生物化学课件：ch8膜脂类固醇和血浆脂蛋白的代谢

1、Chapter 8 Metabolism of membranelipids, steroids and plasma lipoproteins 膜脂、类固醇和血浆脂蛋白的代谢 （脂类代谢）,8.1 甘油磷脂和鞘脂的分解代谢 8.2 甘油磷脂和鞘脂的合成代谢 8.3 胆固醇的代谢 8.4 血浆脂蛋白的代谢,8.1 甘油磷脂和鞘脂的分解代谢 部位：溶酶体 甘油磷脂由特异性磷脂酶（Phospholipase A1、Phospholipase A2、Phospholipase C、Phospholipase D）水解。 溶血磷脂指水解去掉一个脂肪酸的甘油磷脂,即Phospholipase A1、Ph

2、ospholipase A2水解的产物。,磷脂酶的特异性水解,鞘脂的降解是由溶酶体中一套特异性的酶按一定步骤分解极性头部基团，最后生成神经酰胺。 由于一些水解酶基因变异失去活性，鞘脂降解出现障碍导致鞘脂沉积在溶酶体中。这种遗传性脂类沉积症统称溶酶体病。,8.2 甘油磷脂和鞘脂的合成代谢 8.2.1 甘油磷脂的合成代谢 合成部位在光面内质网或线粒体内膜。 合成以磷脂酸为合成前体。 合成有CDP-甘油二酯和CDP-极性头部基团两种策略。 首先，甘油二酯的-OH ( CDP-甘油二酯策略 )或极性头部基团的-OH ( CDP-极性头部基团策略 ) ，通过与胞嘧啶核苷酸相连而激活。 然后，由相应的另外

3、一个-OH 基团通过亲核反应替换CMP ，从而合成甘油磷脂。,Low activity in adipose tissue,Phosphatidic acid is derived from L-glycerol 3- phosphate and two acyl-CoAs.,Often unsaturated,Often saturated,Phosphatidic acid is the common precursor for both triacylglycerols and glycerophospholipids.,How to synthesize glycerophosphol

4、ipids?,CDP-甘油二酯和CDP-极性头部基团两种策略,Bacteria mainly use this strategy,Eukaryotic cells use both strategies,原核细胞主要用CDP-甘油二酯策略合成甘油磷脂。 真核细胞两种策略都用。通常，酸性(阴离子)甘油磷脂，包括磷脂酰甘油、心磷脂、磷脂酰肌醇用CDP-甘油二酯途径合成。,原核细胞用CDP-甘油二酯途径合成甘油磷脂,真核细胞用CDP-甘油二酯途径合成磷脂酰甘油、心磷脂、磷脂酰肌醇,酵母和哺乳动物合成磷脂酰丝氨酸（PS）、磷脂乙醇胺（PE）、磷脂酰胆碱（PC）的途径不同。 酵母通过CDP-甘油二酯途径

5、合成PS，PS通过脱羧或基团交换反应合成PE，PE通过S-腺苷Met ( S-adenosylmethionine, adoMet)甲基化合成PC 。 哺乳动物用CDP-极性基团途径合成PE和PC。PE通过基团交换反应合成PS。PE通过甲基化合成PC 只在肝脏中发生。,酵母从磷脂酰丝氨酸合成磷脂酰乙醇胺和磷脂酰胆碱,CDP-甘油二酯途径合成磷脂酰丝氨酸,哺乳动物CDP-极性基团途径合成PC和PE,Ethanolamine,Phosphoethanolamine,CDP-ethanolamine,Phosphatidylthanolamine,Summary of the synthesis o

6、f PE, PC, PS,呼吸窘迫综合症（Respiratory distress syndrome）是由于二软脂酰磷脂酰胆碱合成障碍引起的一种病理性症状。在健康人中，二软脂酰磷脂酰胆碱和其他一些磷脂以及一些特异性蛋白质存在于肺泡周围的细胞外液中，在呼气时起到减少液体表面张力防止肺塌陷的作用。早产婴儿由于肺没有发育成熟，没有合成足够的二软脂酰磷脂酰胆碱导致发生呼吸窘迫综合症。,8.2.2 醚脂的合成代谢 醚脂如plasmalogens（缩醛磷脂）和 platelet-activating factor（PAF，血小板活化因子）的合成涉及一个脂肪醇基替代脂酰基（形成醚键）的反应。,Ether l

