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1、Lipid Biosynthesis II1. Biosynthesis of fatty acids and eicosanoids2. Biosynthesis of other lipidsa. Triacyloglycerolsb. Membrane phopholipidsc. Cholesterol, steroids and isoprenoidsFatty acidstriacylglycerols（三脂酰甘油）glycerolphospholipidssphingolipids Biological membranescholesterol Steroidhormonesar
2、achidonatederivates脂肪酸膽固醇花生四烯酸衍生物生物膜生物膜類固醇激素Biosynthesis of triacylglycerolsBoth triacylglycerols and glycerophospholipids are synthesized from phosphatidic acid;Phosphatidic acid (磷脂酸, key intermediate for lipid biosynthesis)Acyl-CoA synthetaseBiosynthesis of Phosphatidic AcidDHAPGlycerol kinaseAcy
3、l transferaseAcyl transferaseAcyl-CoA synthetase磷脂酸Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipidsRegulation of triacylglycerol by insulin Triacylglycerol CycleIs this a futile cycle (無效循環(huán)) ?75% of all fatty acids released by lipolysis are reesterified to form TG
4、s rather than used for fuel !Am J Physiol Endocrinol Metab 258: E382-E389, 1990Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exerciseFive normal volunteers were infused with 1-13Cpalmitate and D-5-glycerol throughout rest;4 h of treadmill exercise at
5、40% maximum O2 consumption, and 2 h of recovery. Total fat oxidation was quantified by indirect calorimetry. Lipolysis increased from 2.1 to 6.0 (mol.kg-1min-1) after 30 min of exercise, and increased 10.5 after 4 h. Lipolysis decreased rapidly during the first 20 min of recovery. 75% of released fa
6、tty acids were reesterified at rest. Triglyceride-fatty acid cycling plays an important role in enabling a rapid response of fatty acid metabolism to major changes in energy metabolism. The released FA is taken up by a number of tissues (eg. muscle) where it is oxidized to provide energy. Much of th
7、e FA taken by liver is not oxidized and is recycled to TGs and returned to adipose tissue. This phenomena could represent an energy reserve in blood stream during fasting. The constant recycling of TGs in adipose tissue even during starvation raises a question: where is the source of the glycerol ?
8、(glycolysis is suppressed under starvation !) Adipose tissue generates G3Pby glyceroneogenesis a shortened version of gluconeogenesis, discovered in 1960. glucose is not synthesized in adipose tissue.Regulation of Glyceroneogenesis FAs in blood interfere with glucose utilization in muscle diabetes t
9、ype 2 (treated by Thiazolinediones, 噻唑烷二酮噻唑烷二酮).1.Glucocorticoid hormones stimulate glyceroneogenesis and gluconeogenesis in liver, but suppressing glyceroneogenesis in adipose tissue (reciprocally regulated). As a result, more free FAs are released in to the blood. 2. Thiazolidinediones are used to
10、 treat type 2 diabetes (insulin resistance). This drug activates peroxisome proliferator-activated receptor (PPAR), which induces the activity of PEP carboxykinase. Therapeutically, the drug increases the rate of glyceroneogenesis in adipose tissue and reducing the amount of free FAs in the blood. X
11、PhoPhospholipidsholipids(structural lipids in membrane） : : Glycerophospholipids SphingolipidsPhosphatidic acid + Head groupThe phospholipid head group is attached to a diacylglycerol by a phosphodiester bond, formed when phosphoric acid condenses with two alcohols, eliminating two molecules of H2O.
12、Headgroup Two strategies for synthesis of glycerophospholipidsGlycerophospholipids in E.coli ：phosphatidylethanolamine，phosphatidylglycerol，cardiolipin (diphosphatidylglycerol)Glycerophospholipids in eukaryotes:（biosynthesis：ER and Golgi complex） phosphatidylethanolamine （腦磷脂），phosphatidylcholine（le
13、cithin, 卵磷脂）， phosphatidylinositol； （biosynthesis：inner membrane of mitochondriaphosphatidylglycerol , cardiolipin )CDP-diacylglycerolBiosynthesis of glycerolipids in E.coli Biosynthesis of cardiolipin and phosphatidylinositol in eukaryoteDifference from E.coli system: 2 x phosphatidylglycerolThe ma
14、jor path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotesPathways for phosphatidylserine synthesis via the head group exchange in mammalsPSS1: Ca2+-dependentphosphatidylserine synthasePathways for phosphatidylcholine synthesis in mammals(salvage of cholin
15、e) Phosphatidylcholine (lecithin,卵磷脂)Choline is a lipotropic (親脂) substance which functions in the bodys metabolism as an agent that aids in the digestion of fats. Additionally, it - helps body to burn fat; - lowers blood cholesterol; - a sufficient intake of choline (via lecithin) positive effect o
16、n mental functions because acetylcholine is a neurotransmitter; - helps the absorption of fat soluble vitamins; - In Europe, it has been used to treat hepatitis, alcoholic hepatitis and cirrhosis of the liver Summary of the pathways to synthesis of major phospholipidsonly in liverBiosynthesis and tr
17、ansport of glycerophospholipidsCERT: ceramide transportSynthesis of Plasmalogen- Found in the plasma membranes of all eukaryotic cells- Its concentration is highest in the cells of the central nervous system;- The backbone of a sphingolipid is sphingosine;- The sphingosine backbone of spingolipids i
18、s derived from palmitoyl-CoA and serine- The enzyme catalyzing this reaction requires pyridoxal phosphateSphingolipid BiosynthesisSphingosine-1-phosphate (S1P) : an enigmatic signalling lipidNature Rev. Mol. Cell Biol. 2003, 4: 397Cholesterol Biosynthesis Pathway substantially active only in liver c
