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 17 Fatty Acid Catabolism 2008 W. H. Freeman and Company

2 Chap. 17. Fatty acid oxidation 지방산의소화, 동원그리고운반 1. 식이성지방 1) 흡수과정 ( 소장에서 흡수 ) 1 담즙산염의식이성지방유화시켜 micelle 생성 2 TG 분해 3 지방산, 분해생성물흡수 : 장점막에서 TG로변환 4 TG (+cholesterol+apolipoprotein) 가 chylomicron 생성 5 chylomicron이조직으로운반 (via 림프계 & 혈류 ) 6 lipoprotein lipase가지방산과 glycerol 유리 7 지방산이세포로들어감 8 glycerol이해당과정으로들어감 9 지방산-산화, 저장

3 FIGURE 17-1 Processing of dietary lipids in vertebrates.

4 FIGURE 17-2 Molecular structure of a chylomicron.

5 2) Lipoprotein 1 VLDL (very low density lipoprotein) 2 VHDL (very high density lipoprotein) 3) Hormone-sensitive TG lipase - ester결합의가수분해촉매 * 저혈당 Epinephrine 및 Glucagon이 adenylate cyclase 활성화 camp 생성 camp-dependent protein kinase가 TG Lipase를인산화하여활성화시킴 FA방출 혈류내혈청 albumin과지방산결합 : 지방조직에저장된 TG의동원

6 FIGURE 17-3 Mobilization of triacylglycerols stored in adipose tissue.

7 FIGURE 17-4 Entry of glycerol into the glycolytic pathway.

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

8 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 Phosphoenolpyruvate kinase((pepck) Pyr dehydrogenase FOXO1,HNF-4 GSK3β Akt GS camp SREBP-1,2 Glycogen 합성 PKA PGC1 α PPAR α/β Chol synthesis HMG-CoA reductase Cholesterol

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

10 2. 지방산의활성화와운반 1) 지방산 + CoA + ATP 지방산 (acyl-coa) + AMP + PP i O R-C 2P i 실제로 2개의 ATP 필요 S-CoA ATP 2) Mitochondria(Mt) 내로지방산의도입 acyl CoA 가 carnitine 의 hydroxy 기와 ester 교환반응 (carnitine acyltransferaseⅠ 에 (CH 3 ) 3 N-CH 2 -CH(OH)-CH 2 -COO - 의해촉매 ) 지방산 acyl-carnitine ester 가 Mt. 내막을가로질러 matrix 로이동 지방산 acyl 기가 carnitine 으로부터 Mt. 내의 CoA 로옮겨짐 (carnitine acyltransferaseⅡ 에의해 ) & carnitine 은 Mt. 의내막외막사이로다시들어감 O R-C S-CoA CoA-SH carnitine acyl carnitine <outer membrane> Ⅰ <inner Membrane> carnitine Ⅱ O R-C carnitine <matrix> O R-C S-CoA CoA-SH β-oxidation

11 MECHANISM FIGURE 17-5 Conversion of a fatty acid to a fatty acyl CoA.

13 FIGURE 17-6 Fatty acid entry into mitochondria via the acyl-carnitine/carnitine transporter.

14 FIGURE 17-7 Stages of fatty acid oxidation.

15 β oxidation 지방산산화의단계 1 β- 산화 : 지방산 acyl chain 의연속적산화 2- 탄소단위인 acetyl-coa 생성 2 acetyl-coa 의 acetyl 잔기의산화 : TCA cycle CO 에서생긴 NADH, FADH2 가호흡사슬에전자전달 ADP + P i ATP / 2H + + ½O 2 H 2 O 1) β-oxidation 경로 (palmitoyl-coa) (C16)R-CH 2 CH 2 CH 2 C-S-CoA palmitoyl-coa + 7CoA + 7O P i + 28ADP 8 acetyl-coa + 28ATP + 7H 2 O 실제 palmitoyl-coa 의 ATP 수율 (β-oxidation) 28 개 <( )ⅹ7> + (TCA cycle) = 80 개 - 2 개 ( 지방산활성화 ) =106 개 2) 불포화지방산의산화 1 Monounsaturated FA(Oleoyl-CoA 9): Enoyl-CoA isomerase 필요 double bond 재배치, cis이성질체를 Trans 로바꾸어줌 2 Polyunsaturated FA(Linoleoyl-CoA 9,12 ): Enoyl-CoA isomerase & 2,4-dienoyl-CoA reductase

16 FIGURE 17-8 The β-oxidation pathway

17 FIGURE 17-8a (part 1) The β-oxidation pathway

18 FIGURE 17-8a (part 2) The β-oxidation pathway

19 FIGURE 17-8b The β-oxidation pathway.

20 TABLE 17-1 Yield of ATP during Oxidation of One Molecule of Palmitoyl-CoA to CO 2 and H 2 O

21 FIGURE 17-9 Oxidation of a monounsaturated fatty acid.

22 FIGURE Oxidation of a Polyunsaturated fatty acid.

24 FIGURE Coordinated regulation of fatty acid synthesis and breakdown

FIGURE 17-13 Comparison of β oxidation in

25 FIGURE Comparison of β oxidation in mitochondria and in peroxisomes and glyoxysomes.

26 FIGURE Triacylglycerols as glucose source in seeds.

27 FIGURE The enzymes of β oxidation

28 ω oxidation FIGURE The β oxidation of fatty acids in the endoplasmic reticulum

29 Ketone bodies 케톤체 O OH O CH3 C CH3 CH3 C CH2 C CH3 CHCH2C O O O - O - <acetone> <acetoacetate> <D-β-hydroxybutylate> 호기중발산 ex) 기아상태에서의 E원 간외조직으로운반-간장에서 TCA cycle거쳐산화되어 E 다량공급 1) acetyl-coa 로부터케톤체생성, 운반및축적 2) Ketosis 당뇨, 기아시 glycogen 지방산분해촉진 : acetyl-coa 다량생성 간의처리능력이상으로 acetyl-coa 생성 : TCA cycle 못따라감 ketone체생성 뇨, 혈중 ketoacidosis ex) 절식, 당뇨병환자 : 시큼한냄새가남

30 3) Ketosis 의원인 1 지방조직에서당질이용제한시 insulin 유리지방산유리 2 acetyl-coa 다량생성 ( 지방산을 E원으로 ) 3 ATP생성일정하게 4 TCA 중간체생성불충분 4) Ketone 체생성 & 운반 지방산 CoA β-oxidation 케톤체형성 acetyl-coa ketone bodies TCA 회로 E 원으로방출 ( 심장, 골격근, 심장, 뇌 ) oxaloacetate ( 간세포에서 ) gluconeogenesis glucose 연료로방출 ( 뇌, 조직 )

32 FIGURE Formation of ketone bodies from acetyl-coa

33 FIGURE D-β-Hydroxybutyate as a fuel

34 FIGURE Ketone body formation and export from the liver.

35 만성적으로알콜섭취시 fatty liver 가되는이유 NAD + EtOH NADH β-oxidation 억제 당, 지방대사불안정 / 지방대사늦어짐 간내지방축적 간경화 cf) EtOH 의분해 NAD + NADH + H + EtOH alcohol dehydrogenase Acetaldehyde

Microsoft PowerPoint - pr S3 f ch17 FA cata [호환 모드]

Microsoft PowerPoint - pr S3 f ch17 FA cata [호환 모드] 2013 W. H. Freeman and Company 17 Fatty Acid Catabolism Fatty Acid Catabolism Key topics: How fats are digested in animals How fats are mobilized and transported in tissues How fats are oxidized How ketone