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
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 )
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
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
FIGURE 21-1 The acetyl-coa carboxylase reaction.
FIGURE 21-2 Addition of two carbons to a growing fatty acyl chain: a four-step sequence.
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)
FIGURE 21-4 The overall process of palmitate synthesis.
FIGURE 21-5 Acyl carrier protein (ACP).
FIGURE 21-6 Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 1) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 2) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 3) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 4) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 5) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 6) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 7) Sequence of events during synthesis of a fatty acid.
FIGURE 21-6 (part 8) Sequence of events during synthesis of a fatty acid.
FIGURE 21-7 Beginning of the second round of the fatty acid synthesis cycle.
FIGURE 21-8 Subcellular localization of lipid metabolism.
(c)isocitrate dehydrogenase FIGURE 21-9 Production of NADPH.
FIGURE 21-10 Shuttle for transfer of acetyl groups from mitochondria to the cytosol.
FIGURE 21-11 Regulation of fatty acid synthesis.
FIGURE 21-12 Routes of synthesis of other fatty acids.
FIGURE 21-13 Electron transfer in the desaturation of fatty acids in vertebrates.
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
FIGURE 21-14 Action of plant desaturases.
(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
FIGURE 21-15a The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.
FIGURE 21-15b The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.
COX-2 specific cyclooxygenase inhibitors FIGURE 21-15c The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes.
FIGURE 21-16 The "linear" pathway from arachidonate to leukotrienes.
Lipoxygenase, LTs, lipoxin, and resolvins
Pro-resolution products of Lipoxygenase Nature Immunology 6, 1191-1197 (2005)
FIGURE 21-17 Biosynthesis of phosphatidic acid.
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
FIGURE 21-18 Phosphatidic acid in lipid biosynthesis.
FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin.
FIGURE 21-20 The triacylglycerol cycle.
FIGURE 21-21 Glyceroneogenesis.
FIGURE 21-22a Regulation of glyceroneogenesis.
FIGURE 21-22 Regulation of glyceroneogenesis.
Phospholipid 의생합성 FIGURE 21-23 Head-group attachment.
원핵세포 진핵세포 FIGURE 21-24 Two general strategies for forming the phosphodiester bond of
FIGURE 21-25 Origin of the polar head groups of phospholipids in E. coli.
FIGURE 21-26 Synthesis of cardiolipin and phosphatidylinositol in eukaryotes.
FIGURE 21-27 The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes.
FIGURE 21-28a Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals.
FIGURE 21-28b Pathways for phosphatidylserine and phosphatidylcholine synthesis in mammals.
FIGURE 21-29 Summary of the pathways for synthesis of major phospholipids.
FIGURE 21-30 Synthesis of ether lipids and plasmalogens.
FIGURE 21-30 (part 1) Synthesis of ether lipids and plasmalogens.
FIGURE 21-30 (part 2) Synthesis of ether lipids and plasmalogens.
FIGURE 21-31 Biosynthesis of sphingolipids.
FIGURE 21-31 (part 1) Biosynthesis of sphingolipids.
FIGURE 21-31 (part 2) Biosynthesis of sphingolipids.
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
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
FIGURE 21-32 Origin of the carbon atoms of cholesterol.
FIGURE 21-33 Summary of cholesterol biosynthesis.
FIGURE 21-34 Formation of mevalonate from acetyl-coa.
FIGURE 21-34 (part 1) Formation of mevalonate from acetyl-coa.
FIGURE 21-34 (part 2) Formation of mevalonate from acetyl-coa.
FIGURE 21-35 Conversion of mevalonate to activated isoprene units.
FIGURE 21-36 Formation of squalene.
FIGURE 21-37 Ring closure converts linear squalene to the condensed steroid nucleus.
FIGURE 21-38 Synthesis of cholesteryl esters.
TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties
FIGURE 21-39 Lipoproteins.
FIGURE 21-39b Lipoproteins.
TABLE 21-2 Apolipoproteins of the Human Plasma Lipoproteins
FIGURE 21-40a Lipoproteins and lipid transport.
FIGURE 21-40 Lipoproteins and lipid transport.
FIGURE 21-41 Reaction catalyzed by lecithin-cholesterol acyl transferase (LCAT).
FIGURE 21-42 Uptake of cholesterol by receptor-mediated endocytosis.
FIGURE 21-43 SREBP activation.
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
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
FIGURE 21-44 Regulation of cholesterol formation balances synthesis with dietary uptake.
BOX 21-3 FIGURE 1 Statins as inhibitors of HMG-CoA reductase.
FIGURE 21-45 Some steroid hormones derived from cholesterol.
FIGURE 21-46 Side-chain cleavage in the synthesis of steroid hormones.
FIGURE 21-47 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 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
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
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
insulin