19、ellsAll carbon atoms arise from acetyl-CoASqualene, C30 linear hydrocarbon, is an intermediateSqualene is formed from 5 carbon units (isoprene)All 27 carbons in cholesterol can be traced to a two-carbon precursor - acetateThe carbon origins of cholesterol as revealed byradioisotope labeling studiesT
20、he brief biosynthesis pathway and fates of cholesterolBiosynthesis of cholesterol:1. Stage I is the synthesis of isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol.2. Stage II is the condensation of six molecules of isopentenyl pyrophosphate to form s
21、qualene.3. In stage III, squalene cyclizes in an astounding reaction and the tetracyclic product is subsequently converted into cholesterol. The brief biosynthesis pathway of cholesterol1. Formation of mevalonateThe committing step for cholesterol biosynthesis甲羥戊酸甲羥戊酸2. Mevalonate to squalene3. Squa
22、lene to cholesterolBiosynthesis of cholesterolLynen FeodorKonrad BlochMichael Brown Joseph GoldsteinJohn CornforthGeorge PopjkRegulation of HMG-CoA Reductase as rate-limiting step, it is the principal site of regulation in cholesterol synthesis1.Phosphorylation by cAMP dependent kinase inactivates H
23、MG-CoA reductase2. Half-life of HMG-CoA reductase is 3 hours and depends on cholesterol level3. Gene expression (mRNA production) is controlled by cholesterol levelsSynthesis of cholesterol is regulated to complement dietary intake (maintaining a cholesterol homeostasis)HMG-CoA reductase along with
24、other genes encoding enzymes involved in cholesterol synthesis is controlled by a family of SREBPs (sterol regulatory element-bindingproteins) SREBP activationSCAP: SREBP cleavage-activating proteinsterolsterolStatins (他汀類藥物) as Inhibitors of HMG-CoA reductaseThe mevalonate analogsare used to treath
25、ypercholesterolemiapatients Development of Statin + HSCoAH2CCCH3HOCH2COOCSCoAOH2CCCH3HOCH2COOH2COH2NADP+2NADPHHMG-CoA mevalonate HMG-CoA Reductase 5-pyrophosphomevalonateisopentenyl pyrophosphategeranyl pyrophosphatefarnesyl pyrophosphatesqualene 2,3-oxidosqualene HOHOlanosterol cholesterol 19 steps
26、 In 1976, Akira Endo, incorporation of 14Cacetate into nonsaponifiable lipids,searched for inhibitors among thousands of fungi culture broths. the 2008 Albert LaskerDeBakey Clinical Medical Research AwardThe scientists who developed StatinsLipids are transportedas various lipoprotein particles in ve
27、rtebrateplasmaAn LDL particleLipoproteins were classified according to the relative amounts of lipid and protein in the complex (the more protein and less lipid the denser the complex).Chylomicrons (synthesized in the intestine): transport mostly triacylglycerols from intestine to other tissues;VLDL
28、(synthesized in liver): released into bloodstream, it is converted to IDL and LDL by lipases;LDL (from VLDL or synthesized in liver, bad cholesterol): major circulatory complex for transport of cholesterol and cholesterol esters from liver to other tissues;HDL (synthesized in liver, good cholesterol
29、): newly formed HDL contain no cholesterol esters, and it functions to return cholesterol and its esters to the liver. Receptor-mediated endocytosis of LDL (A) Electron micrograph showing LDL (conjugated to ferritin for visualization, dark spots) bound to a coated-pit region on the surface of a cult
30、ured human fibroblast cell. (B) Micrograph showing this region invaginating and fusing to form an endocytic vesicle From R. G. W. Anderson, M. S. Brown, and J. L. Goldstein. Cell 10 (1977): 351.Endocytosis of LDL Bound to Its Receptor1.Apolipoprotein B-100 on the surface of an LDL particle binds to
31、LDL receptor on the plasma membrane of nonhepatic cells. The LDL receptor are localized in coated pits, which contain a specialized protein called clathrin.2.The receptor-LDL complex is internalized by endocytosis which brings the complex into endosome. Endosomes fuse with lysosome, releasing choles
32、terol and fatty acid. The protein component of the LDL particle is hydrolyzed to free amino acids, but the LDL receptor is recycled back to the plasma membrane.3.The released unesterified cholesterol can then be used for membrane biosynthesis. Alternatively, it can be reesterified (acyl CoA:choleste
33、rol acyltransferase) for storage inside the cell. Human LDL receptorThere are different defects in LDL receptor that lead to the same overall phenotype:1. LDL receptor not made2. LDL receptor unable to bind LDL (mutations in N-terminal region)3. Mutations in C-terminal region, which prevents the for
34、mation of LDL-receptor complex.atherosclerotic plaquesDefective LDL receptors results in the genetic disease familial hypercholesterolemia, characterized by the inability of cells to take up cholesterol. The excess blood cholesterol accumulates and contributes to the formation of atherosclerotic pla
35、ques. Heart failure from atherosclerosis is the leading cause of death in industrialized countries. Family hypercholesterolemia(Homozygous 1:1000000； Heterozygous: 1:500) Biosynthesis of steroid hormonesOverview of isoprenoid biosynthesislPhosphatidic acid (diacylglycerol 3- phosphate) is the common
36、 precursor of both triacylglycerol and glycerophospholipids.lGlycerophospholipids are made using two alternative strategies of CDP modification.lThe backbone of sphingolipids are made from palmitoyl-CoA and SerinelRadioisotope tracer experiments revealed that all the 27 carbons of cholesterol are fr
37、om acetyl- CoA.SummarylThe biosynthesis of cholesterol takes a long pathway, with the reaction catalyzed by HMG-CoA reductase 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.
生物化學(xué)：Chapter 21 Lipid Biosynthesis II
