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1、Chapter 21 Lipid Biosynthesis1. Fatty acids;2. Eicosanoids;3. Triacylglycerols;4. Membrane phospholipids;5. Cholesterol, steroids, and isoprenoids;1. Fatty acid synthesis takes a different pathway from its degradationlOccurs in the cytosol (chloroplasts in plants).lAcetyl-CoA provides the first two
2、carbons, which is elongated by sequential addition of two-carbon units donated from malonyl-CoA.lIntermediates are attached to the -SH groups of an acyl carrier protein (ACP).lNADPH is the reductant.lThe enzymes are associated as a multi-enzyme complex or even being in one polypeptide chain in highe
3、r organisms (fatty acid synthase).lElongation by the fatty acid synthase complex stops upon formation of palmitate (C16), further elongation and desaturation are carried out by other enzyme systems.2. Malonyl-CoA is formed from acetyl-CoA and bicarbonate lSalih Wakil discovered that HCO3- is require
4、d for fatty acid synthesis.lAcetyl-CoA carboxylase (being trimeric in bacteria, monomeric in animals and both in plants) catalyzes this carboxylation reaction.lThe enzyme has three functional parts: a biotin carrier protein; an ATP-dependent biotin carboxylase; and a transcarboxylase.lThe enzyme exe
5、mplifies a ping-pong reaction mechanism.lThis irreversible reaction commits acetyl-CoA to fatty acid synthesis.biotin carboxylaseTrans-carboxylaseAcetyl-CoA carboxylasecatalyzes the two-step carboxylation reaction of acetyl-CoA in two active sites.3. The acetyl and malony groups are first transferre
6、d to two SH groups of the fatty acid synthase complexlThe acetyl group of acetyl-CoA is first transferred to the SH group of a Cys residue on the b-ketoacyl-ACP synthase (KS) in a reaction catalyzed by acetyl-CoA-ACP transacetylase (AT).lThe malonyl group is transferred from malonyl-CoA to the SH gr
7、oup of the 4-phosphopantetheine covalently attached to a Ser residue of the acyl carrier protein (ACP).The acyl carrier protein (ACP) is very similar to The acyl carrier protein (ACP) is very similar to CoA (thus can be regarded as “macro CoA”)CoA (thus can be regarded as “macro CoA”)4. Fatty acids
8、are synthesized by a repeating four-step reaction sequencelIn the condensation reaction (step 1), catalyzed by b-ketoacyl-ACP synthase, the methylene group of malonyl-CoA (linked to ACP) undergoes a nucleophilic attack on the carbonyl carbon of the acetyl group linked to KS, forming the b-ketobutyry
9、l-ACP with simultaneous elimination of CO2.lthe b-ketobutyryl-ACP is then reduced to D-b-hydroxybutyryl-ACP (step 2), using NADPH and the b-ketobutyryl-ACP reductase (KR).lA water molecule is then removed from the b-hydroxybutyryl-ACP to produce trans-2-butenoyl-ACP in a reaction catalyzed by b-hydr
10、oxybutyryl-ACP dehydratase (step 3).l A further reduction (step 4), also using NADPH, of the carbon-carbon double in trans-2-butenoyl-ACP, catalyzed by enoyl-ACP reductase produces a saturated acyl on ACP (butyryl-ACP).lThe butyryl group is then transferred to the Cys SH group of b-ketoacyl-ACP synt
11、hase for another round of four reactions, which will extend the chain by two more carbons.lSeven rounds of the four-step lengthening reactions produces palmitoyl-ACP, which will be hydrolyzed to release a free palmitate.lThe flexible 4-phosphopantetheine group covalently attached to ACP is believed
12、to act as a switch arm to move the intermediates from one active site to the next on the enzyme complex (i.e., the substrates are channeled).lA total of 7 ATP and 14 NADPH will be consumed for making one palmitate molecule. 5. The seven activities of fatty acid synthesis from different organisms hav
13、e different level of integrationlEach activity resides in a separate polypeptide chain in bacteria and higher plants.lThe seven activities reside in two separate polypeptide chains, with the synthase present as dodecamers (a6b 6).lThe seven activities reside in one large polypeptide chain in vertebr
14、ates, with the synthase present as dimers.The seven activitiesThe seven activities of fatty acid synthase of fatty acid synthaseare integrated toare integrated todifferent levels indifferent levels indifferent organisms.different organisms.6. Fatty acid synthesis occurs in cellular compartments havi
