Lehninger Principles of Biochemistry 5/e

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1 David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 21 Lipid Biosynthesis Biosynthesis of TG, phospholipid, cholesterol, PGs & LTs? 2008 W. H. Freeman and Company

3 Lipid Biosynthesis Lipid 의역할 1 저장 E 2 세포막의구성성분 3 색소, 보조인자 (Vit.E), 계면활성제 (bile acid), carrier(dolichol), Vt.D 유도체, 성 Hormone 세포내 / 외 messenger (Eicosanoid/phosphatidyl inositol 유도체 ) 막단백 anchor( 닻 ) 지방질의생합성반응 E 투입 (ATP), NADPH( 전자운반체 )

4 Fatty acid 의생합성 Malonyl-CoA 의 active form : 간, 뇌, 신장, 유선, 지방조직의 cytosol 1) Malonyl-CoA 의합성 O O C-CH 2 -C - O S-CoA (1) Acetyl-CoA carboxylase 1 Biotin carrier protein 2 Biotin carboxylase: ATP-dependent 반응 CO 2 를 biotin 에부착시켜 CO 2 를활성화 3 Transcarboxylase: 활성화된 CO 2 를 acetyl-coa 에전하여 malonyl-coa 생성 (2) Malonyl-CoA 합성 Biotin carrier protein ATP ADP+P i O acetyl-coa + HCO - 3 biotin N C O - malonyl-coa transcarboxylase carboxylase 일시적 CO 2 운반체

5 2) Lipid 생성효소 (1) Fatty acid synthase complex β-ketoacyl-acp synthase (KS), malonyl/acetyl-coa ACP transferase (MAT), β-hydroxyacyl-acp dehydratase (DH), enoyl-acp reductase (ER), and β-ketoacyl-acp reductase (KR). ACP is the acyl carrier protein, thioesterase(te) COO - 1 ACP thioester 결합된 acyl 기운반 CO 2 2 TE 합성된 acyl 기유리 최초의 acyl 기 β-ketoacyl -ACP 생성효소 (KS) CH 3 C=O S CH 2 C=O S Malonyl gr Acyl Carrier Protein (ACP) 3 KS 4 MAT 5 KR 6 DH Acyl 기와 malonyl 기축합 Malonyl, acetyl 기전달 β-keto 기 β-hydroxyl 기 β-hydroxyacyl-acp 의 H 2 O 제거 생성 7 ER = 환원, 포화 acyl-acp 생성 (2) 역할 Acetyl 기와 malonyl 기를받아들여지방산사슬을늘리기위한축합반응을준비

7 FIGURE 21-1 The acetyl-coa carboxylase reaction.

8 FIGURE 21-2 Addition of two carbons to a growing fatty acyl chain: a four-step sequence.

9 porcine fungus FIGURE 21-3 The structure of fatty acid synthase type I systems. β-ketoacyl-acp synthase (KS), malonyl/acetyl-coa ACP transferase (MAT), β-hydroxyacyl-acp dehydratase (DH), enoyl-acp reductase (ER), and β-ketoacyl-acp reductase (KR). ACP is the acyl carrier protein, thioesterase(te)

10 FIGURE 21-4 The overall process of palmitate synthesis.

11 FIGURE 21-5 Acyl carrier protein (ACP).

12 FIGURE 21-6 Sequence of events during synthesis of a fatty acid.

13 FIGURE 21-6 (part 1) Sequence of events during synthesis of a fatty acid.

14 FIGURE 21-6 (part 2) Sequence of events during synthesis of a fatty acid.

15 FIGURE 21-6 (part 3) Sequence of events during synthesis of a fatty acid.

16 FIGURE 21-6 (part 4) Sequence of events during synthesis of a fatty acid.

17 FIGURE 21-6 (part 5) Sequence of events during synthesis of a fatty acid.

18 FIGURE 21-6 (part 6) Sequence of events during synthesis of a fatty acid.

19 FIGURE 21-6 (part 7) Sequence of events during synthesis of a fatty acid.

20 FIGURE 21-6 (part 8) Sequence of events during synthesis of a fatty acid.

21 FIGURE 21-7 Beginning of the second round of the fatty acid synthesis cycle.

22 FIGURE 21-8 Subcellular localization of lipid metabolism.

23 (c)isocitrate dehydrogenase FIGURE 21-9 Production of NADPH.

24 FIGURE Shuttle for transfer of acetyl groups from mitochondria to the cytosol.

25 FIGURE Regulation of fatty acid synthesis.

26 FIGURE Routes of synthesis of other fatty acids.

27 FIGURE Electron transfer in the desaturation of fatty acids in vertebrates.

28 3) 다양한지방산생합성의조절 (1) Palmitate 를전구체로하는생합성 ( unsaturation, elongation) arachidonate palmitoleic acid 16:1( 9 ) eicosatriene Palmitate 16 : 0 (2) 조절 stearate 18:0 길어진포화지방산 oleic acid 18:1( 9 ) linoleic acid 18:2( 9,12 ) γ-linoleic acid α-linoleic acid EPA citrate 분해효소 +insulin Acetyl-CoA carboxylase Citrate acetyl-coa malonyl-coa palmitoyl-coa -glucagon, epinephrine +citrate -palmitoyl-coa

