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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顺序分解极性头部基团，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，由相应的另外一个
3、-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 glycerophospholip
4、ids?,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,CDP-甘油二酯,PS,PG,PE,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）的途径有不
5、同之处。 酵母通过CDP-甘油二酯途径合成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和PC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,哺乳动物
6、合成PC和PS,只在肝脏发生,Choline,Summary of the synthesis of PE, PC, PS,Serine,Choline,新生儿呼吸窘迫综合症（Respiratory distress syndrome）是由于二软脂酰磷脂酰胆碱( Dipalmitoyllecithin )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pla
7、smalogens（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 lipids,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
8、then reduced to sphinganine (二氢鞘氨醇). Sphinganine is then acylated and desaturated to form 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 be
9、tween 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
10、most complex known, was elucidated mainly by Konrad Bloch and Feodor Lynen in the 1950s.,“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
11、gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists 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.,1912 - 2000,8.3.1.2
12、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: mevalonate 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
13、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. H
14、MG-CoA reductase (an integrated membrane protein in the smooth ER) catalyzes the irreversible reduction 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 mol
15、ecules.,The committing step,HMG-CoA reductase in cytosol,Acetyl-CoA + acetoacetate,HMG-CoA lyase in mitochondria,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 t
16、he 3-phosphate groups leads to the formation of 3-isopentenyl pyrophosphate. 3-Isopentenyl pyrophosphate 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 geranyl pyrophosphate (牻牛儿焦磷酸酯). A geranyl pyrophosp
