中南大学-生物化学-考研课件-ch25-脂类生物合成-lipid-biosynthesis.ppt

1、BiochemistryFor Speciality of Biotechnology or Bioengineering at CSUMr.XIA JinlanChapter 25 Lipid biosynthesisFatty acid synthesisSynthesis of saturated fatty acidsSynthesis and degradation of fatty acids take place in different placesCYTOSOLMITOCHONDRIONAcetyl CoAMalonyl CoACO2C4C6C8C10C12C14Fatty

2、acidC16C14C12C10C8C4Acetyl CoATo TCAcyclePyruvateCO2C6KetonebodiesSynthesisDegradationMitochondrion membraneDifferences between fatty acid breakdown and synthesisBreakdownSynthesisSite of actionsCytosol for prokaryotesMitochondria for eukaryotesCytosol for both prokaryotes and eukaryotesRole of NADP

3、H or NADHNADH produced in b b-oxidationUse NADPH as the reductantLinkage of Fatty acid Fatty acid-CoAFatty acid-acyl carrier proteinUse of enzyme(s)Several individual separate enzymesSeparate enzymes for plants and bacteriaSingle multifunctional enzyme complex-fatty acid synthase for animalsSaturate

4、d fatty acid-CoAAcetyl-CoA乙酰-CoA8CH3CCoA ATP4-NADPH H+O+7+14+7Palmitic acid-CoA棕榈酰-CoACH3(CH2)14COCoA CoASH NADP+ADP3-Pi2-+7+7+14+7 The general reaction(for palmitic acid synthesis)CH3(CH2)14COO-CO2 CoA NADP+H2O+7+8+14+7 CH3CCoA -OCCH2CCoA NADPH H+OOO+7+14+14 Acetyl-CoA乙酰-CoAMalonyl-CoA丙二酰-CoAPalmit

5、ic acid棕榈酸Alternatively expressed as:Fatty acid is synthesizedfrom acetyl-CoA in cytosolIn one word:Where does the acetyl-CoA come from and how does it transfer?CH3CCoAOacetyl-CoACytosolAcetyl-CoAAmino aciddegradationMitochondrionAcetyl-CoAFatty acidoxidationGlycolysisPyruvatecytosolRequiredcytosolM

6、TMTMT:mitochondrionCitrate-malate-pyruvate shuttleWhy is malonyl-CoA needed?How does it commonly form?-OOCCH2CCoAOmalonyl-CoAThe first step is to form acetyl-and,malonyl-acyl carrier proteinCH3CSCoAOCO-OCH2COSCoACO-OCH2COACPCH3CACPOHCO3-ATPPiADPAcetyl CoAcarboxylaseMalonyltransacylaseACPCoAACPCoAAce

7、tyltransacylaseAcetyl-ACP乙酰-ACPMalonyl-ACP丙二酸单酰-ACPAcetyl transacylase is not highly specific,but not at much lower rates;malonyl transacylase is just contrary.Structures of ACP and CoA(CoASH)NH COCHOHCCH3CH3CH2CH2OHCOCH2HOPantothenic acid 泛酸SerCH2ACPHSCH2CH2NHCOCH2ONHCOCOHCCH3CH3CH2OOO-PCH2Hb-Merca

8、ptoethylaminePantothenic acidACPor HS-ACPHSCH2CH2NHCOCH2NNNNNH291234512354678P-OOO-OOHOCH2OPO-OOHHHHNHCOCOHCCH3CH3CH2OOO-PCH2Hb-MercaptoethylaminePantothenic acidCoenzyme ACoAorCoASHAcetyl-CoA carboxylase is Biotin-dependent and displays ping-pong kineticsThe carboxylation of biotinThe transcarboxyl

9、ation of biotinThe carboxylation of acetyl-CoAIn animals,acetyl-CoA carboxylase is a multifunctional proteinThe ACCaseIs modulated byphosphorylation and dephosphorylationP808Also seep819More activeformThen,how does the fatty acid chain elongate and Is there also a common cycle?The elongation cycle o

10、f fatty acid synthesisAcetyl-ACP乙酰-ACPMalonyl-ACP丙二酸单酰-ACPCO-OCH2COACPCH3CACPOCondensation缩合Acyl-malonyl-ACP condensing enzymeACP+CO2COCH2COACPH3CCHCH2COACPH3COHCCCOACPH3CHHCH2CH2COACPH3CNADPH+H+NADP+b-Ketoacyl-ACPreductaseD-3-Hydroxy-butyryl-ACPD-3-羟基-丁酰-ACP3-Hydroxyacyl-ACP dehydrataseH2OAcetoacet