15、ng a high NADPH/NADP+ ratiolNAD and NADP have selected for functioning as electron carriers in oxidative catablism and reductive anabolism respectively.lIn the hepatocytes and adipocytes, NADPH is mainly produced in the cytosol via the pentose phosphate pathway and by the malic enzyme.lIn photosynth
16、etic plants, fatty acid synthesis occur in the chloroplast stroma, using NADPH made from photophosphorylation.Malic Malic enzymeenzymePentose phosphatePentose phosphatepathwaypathwayNADPH in the cytosol of animal cellsis largely produced by the oxidativedecarboxylation of malate and thepentose phosp
17、hate pathway7. The acetyl groups of the mitochondrion are transported into the cytosol in the form of citratelThe acetyl-CoA molecules are made from glucose and amino acids in mitochondria.lThe are shuttled into the cytosol in the form of citrate via the citrate transporter of the inner membrane.lAc
18、etyl-CoA is regenerated by the action of ATP-dependent citrate lyase in the cytosol.lOxaloacetate is shuttled back into the mitochondria as malate or pyruvate.8. The rate of fatty acid biosynthesis is controlled by acetyl-CoA carboxylaselExcess fuel is generally converted to fatty acids/triacylglyce
19、rol for longer term storage.lAcetyl-CoA carboxylase, catalyzing the committing and rate-limiting step of fatty acid synthesis, is allosterically inhibited by palmitoyl-CoA and activated by citrate.lGlucagon and epinephrine triggers the phosphorylation and disassociation of the polymeric enzyme subun
20、its, which inactivates the enzyme.lCitrate partially activate the phosphorylated acetyl-CoA carboxylase (similar to how AMP partially active the dephosphorylated glycogen phosphorylase).lIn plants, acetyl-CoA carboxylase is activated by a increase of Mg 2+ concentration and decrease of H+ concentrat
21、ion that accompany illumination.l(Malonyl-CoA inhibits carnitine acyltransferase I)Dephosphorylatedacetyl-CoA Carboxylase (active)Acetyl-CoA carboxylaseis regulated by allostericeffectors and reversiblephosphorylationCitrate partially activate the phosphorylated acetyl-CoA carboxylase9. Palmitate ca
22、n be further elongated and desaturated in smooth ERlPalmitoyl-CoA can be further elongated by the fatty acid elongation system present mainly in the smooth endoplasmic reticulum, with two-carbon units also donated by malonyl-CoA.lPalmitoyl-CoA and Stearoyl-CoA can be desaturated between C-9 and C-10
23、 to produce palmitoleate, 16:1(9), and oleate, 18:1(9) respectively.lThe double bonds are introduced by the catalysis of fatty acyl-CoA desaturase (a mixed-function oxidase), where both the fatty acyl group and NADPH are oxidized by O2.lThe electrons of NADPH are transferred to O2 via Cyt b5 reducta
24、se and cytochrome b5.lFurther desaturation of oleate occur on phosphatidylcholine and is catalyzed by another desaturase, which is present only in plant cells.lLinoleate and linolenate, needed to make other polyunsaturated fatty acids like arachidonate are essential fatty acids for mammals.Palmitate
25、 is the Precursor for the biosynthesis ofother fatty acidsFatty acyl-CoA is desaturated (oxidized) by O2 and NADPH.Oleate can be desaturated on Phosphatidylcholine(often attaching to C-2)to form linoleate and linolenate10. Eicosanoids are derived from arachidonate, 20:4 ( 5,8,11,14)lThe arachidonate
26、 (花生四烯酸) is first cleaved off from membrane phospholipids by phospolipase A2, in response to hormonal or other stimuli.lArachidonate is then converted to PGH2 by the catalysis of the bifunctional cyclooxygenase (COX): the cyclooxygenase activity converts arachidonate to PGG2; the peroxidase activity
27、 then converts PGG2 to PGH2. lPGH2 is the immediate precursor of other prostaglandins and thromboxanes. lAspirin (acetylsalicylate) irreversibly inhibits the cyclooxygenase by acetylating an active site Ser, thus blocking the synthesis of prostglandins and thromboxanes; Ibuprofen also inhibit the sa
28、me enzyme.lArachidonate can also be modified by adding hydroperoxy groups at various positions to form various hydroperoxyeicosatetraenoates (HPETEs) in reactions catalyzed by various lipooxygenases with the incorporation of O2.lThe HPETEs will be further converted to leukotrienes (白细胞三烯).Prostaglan
