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 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
FIGURE 17-1 Processing of dietary lipids in vertebrates.
FIGURE 17-2 Molecular structure of a chylomicron.
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
FIGURE 17-3 Mobilization of triacylglycerols stored in adipose tissue.
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 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
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
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
MECHANISM FIGURE 17-5 Conversion of a fatty acid to a fatty acyl CoA.
FIGURE 17-6 Fatty acid entry into mitochondria via the acyl-carnitine/carnitine transporter.
FIGURE 17-7 Stages of fatty acid oxidation.
β oxidation 지방산산화의단계 1 β- 산화 : 지방산 acyl chain 의연속적산화 2- 탄소단위인 acetyl-coa 생성 2 acetyl-coa 의 acetyl 잔기의산화 : TCA cycle CO 2 3 2 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 2 + 28P i + 28ADP 8 acetyl-coa + 28ATP + 7H 2 O 실제 palmitoyl-coa 의 ATP 수율 (β-oxidation) 28 개 <(2.5+1.5)ⅹ7> + (TCA cycle) 3 2.5 8 + 1.5 8 + 1 8 = 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
FIGURE 17-8 The β-oxidation pathway
FIGURE 17-8a (part 1) The β-oxidation pathway
FIGURE 17-8a (part 2) The β-oxidation pathway
FIGURE 17-8b The β-oxidation pathway.
TABLE 17-1 Yield of ATP during Oxidation of One Molecule of Palmitoyl-CoA to CO 2 and H 2 O
FIGURE 17-9 Oxidation of a monounsaturated fatty acid.
FIGURE 17-10 Oxidation of a Polyunsaturated fatty acid.
FIGURE 17-12 Coordinated regulation of fatty acid synthesis and breakdown
FIGURE 17-13 Comparison of β oxidation in mitochondria and in peroxisomes and glyoxysomes.
FIGURE 17-14 Triacylglycerols as glucose source in seeds.
FIGURE 17-15 The enzymes of β oxidation
ω oxidation FIGURE 17-16 The β oxidation of fatty acids in the endoplasmic reticulum
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
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 )
FIGURE 17-18 Formation of ketone bodies from acetyl-coa
FIGURE 17-19 D-β-Hydroxybutyate as a fuel
FIGURE 17-20 Ketone body formation and export from the liver.
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