29 FIGURE Action of plant desaturases.

30 (3) Eicosanoid 합성 1 Eicosanoid: Paracrine hormone으로 arachidonate에서유래되었으며, PG / TX / Leukotriene 3종류가존재한다 2 합성과정 Arachidonate 20:4( 5,8,11,14 ) COX의 COX의 cyclooxygenase peroxidase PGG 2 PGH 2 -aspirin,iboprofen 다른 PGs : 동통유발, 염증물질 Thromboxane : 혈관수축, 혈소판응집 2O 2 3 aspirin: COX의 ser잔기를 acetylation시켜비가역적으로불활성화시킴 cf) 50~80mg 복용 : 혈중 TX만억제 / 500mg 복용 : 동통억제 iboprofen: 경쟁적억제제 심장마비, 뇌졸중

31 FIGURE 21-15a The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.

32 FIGURE 21-15b The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.

33 COX-2 specific cyclooxygenase inhibitors FIGURE 21-15c The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.

34 FIGURE The "linear" pathway from arachidonate to leukotrienes.

35 Lipoxygenase, LTs, lipoxin, and resolvins

36 Pro-resolution products of Lipoxygenase Nature Immunology 6, (2005)

37 FIGURE Biosynthesis of phosphatidic acid.

38 TG 의생합성 지방산의운명 ( 저장형태 ) 1 성장이왕성 ( 새로운막형성필요 ) : 인산지방질로들어감 2 저장지방질 ( 충분한음식물공급 or 성장활발 ) : TG 1) TG: 저장된영양분의가장높은 E 량 (~38kJ/g 이상 ) glycogen 으로저장할수있는양이상의당질을섭취할때 TG 로지방조직에저장 Glucose 2) Insulin 에의한조절 Dihydroxyacetone NADH + H + NAD + Acyl transferase Glycerophospholipid glycerol L-glycerol 3-phosphate Phosphatidate TG ATP ADP ketone body 1 식이성당질 glucose ( 당질의 TG의변환을촉진시킴 ) +insulin Acetyl-CoA 식이성단백질 a.a +insulin 지방산 TG 2 당뇨병환자 : Insulin 의분비, 작용에결함 glucose 를잘이용, 당질 a.a 로부터지방산형성 지방산의산화, ketone body 체중

39 FIGURE Phosphatidic acid in lipid biosynthesis.

40 FIGURE Regulation of triacylglycerol synthesis by insulin.

41 FIGURE The triacylglycerol cycle.

42 FIGURE Glyceroneogenesis.

44 FIGURE 21-22a Regulation of glyceroneogenesis.

45 FIGURE Regulation of glyceroneogenesis.

47 Phospholipid 의생합성 FIGURE Head-group attachment.

48 원핵세포 진핵세포 FIGURE Two general strategies for forming the phosphodiester bond of

49 FIGURE Origin of the polar head groups of phospholipids in E. coli.

50 FIGURE Synthesis of cardiolipin and phosphatidylinositol in eukaryotes.

51 FIGURE The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes.

52 FIGURE 21-28a Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals.

53 FIGURE 21-28b Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals.

54 FIGURE Summary of the pathways for synthesis of major phospholipids.

55 FIGURE Synthesis of ether lipids and plasmalogens.

56 FIGURE (part 1) Synthesis of ether lipids and plasmalogens.

57 FIGURE (part 2) Synthesis of ether lipids and plasmalogens.

58 FIGURE Biosynthesis of sphingolipids.

59 FIGURE (part 1) Biosynthesis of sphingolipids.

60 FIGURE (part 2) Biosynthesis of sphingolipids.

61 Cholesterol, steroid, isoprenoids 의생합성 1) Cholesterol 1 모든조직에서 acetyl CoA Cholesterol 2 난황, 게, 새우, 육류에많다 3 기능 : 세포막구성성분, 담즙산의전구체, steroid H. 전구체, vit.d 의전구체 2) Cholesterol 합성 1 acetate 로부터 mevalonate 합성 CoA-SH thiolase CH 3 C O S-CoA HMG-CoA synthase CoA-SH 2NADP + 2NADPH +2H + CoA-SH acetyl CoA acetoacetyl CoA HMG-CoA mevalonate 2 mevalonate 로부터활성형 isoprene 으로의전환 3 squalene 합성 (mevalonate 6, acetyl-coa 18) (acetyl CoA 3) -Statin, Mevastatin, Lovastatin +insulin -glucagon mevalonic acid( 전구체 ): demethylallyl pyrophosphate, 4 cholesterol 합성 HMG-CoA reductase 3 -isopentenyl pyrophospate

62 3) Cholesterol 의운명 1 담즙중의 cholesterol 2 cholesterol ester: Chol ACAT C.E. (ACAT: Acyl-CoA-cholesterol acyl transferase) 4) 지방질의운반 Lipoprotein 1 Chylomicron: TG( 90%) 다량함유, 식이성 TG 운반 ( 장 조직 ) 2 VLDL: 내인성 TG 운반, 간에서 TG를내놓을때의형태 3 HDL: 간외조직의유리 cholesterol을 C.E. 로간에운반 동맥경화억제 LCAT (Lecithin-cholesterol acyl transferase) 4 LDL: VLDL의최종대사형태, 말초조직에 cholesterol운반, chol 함량높다 동맥경화의원인 5) Cholesterol 이세포내로들어가는기전