29、dins andthromboxanes are synthesized from arachidonateCyclooxygenaseactivity of COXPeroxidaseactivity of COXThe dimeric bifunctional cyclooxygenase(COX-1)Heme for the peroxidaseactive siteTyr385, a keyresidue for thecyclooxygenaseactivityflurbiprofenSer53011. Newly synthesized fatty acids have mainl
30、y two alternative fates in cellslFate I: be incorporated into triacylglycerols as a form to store metabolic energy in long terms.lFate II: be incorporated into membrane phospholipids (during rapid growth).12. Phosphatidic acid is the common precursor for the syntheses of both triacylglycerols and gl
31、ycerophospholipidslPhosphatidic acid (or diacylglycerol 3-phosphate) is made by transferring two acyl groups from two acyl-CoAs to L-glycerol 3-phosphate, which is derived from either glycerol or dihydroxyacetone phosphate.lA phosphatidic acid is converted to a triacylglycerol via a dephosphorylatio
32、n reaction (catalyzed by phosphatidic acid phosphatase) and a acyl transferring reaction.Phosphatidic Phosphatidic acid is derivedacid is derivedfrom L-glycerol 3-from L-glycerol 3-phosphate and twophosphate and twoacyl-CoAs.acyl-CoAs.Often unsaturatedOften unsaturatedOften saturatedOften saturatedP
33、hosphatidic acidPhosphatidic acidphosphatasephosphatasePhosphatidic acidis the commonprecursor for bothtriacylglycerols and glycerophospholipids13. Insulin stimulates conversion of dietary carbohydrates/proteins into fatlDiabetes patients due to lack of insulin would neither be able to use glucose p
34、roperly, nor to synthesize fatty acids from carbohydrates and amino acids.lThey show increased rates of fatty acid oxidation and ketone body formation, thus losing weight.14. Two strategies are taken for converting phosphatidic acid to glycerophospholipidlEugene Kennedy revealed in 1960s that either
35、 the OH group of the diacylglycerol (strategy 1) or that of the polar head (strategy II) is first activated by attaching to cytidine nucleotide.lThe CMP moiety is displaced by the other OH group in a nucleophilic attack reaction to synthesize a glycerophospholipid.lBoth strategies are used in eukary
36、otic cells, but only strategy I is use in bacterial cells.Bacteria mainly usethis strategyEukaryotic cellsuse both strategies(occurring on sER andinner membrane of mitochondria)phosphatasedecarboxylasePhospholipid synthesisin E. coli employsCDP-diacylglcerol15. Acidic (anionic) phospholipids in euka
37、ryotic cells are synthesized using CDP-diacylglycerollThese include phosphatidylglycerol, cardiolipin, phosphatidylinositol, phosphatidylserine.leukaryotic cardiolipin is synthesized from one phosphatidylglycerol and one CDP-diacylglycerol (from two phosphatidylglycerols in bacteria).4 45 516. Phosp
38、hatidyl choline (PC) and phosphatidyl ethanolamine (PE) are often made from the salvage (reuse) pathway in mammalslDiet choline and ethanolamine are first converted to CDP-choline and CDP-ethanolamine after an initial phosphorylation step.lThe CMP moiety is then replaced by a diacylglycerol, forming
39、 PC and PE.lPhosphatidylserine (PS) is often made from PE by a head exchange reaction (reversible).lPC can be made from PE by three methylation reactions using S-adenosylmethionine (adoMet) in the liver cells.lPS can also be converted to PE by a decarboxylation reaction.(ethanolamine)(ethanolamine)(
40、Phosphoethanolamine)(Phosphoethanolamine)(CDP-ethanolamine)(CDP-ethanolamine)(Phosphatidylthanolamine)(Phosphatidylthanolamine)PC and PE are PC and PE are made from themade from thesalvage pathwaysalvage pathway in mammals in mammalsThe synthesis of PE,PC, PS in eukaryoticcells.17. The synthesis of
41、ether lipids involves a displacement of fatty acyl by fatty alcohol step and a desaturation steplBoth plasmalogen (缩醛磷脂) and platelet-activating factor are made using this pathway.lThe acyl group on 1-acyldihydroxyacetone 3-phosphate is replaced by a long chain alcohol group to form the ether linkag
42、e.lThe double bond in plasmalogen is introduced at the end by the catalysis of a mixed-funciton oxidase.Synthesis of the ether lipids (醚脂类醚脂类）1-alkylglycerol 3-phosphate1-alkylglycerol 3-phosphate18. The sphingosine backbone of spingolipids is derived from palmitoyl-CoA and SerlPalmitoyl-CoA condens