7、ipids,Synthesis of the ether lipids,8.2.3 鞘脂的合成代谢 合成部位在光面内质网或线粒体内膜。 鞘脂的鞘氨醇骨架来源于软脂酰CoA和Ser。,合成过程: Palmitoyl-CoA condenses with serine (PLP is needed for decarboxylate serine) to form b-ketosphinganine, which is then reduced to sphinganine (二氢鞘氨醇). Sphinganine is then acylated and desaturated to form

8、ceramide (containing sphingosine). Addition of sugar(s) or phosphocholine heads leads to the synthesis of cerebroside, gangliosides, or sphingomyelin.,二氢鞘氨醇,Spingolipid synthesis begins with the condensation between palmitoyl-CoA and Ser.,神经酰胺,(not CDP-choline!),鞘脂的来源? 鞘脂的进化除了赋予脂类结构的多样性，更重要的一点是功能的多样

9、性。研究发现，鞘脂具有第二信使的功能。如神经酰胺可启动一些细胞的程序性死亡过程。,8.3 胆固醇的代谢 8.3.1 胆固醇的合成代谢 8.3.1.1 概述 合成主要在肝脏，少量在肠。脑细胞、红细胞不能合成。合成部位在胞液和内质网。 胆固醇全部27个C来源于乙酰CoA，这是用同位素标记实验研究的结果(1940s) 。 The biosynthetic pathway of cholesterol, being the most complex known, was elucidated mainly by Konrad Bloch and Feodor Lynen in the 1950s.,“

10、Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes has been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists

11、from the most diverse areas of science and medicine” -Michael Brown and Joseph Goldstein Nobel lectures(1985),The carbon origins of cholesterol as revealed by radioisotope labeling studies.,8.3.1.2 胆固醇的合成过程 胆固醇的生物合成过程可以分为4个阶段: Stage I: 3个acetyl-CoA缩合还原生成 1个6C的 mevalonate (甲羟戊酸) 。 Stage II: mevalonat

12、e 转变为活化的 5C isoprene units (异戊二烯单位) 。 Stage III: 6个 isoprene units 缩合生成线性的30C squalene(鲨烯) 。 Stage IV: Squalene 环化生成1个四环结构, 通过一系列复杂的反应最后转变为27C的胆固醇。,甲羟戊酸，MVA,异戊二烯,鲨烯,Reactions assembling cholesterol from 18 molecules of acetyl-CoA can be divided into four stages.,(6C),(5C),(30C),(27C),(2C),由乙酰CoA合成甲羟

13、戊酸。 One 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. HMG-CoA reductase (an integrated membrane protein in the smooth ER) catalyzes the irreversible reductio

14、n of HMG-CoA to form mevalonate: the committing step of cholesterol synthesis (thus being a major regulation). HMG-CoA还原酶催化的是限速步骤。,羟甲基戊二酸单酰CoA,One mevalonate is synthesized from three acetyl-CoA molecules.,The committing step,HMG-CoA reductase in cytosol,Acetyl-CoA + acetoacetate,HMG-CoA lyase in mi

15、tochondria,甲羟戊酸通过三步磷酸化反应合成两个活化的异戊二烯单位。 Three phosphate groups are transferred from three ATP molecules to mevalonate to form 3-phospho-5-pyrophosphomevalonate. The leaving of both the carboxyl and the 3-phosphate groups leads to the formation of 3-isopentenyl pyrophosphate. 3-Isopentenyl pyrophospha

16、te is isomerized to form the second activated isoprene: dimethylallyl pyrophosphate.,3-异戊烯焦磷酸酯, IPP,二甲基丙烯焦磷酸酯, DPP,Two activated isoprenes are formed from mavelonate.,6个活化的异戊二烯单位合成30C的线性角鲨烯。 A dimethylallylpyrophosphate is joined to an isopentenylpyrophosphate (head-to-tail) to form the 10-carbon ge

17、ranyl pyrophosphate (牻牛儿焦磷酸酯). A geranyl pyrophosphate is joined to another 3-isopentenyl pyrophosphate (head-to-tail) to form the 15-carbon farnesyl pyrophosphate(法尼基焦磷酸). Two farnesyl pyrophosphate join (head-to-head) to form the 30-carbon squalene.,异戊二烯基转移酶,牻牛儿焦磷酸酯,法尼基焦磷酸,Squalene is formed from

