety.
The chloroform is used to extract the incubation mixture.
The intact radioactive sphingomyelin will be taken from the lower chloroform layer.
Incubation with cell extracts followed by chloroform extract results in little or no radioactivity in the aqueous phase, which shows the deficiency of sphingomyelinase activity.
Three ATPs are used to convert three fatty acids to acyl CoAs.
The total of seven Pi in the equation above is the result of three PPi being converted to Pi.
The equation above is a summary of the equations shown in the text.
cytidine to uridine is deamination.
The 5 a-reductase can be used to treat prostatic hypertrophy.
Patients taking the drug have lower levels of testosterone and dihydrotestosterone.
J. E discussed genetic deficiencies of 5a-reductase.
This characteristic is an inheritable trait.
The ability to degrade other drugs may be impaired in people who hydroxylate debrisoquine at a slow rate.
There are many odorants.
O2 is activated by a monooxygenase.
The reductant is NADPH.
One oxygen atom of O2 goes into the odorant, while the other is reduced to water.
The drug lowers the level of dihydrotestosterone.
The development and differeniation of the male phenotype is initiated by dihydrotestosterone.
If a pregnant woman had contact with the drug, her unborn male children would be at risk.
Two categories of function are served by the various P450 isozymes.
Some of them will be important in the removal of foreign substances from the plant's environment.
Plants may use P450 enzymes to synthesise toxins to fight pests, or to attract organisms that aid in dispersal of pollen or seeds.
Some of the P450 isozyme genes are likely to alter the rates of metabolism.
Knowledge of the individual differences would help to prescribe the correct dose of the medicine for each patient.
The negative charge next to the histidine side chain will be Phosphorylation of the serine, thus stabilizing the positively charged form of the histidine.
The key step of the reaction will be stopped.
One oxygen from O2 will be reduced to water and another oxygen will be hydroxylated.
The translation of the message and synthesis of HMG-CoA reductase by ribosomes could be affected by cholesterol.
The cholesterol-fed mice degraded the protein rapidly.