43、es with serine (PLP is needed for decarboxylate serine) to form b-ketosphinganine, which is then reduced to sphinganine (二氢鞘氨醇).lSphinganine is then acylated and desaturated to form ceramide (containing sphingosine).lAddition of sugar(s) or phosphocholine heads leads to the synthesis of cerebroside,
44、 gangliosides, or sphingomyelin. lThe ways for the membrane lipids (glycerolphospholipids and spingolipids) synthesized at smooth endoplasmic reticulum or inner membrane of Mitochondria to be transported to specific cellular locations are not well understood yet.PLPSpingolipid synthesis beginswith t
45、he condensation betweenpalmitoyl-CoA and Ser.(not CDP-choline!)(not CDP-choline!)A glycolipid, not aA glycolipid, not aphospholipidphospholipid19. Radioisotope tracer experiments revealed that all the 27 carbons of cholesterol is derived from acetyl-CoAlThe origin of the carbon atoms of cholesterol
46、was deduced from tracer experiments where either with the methyl carbon or the carboxyl carbon in acetate is labeled with 14C (1940s).lThe pattern of labeling provided the blueprint for revealing the detail enzymatic steps for cholesterol biosynthesis occurring in mammals.lThe 30-carbon squalene (of
47、 six isoprene units) and later on mevalonate were found to be intermediates of cholesterol biosynthesis.lThe biosynthetic pathway of cholesterol, being the most complex known, was elucidated mainly by Konrad Bloch and Feodor Lynen in the 1950s. The carbon origins of cholesterol as revealed byradiois
48、otope labeling studies.20. The cholesterol biosynthesis pathway can be divided into four stageslStage I: three acetyl-CoA molecules condense to form the 6-carbon mevalonate (甲羟戊酸).lStage II: mevalonate is converted to activated 5-carbon isoprene (异戊二烯) units.lStage III: Six isoprene units condense t
49、o form the linear 30-carbon squalene(鲨烯).lStage IV: The linear squalene is cyclized to form a four-ring structure, which is eventually converted to the 27-carbon cholesterol through a series of complicated reactions.(6C)(5C)(30C)(27C)(2C)Reactions assemblingcholesterol from 18 molecules of acetyl-Co
50、Acan be divided into four stages.21. Mevalonate commits the acetyl groups for cholesterol synthesis lOne molecule of b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) is formed from three acetyl-CoA molecules in the cytosol via the same reactions as occurring in mitochondria for ketone body formation.lHMG-Co
51、A reductase (an integrated membrane protein in the smooth ER) catalyzes the irreversible reduction of HMG-CoA (using two molecules of NADPH) to form mevalonate: committing the acetyl groups for cholesterol synthesis (thus being a major regulation step).The irreversibleThe irreversiblecommitting step
52、committing stepfor cholesterolfor cholesterolbiosynthesisbiosynthesisHMG-CoAHMG-CoAReductaseReductaseIn cytosolIn cytosolOne mevalonate issynthesized fromthree acetyl-CoAmolecules.Acetyl-CoA + acetoacetateAcetyl-CoA + acetoacetateHMG-CoA lyaseHMG-CoA lyase in mitochondria in mitochondria22. Two acti
53、vated isoprenes are formed from mavelonate after going through three phosphorylation stepslThree phosphate groups are transferred from three ATP molecules to mevalonate to form 3-phospho-5-pyrophosphomevalonate.lThe leaving of both the carboxyl and the 3-phosphate groups leads to the formation of 3-
54、isopentenyl pyrophosphate.l3-Isopentenyl pyrophosphate is isomerized to form the second activated isoprene: dimethylallyl pyrophosphate.Two activatedisoprenes are formed frommavelonate.23. The 30-carbon linear squalene is formed from the condensation of six activated isoprene unitslA dimethylallylpy
55、rophosphate is joined to an isopentenylpyrophosphate (head-to-tail) to form the 10-carbon geranyl pyrophosphate.lA geranyl pyrophosphate is joined to another 3-isopentenyl pyrophosphate (head-to-tail) to form the 15-carbon farnesyl pyrophosphate(法呢基焦磷酸).lTwo farnesyl pyrophosphate join (head-to-head
56、) to form the 30-carbon squalene.Farnesyl pyrophosphateis formed fromthree activatedisoprene units15-carbonSqualene is formedfrom the condensationof two farnesylpyrophosphates24. The rings of cholesterol are formed via a concerted reaction across four double bonds of the linear squalene epoxide inte