18、the condensation of two farnesyl pyrophosphates.,由角鲨烯合成胆固醇 Squalene 2,3-epoxide, is first formed in a reaction catalyzed by squalene monooxygenase using O2 and NADPH. Concerted movement of electrons through four double bonds and the migration of two methyl groups generates lanosterol (羊毛固醇). Lanoste

19、rol is converted to cholesterol via about 20 enzymatic reactions including many double bond reduction and demethylations., 20 reactions,Oxygenation induced ring closing converts the linear squalene to lanosterol of four rings, which is converted to cholesterol after going through another 20 or so re

20、actions!,8.3.2 胆固醇酯的合成 由脂酰CoA-胆固醇脂酰转移酶(Acyl-CoA-Cholesteryl acyl transferase, ACAT)催化。 胆固醇酯在肝内合成，贮存于肝脏或以脂蛋白形式运送到其他组织。,Acyl-CoA-Cholesteryl acyl transferase (ACAT) catalyzes the addition of an acyl group to the hydroxyl group of cholesterol.,8.3.3 胆固醇的转化 转化为胆汁酸 Cholesterol can be converted to bile ac

21、ids (salts) ： glycocholate (甘胆酸盐) and taurocholate (牛黄胆酸盐).,牛黄胆酸,转化为类固醇激素 The 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): the common precursor of all steroid hormones. Progesterone (

22、孕酮) is synthesized from pregnenolone by oxidizing the 3-OH group and the isomerization of the double bond (from 5 to 4 position).,( 续 ) Cortisol (a major glucocorticoid) is synthesized from progesterone by hydroxylation at C-17, C-21, and C-11. Aldosterone (a mineralocorticoid) is synthesized from p

23、rogesterone by hydroxylation at C-21, C-11, and oxidation of C-18 to an aldehyde. Testosterone (an androgen, or male hormone) is synthesized from progesterone by the removal of 2-carbon unit and hydroxylation at C-17. Estradiol ( an estrogen, or female hormone) is synthesized from testosterone by th

24、e removal of C-19 and formation of the aromatic A ring.,孕烯醇酮,孕酮,糖皮质激素,雄性激素,雌性激素,盐皮质激素,碳链裂解酶,Prognenolone, the common precursor of steroid hormones, is synthesized from Cholesterol.,孕烯醇酮,cytochrome P450 monooxygenases,Progesterone is synthesized from pregnenolone by oxidizing the 3-OH group and the i

25、somerization of the double bond from 5 to 4 position,Cortisol and aldosterone are synthesized from progesterone by several oxygenation reactions (forming hydroxyl and aldehyde groups).,Testosterone is synthesized from progesterone by the removal of a 2-carbon unit and hydroxylation at C-17,Estradiol

26、 is synthesizedfrom testosterone by the removal of C-19 and formation of the aromatic A ring,转化为7-脱氢胆固醇 7-脱氢胆固醇是VitD的前体。VitD可以调节小肠钙的吸收以及肾和骨钙的水平。,VitD and rickets（佝偻病）,8.3.4 活化异戊二烯是一大类物质类异戊二烯的合成前体。 These include many pigments (carotenoids, phytol chain of chlorophylls), fragrant principles, vitamines

27、 (A, D, E, K), rubber, dolichols, quinones (ubiquinone, plastoquinone), juvenile hormones of insects. Prenylation of proteins (attaching of geranylgeranyl and farnesyl groups) leads to membrane association.,Some plant pigments are isoprenoids.,Some fragrant molecules are isoprenoids. (called terpene

28、s),Natural rubber is cis-polyisoprene.,lipid-anchored proteins脂錨定蛋白,Prenylation of proteins (attaching of geranylgeranyl and farnesyl groups) leads to membrane association.,Isoprenoid tails function to anchor proteins to membranes,8.3.5 胆固醇代谢的调节 胆固醇代谢主要受细胞内胆固醇水平和激素两方面的调节。细胞内胆固醇水平指的是内源胆固醇和外源胆固醇的总和，因此

29、胆固醇代谢调节的特点是生物合成途径和食物摄取的平衡。 HMG-CoA还原酶，催化胆固醇合成的限速步骤，其活性变化可达100倍。其调节包括: 一个固醇类分子促进HMG-CoA还原酶的酶原降解以及抑制HMG-CoA还原酶基因和LDL 受体基因的转录。 激素 (insulin and glucagon)通过可逆的磷酸化/去磷酸化调节限速酶的活性。,The de novo synthesis of cholesterol is regulated to complement the dietary uptake.,(For storage),8.4 血浆脂蛋白(plasma lipoprotein)的