11、yl-ACP乙酰乙酰-ACPCrotonyl-ACP巴豆酰-ACPButyryl-ACP 丁酰-ACPNADP+NADPH+H+Enoyl-ACPreductaseReduction还原Dehydration脱水Reduction还原CH2CH2COACPH3CCO-OCH2COACPCH3(CH2)14CACPOPalmitoyl-ACP软脂酰-ACPSTOP ATThioesteraseACPCH3(CH2)14COHOPalmitate 软脂酸或棕榈酸Six cyclesThe final product of fatty acid synthesisTotal cycles:7The

12、initial andcontinuation reaction of fatty acidsynthesisFor the further synthesis of C16 fatty acids,how does it process?nCatalyzed by enzymes on smooth ER(SER)nMalonyl-CoA,rather than malonyl-ACP as the two-carbon donornElongated chain as CoA derivative rather than ACP derivativeAdditional elongatio

13、nIn ERHow is the fatty acid synthesis regulated?The key enzyme:acetyl-CoA carboxylase(ACC)Regulation of ACCnShort-term effectsnCitrate activites ACC polymerizationnLong-chain fatty acids inhibit ACCnInsulin stimulates de-phosphorylation and activationnGlucagon stimulates phosphorylation and inhibiti

14、onnPhosphorylation by AMP-regulated kinase which itself is phosphorylated and activated by a kinase kinase,PKA phosphorylates PPI-1 leading to reduced phosphate removal from ACCnLong-term effectsnHigh carbo and fat-free diets lead to increased synthesisnhigh-fat diets,fasting and glucagon lead to de

15、creased synthesisPPAMP-activatedprotein kinaseProteinphosphatase 2AInactivecarboxylasePartially activecarboxylaseActivecarboxylaseAMPATPGlucagonEpinephrineInsulinPalmitoylCoACitrateATPADPH2OPiSummary of the control of acetyl CoA carboxylase by Phosphorylation and allosteric regulationKey enzyme:Acet

16、yl CoAcarboxylaseHomeworkn1,2,11 p850Fatty acid synthesisSynthesis of unsaturated fatty acidsAppendix:nBiosynthesis of monounsaturated fatty acids follows distinct routes in E.coli and animal cellsnAnaerobic pathway厌氧途径 for E.colinAerobic pathway好氧途径 in EukaryotesnBiosynthesis of polyunsaturated fat

17、ty acids occurs mainly in EukaryotesAnaerobic pathway for E.coliCCCOAC PH3C(C H2)5C H2HH4CCCOAC PH3C(C H2)5C H2HOHH2O3-Hydroxydecanoyl-ACP dehydrase(3-羟癸酰-ACP脱水酶)COAC PC H2HH3C(C H2)5CCabbg3-hydroxy-decanoyl-ACPdehydraseHC H2C H2COAC PH3CCO-OC H2COAC PC H3(C H2)14CAC POPalmitoyl-ACP软脂酰-ACPNomal path

18、way forsaturated fatty acidsynthesisSaturatedfatty acidsynthesisSaturatedfatty acidsynthesisCOAC P(C H2)7HH3C(C H2)5CCHCOAC P(C H2)9HH3C(C H2)5CCH3-ketoacyl-ACPsynthesis II and saturated fattyacid synthesis16:19-ACP16:0-ACP18:111-ACPAerobic pathway for EukaryotesCH3(CH2)16CCoAONAD+Cytochrome b5 redu

19、ctase(F)Cytochrome b5 reductase(FH2)Desaturase+NADHH+2Cytochrome b5(Fe2+)(Reduced)2Cytochrome b5(Fe3+)(Oxidized)2H+CH3(CH2)7CHC(CH2)7CHOCoAH2O+Oleoyl-CoA 油酰-CoAStearoyl-CoA 硬脂酰-CoAIN SERBiosynthesis of polyunsaturated fatty acids occurs mainly in EukaryotesnMammals can desaturate only between the 9

20、position and the carboxyl end of an acyl chainnUnable to synthesize linoleic acid(亚油酸18:2 9,12)and linolenic acid(亚麻酸18:3 9,12,15)nTake only from diet-essential fatty acidsnStarting points for synthesis of other unsaturated fatty acids,such as arachidonate 花生四烯酸(C20:4)，a precursor of several biologi

21、cally important molecules,e.g.,prostaglandins前列腺素 etc.,nPlants have the enzymes to desaturate at positions 9,12 and 15 arachidonate 花生四烯酸(C20:4)，a precursor of several biologically important moleculesArachidonate花生四烯酸Leukotrienes白三烯Prostaglandin synthase前列腺合酶Prostacyclin前列环素Otherprostaglandins其它前列腺素Thromboxanes血栓烷Prostaglandin H2前列腺素H2Linoleic acid(18:2 9,12)FromLinoleic acidToArachidonic acid