57、rmediate lSqualene 2,3-epoxide, is first formed in a reaction catalyzed by squalene monooxygenase using O2 and NADPH.lConcerted movement of electrons through four double bonds and the migration of two methyl groups generates lanosterol (羊毛固醇).lLanosterol is converted to cholesterol via about 20 enzy
58、matic reactions including many double bond reduction and demethylations.Squalenemonooxygenasecyclase 20reactionsOxygenation inducedring closing convertsthe linear squalene to lanosterol of fourrings, which is converted tocholesterolafter going throughanother 20 or soreactions!25. Cholesterols made i
59、n vertebrate livers can be converted to bile acids and cholesterol esters before exportinglCholesterol can be converted to bile acids and bile salts, which will be secreted to the intestine for emulsifying lipids.lCholesterol can also be converted to the more hydrophobic cholesterol esters, which wi
60、ll be stored in the liver or transported to other tissues after being incorporated into lipoprotein particles.Cholesterol can be convertedCholesterol can be converted to bile acids (salts) to bile acids (salts) ： glycocholate and taurocholate glycocholate and taurocholate（甘胆酸盐）（甘胆酸盐）（甘胆酸盐）（甘胆酸盐）牛黄胆酸
61、盐牛黄胆酸盐牛黄胆酸盐牛黄胆酸盐Acyl-CoA-CholesterylAcyl-CoA-Cholesterylacyl transferaseacyl transferase(ACAT) catalyzes the (ACAT) catalyzes the addition of an acyl addition of an acyl group to the hydroxyl group to the hydroxyl group of cholesterolgroup of cholesterol26. Lipids (including cholesterols) are transp
62、orted in the vertebrate plasmia as various lipoprotein particleslThe different lipoprotein particles, having different combinations of lipids and apolipoproteins, can be separated by untracentrifugation due to different densities and sizes.lThe human plasma lipoproteins include chylomicrons (which t
63、ransports lipids from intestine to various tissues), VLDL (very low density lipoproteins), LDL(Low density lipoproteins), HDL (high density lipoproteins).lAt least nine apolipoproteins (named as apo A, B, C, D, E) have been revealed in human, which act as signals to target the lipoprotein particles
64、to various tissues or activating enzymes that will act on the lipoproteins.lEndogenous lipids made in liver are transported to other tissues as VLDL particles ( 87% lipids and 12% proteins).lThe apoC-II protein in VLDL activates the lipoprotein lipase in muscle and adipocyte tissues, thus releasing
65、free fatty acids there.lSome VLDL remnants is then converted to LDL (with 23% proteins and 75% lipids) and with the others being absorbed by the liver cells via receptor-mediated endocytosis.lLDL delivers cholesterols to extrahepatic tissues, where its apoB-100 protein (4636 residues) is recognized
66、by specific LDL receptors and LDL is endocytosed. lHDL, with its precursors formed in the liver or intestine cells, collects the cholesterols in the plasma and deliver them to the liver cells. l(A negative correlation between blood HDL level and arterial diseases has been observed.)Lipids are transp
67、ortedLipids are transportedas various lipoprotein as various lipoprotein particles in vertebrateparticles in vertebrateplasmaplasmaLDL is uptaken by cellsLDL is uptaken by cellsvia the LDL receptors,via the LDL receptors, LDL receptors are recycled to the cell surfaces27. The de novo synthesis of ch
68、olesterol is regulated to complement dietary intakelHMG-CoA reductase, catalyzing the rate-limiting step of the de novo cholesterol synthesis, has an activity variable over 100 fold!lAn yet characterized sterol promotes proteolytic degradation of HMG-CoA reductase and inhibits the transcription of t
69、he genes of HMG-CoA reductase and LDL receptor.lHormones (insulin and glucagon) regulate the activity of the HMG-CoA reductase via reversible phosphorylation.lGenetic defect of the LDL receptor was found to cause the familial hypercholesterolemia and atherosclerosis: the LDL cholesterols can not ent
70、er the cells, while de novo synthesis continues despite the high cholesterol level in the blood.lMevalonate analogs (e.g., compactin and lovastatin) can be used to treat patients with familial hypercholesterolemia.l The de novo synthesis of The de novo synthesis of cholesterol is regulatedcholestero
71、l is regulatedto complement the to complement the dietary uptakedietary uptake(For storage)(For storage)The mevalonate analogsThe mevalonate analogsare used to treatare used to treathypercholesterolemiahypercholesterolemiapatients.patients.28. Pregnenolone, the common precursor of all steroid hormon