30、代谢 8.4.1 血浆脂蛋白的一些概念 血脂：血浆所含的脂类。包括TG、CH、CHE、PL、FFA等。 来源：外源性脂类（食物摄取） 内源性脂类（体内合成） 血脂含量不如血糖恒定，受膳食、年龄、性别、职业以及代谢等的影响，波动范围较大。,血浆脂蛋白：是脂类在血浆中的运输形式。以疏水性脂类为核心围绕着极性脂类和载脂蛋白组成。 不同的脂蛋白脂类和载脂蛋白的种类和数量不同。大小和密度也不同，可通过超速离心分离。一般分为四种： 乳糜微粒chylomicrons, 极低密度脂蛋白VLDL (very low density lipoproteins),低密度脂蛋白LDL(Low density lipo

31、proteins),高密度脂蛋白HDL (high density lipoproteins) 。,LDL的结构,血浆脂蛋白的电镜图,载脂蛋白（apolipoproteins）：脂蛋白中的蛋白质部分。 At least 18 apolipoproteins (named as apo A, B, C, D, E) have been revealed in human, which act as signals to target the lipoprotein particles to various tissues or activating enzymes that will act o

32、n the lipoproteins. （靶向功能和酶激活功能）,8.4.2 血浆脂蛋白的代谢 CM：把外源性TG从小肠运输到各种组织。 CM的 apoC-II激活肌肉或脂肪组织毛细血管中的脂蛋白脂肪酶，向这些组织释放出游离的脂肪酸。 CM的残余颗粒（含CHE）通过血液循环运到肝脏细胞进行代谢。,VLDL：把内源性TG从肝脏运输到其他组织。 VLDL的 apoC-II激活肌肉或脂肪组织中的脂蛋白脂肪酶， 向这些组织释放出游离的脂肪酸。 剩余的VLDL残粒一部分通过受体介导的内吞作用进入肝细胞代谢，另一部分形成LDL 。,脂蛋白脂肪酶,Lipids are transported as vari

33、ous lipoprotein particles in vertebrate plasma,LDL,HDL,VLDL,CM,LDL：主要把内源性CH运输到肝外组织。 这是LDL 受体介导的内吞作用。识别LDL 受体的是LDL 上的apoB-100 蛋白。 血浆中LDL与细胞膜上LDL 受体结合后引起了一系列的代谢过程，称为LDL受体代谢途径。,LDL受体代谢途径,LDL,细胞膜,LDL受体合成,ACAT,HMG CoA还原酶,游离CH,溶酶体水解,内吞,与LDL受体结合,LDL receptors are recycled to the cell surfaces,HDL：逆向运输CH，清除

34、血中CH。 HDL的前体来源于肝细胞或小肠细胞，从肝外组织收集CH，然后转化为CHE向肝细胞运输。 胆固醇的逆向运输途径（reverse cholestrol transport pathway）：指胆固醇从肝外组织向肝运输的过程。是机体将外周组织中衰老细胞膜中的胆固醇运输到肝代谢并排出体外的途径。,LCAT位于nascent HDL 的表面。通过LCAT合成CHE，使disk-shaped nascent HDLs 转变为spherical mature HDLs。,8.4.3 血浆脂蛋白的代谢异常 高脂血症：指血脂高于正常人上限。亦称高脂蛋白血症。 成人空腹1214小时血中的TG2.26m

35、mol/L，CH6.21mmol/L 儿童 CH4.14mmol/L,动脉粥样硬化症（atherosclerosis） 动脉粥样硬化症与血清中的CH水平过高相关。引起高血脂症的遗传因素主要有两种： LDL受体基因突变使得LDL的CH不能进入细胞，血液中CH水平升高，而另一方面， 细胞内CH合成继续进行，从而引起胆固醇摄取和合成代谢紊乱，造成家族性高胆固醇血症（familial hypercholesterolemia）和动脉粥样硬化症。 Mevalonate analogs (e.g., compactin密实菌素 and lovastatin洛伐他订) can be used to treat patients with familial hypercholesterolemia.,The mevalonate analogs are used to treat hypercholesterolemia patients.,某些载脂蛋白基因突变引起HDL水平下降。 A negative correlation between blood HDL level and art