64 FIGURE Origin of the carbon atoms of cholesterol.

65 FIGURE Summary of cholesterol biosynthesis.

66 FIGURE Formation of mevalonate from acetyl-coa.

67 FIGURE (part 1) Formation of mevalonate from acetyl-coa.

68 FIGURE (part 2) Formation of mevalonate from acetyl-coa.

69 FIGURE Conversion of mevalonate to activated isoprene units.

70 FIGURE Formation of squalene.

71 FIGURE Ring closure converts linear squalene to the condensed steroid nucleus.

72 FIGURE Synthesis of cholesteryl esters.

73 TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties

74 FIGURE Lipoproteins.

75 FIGURE 21-39b Lipoproteins.

76 TABLE 21-2 Apolipoproteins of the Human Plasma Lipoproteins

77 FIGURE 21-40a Lipoproteins and lipid transport.

78 FIGURE Lipoproteins and lipid transport.

79 FIGURE Reaction catalyzed by lecithin-cholesterol acyl transferase (LCAT).

80 FIGURE Uptake of cholesterol by receptor-mediated endocytosis.

87 FIGURE SREBP activation.

88 6) Cholesterol 생합성의조절 Acetyl-CoA β-hydroxyβ-methylglutayl-coa (HMG-CoA) HMG-CoA reductase -sterol -glucagon +insulin Mevalonate LDL-chol. ( 수용체를통한 Endocytosis) Chol. ACAT + 고농도의 chol. Chol.ester ( 저장 ) HMG-CoA reductase 조절 1 sterol: 효소의억제 유전자의전사억제 (SREBP2 에의한 ) 2 glucagon: 효소의인산화촉진 불활성화 3 insulin: 탈인산화촉진 활성화 4 Lovastatin, compactin, etc : mevalonate 와구조적유사 HMG-CoA 의경쟁적억제제

89 7)Cholesterol 의운명 (1) Steroid hormone 생성 a) Mineralocorticoid aldosterone ( 신장에서 Na +, Cl - 재흡수조절 ) b) Glucocorticoid: 글루코스신생합성조절, 염증반응억제 c) Testosterone estradiol ( 성H.) 5α-reductase dihydro-testosterone androgen R. 에친화력높음 탈모 dihydro-testosterone 합성의 inhibitor 대머리치료제, 전립선비대억제 (2) Isoprenoids 생성 Vit A, E, K/ carotenoid, chloropyll( 식물색소 )/ 천연고무 / lemon 기름, eucalyptus 기름, 사향의방향성분 / 곤충변태 hormone/ dolicol, ubiquinone, plastoquinone (3) Bile acid 생성

90 FIGURE Regulation of cholesterol formation balances synthesis with dietary uptake.

91 BOX 21-3 FIGURE 1 Statins as inhibitors of HMG-CoA reductase.

92 FIGURE Some steroid hormones derived from cholesterol.

94 FIGURE Side-chain cleavage in the synthesis of steroid hormones.

95 FIGURE Overview of isoprenoid biosynthesis.

Overview of metaboilsm 단백질합성 Glycogenesis Glycogenolysis S70S6K mtor Glu Insulin Glucagon Epinephrine F-1,6-bisphosphatase Phosphofructokinase Glut4 IR IRS GProtein F-6-P Glu

98 Overview of metaboilsm 단백질합성 Glycogenesis Glycogenolysis S70S6K mtor Glu Insulin Glucagon Epinephrine F-1,6-bisphosphatase Phosphofructokinase Glut4 IR IRS GProtein F-6-P Glu PI 3 K GSK3β Akt Phosphoenolpyruvate kinase((pepck) FOXO1,HNF-4 GS SREBP-1,2 Glycogen 합성 camp PKA PGC1 α PPAR α/β Pyr dehydrogenase Chol synthesis HMG-CoA reductase Cholesterol

99 Blood Cell Glu Glut4 FFA FATP gluconeogenesis Pyr glycolysis FFA ACS Acyl CoA CPTⅠ Chol Mt Ketone body Pyr Pyr dehydrogenase CPTⅡ FA synthesis HMG-CoA Acetyl CoA β-oxidation Chol synthesis Chol TCA cycle Acetyl CoA ATP

100 Fasting Diet Glucagon Insulin camp IRS S6protein PKA PI 3 K S70S6K CREB AMPK Akt mtor PGC-1α GSK3β CBP/p300 SREBP-1,2 FOXO1, HNF-4 PPARα, β(δ) Glycogen 합성 FA 합성 Chol 합성 gluconeogenesis β -oxidation

101

102

103 insulin

Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 17 Fatty Acid Catabolism 2008 W. H. Freeman and Company Chap. 17. Fatty acid oxidation 지방산의소화, 동원그리고운반 1. 식이성지방