72、es, is derived from cholesterollThe tail chain of cholesterol is first hydroxylated at C20 and C22, and then cleaved between these two carbons to remove a 6-carbon unit, forming pregnenolone(孕烯醇酮).lThe hydroxylation is catalyzed by cytochrome P450 monooxygenases (a mitochondrial enzyme) that utilize
73、 NADPH and O2.lCytochrome P450 is a large family of enzymes with different substrate specificity, hydroxylates many hydrocarbon chains. cytochrome P450monooxygenasesDesmolase碳链裂解酶碳链裂解酶Prognenolone, the common precursorof steroid hormones,is synthesized from cholesterol29. All steroid hormones are de
74、rived from cholesterollProgesterone (孕酮) is synthesized from pregnenolone by oxidizing the 3-OH group and the isomerization of the double bond (from 5 to 4 position).lCortisol (a major glucocorticoid) is synthesized from progesterone by hydroxylation at C-17, C-21, and C-11.lAldosterone (a mineraloc
75、orticoid) is synthesized from progesterone by hydroxylation at C-21, C-11, and oxidation of C-18 to an aldehyde.lTestosterone (an androgen, or male hormone) is synthesized from progesterone by the removal of 2-carbon unit and hydroxylation at C-17.lEstradiol ( an estrogen, or female hormone) is synt
76、hesized from testosterone by the removal of C-19 and formation of the aromatic A ring.Progesterone is synthesized from pregnenolone by oxidizing the 3-OH group and the isomerization of the double bond from 5 to 4 positionCortisol and aldosterone Cortisol and aldosterone are synthesized from are synt
77、hesized from progesterone by several progesterone by several oxygenation reactionsoxygenation reactions (forming hydroxyl and (forming hydroxyl and aldehyde groups)aldehyde groups)Testosterone is synthesized from progesterone by the removal of a 2-carbon unit and hydroxylation at C-17Estradiol is sy
78、nthesized from testosterone by the removal of C-19 and formation of the aromatic A ring30. A hugh array of biomolecules, all called isoprenoids are synthesized using activated isopreneslThese include many pigments (carotenoids, phytol chain of chlorophylls), fragrant principles, vitamines (A, D, E,
79、K), rubber, dolichols, quinones (ubiquinone, plastoquinone), juvenile hormones of insects.lPrenylation of proteins (attaching of geranylgeranyl and farnesyl groups) leads to membrane association.Some plant pigments are isoprenoidsSome fragrant molecules are isoprenoids (called terpenes)Natural rubbe
80、r is cis-polyisopreneIsoprenoid tails function to anchor proteins to membranes“Perfumes, colors and sounds echo one another.”Charles BaudelaireCorrespondances SummarylFatty acid biosynthesis takes a different pathway from the reverse of its degradation and takes place in different cellular compartme
81、nts.lThe aceytl-CoA units are transported out of mitochondrial matrix as citrate.lAcetyl-CoA carboxylase catalyzes the rate-limiting step of fatty acid synthesis and is highly regulated by allosteric and covalent modifications.lPalmitate, the usual final product of fatty acid synthesis, can be furth
82、er elongated and desaturated in sER.lEicosanoids are derived from arachidonate by the action of cyclooxygenases and peroxidases.lPhosphatidic acid (diacylglycerol 3-phosphate) is the common precursor of both triacylglycerol and glycerophospholipids.lGlycerophospholipids are made using two alternativ
83、e strategies of CDP modification.lThe backbone of sphingolipids are made from palmitoyl-CoA and Ser.lRadioisotope tracer experiments revealed that all the 27 carbons of cholesterol are from acetyl-CoA.lThe biosynthesis of cholesterol takes a long pathway, with the reaction catalyzed by HMG-CoA reduc
84、tase being the rate-limiting step for de novo synthesis of cholesterol.lActivated isoprene untis, mevalonate, squalene were found to be important intermediates of cholesterol biosynthesis.lThe lipids are transported as lipoprotein particles (including chylomicrons, VLDL, LDL, and HDL).lThe de novo biosynthesis of cholesterol is regulated to complement the dietary uptake.lAll streroid hormones are derived from choleterol.lA huge arrays of isoprenoids are made using activated isoprene units.
