Lecture'20*'Chapters'27'&'28'Fa4y'Acid'Metabolism!The'hummingbird’s'tremendous'capacity'to'store'and'use'fa4y'acids'enables'it'to'make'migratory'journeys'of'remarkable'distances.'1'Outline'v 'Fa4y'acid'catabolism:''* ''β*oxidaKon'of'saturated'(even'C)'fa4y'acids'and'the'ATP'count''* ''β*oxidaKon'of'saturated'(uneven'C)'fa4y'acids'*''β*oxidaKon'of'polyunsaturated''fa4y'acids'* ''Ketone'bodies''v Fa4y'acid'biosynthesis''* ''Overview'*''How'the'cell'ensures'supply'of'the'precursors'acetyl*CoA'and'NADPH'*''Steps'of'biosynthesis'* ''Overall'equaKon'for'the'synthesis'of'one'molecule'of'palmiKc'acid'(16:0)'*''RegulaKon'of'fa4y'acid'metabolism'(allosteric,'covalent,'hormonal)'2'''Triaglyceride'as'Fuel' Ester R-C-OR′ = O Triglyceride/triacylglycerols'3'Adipocyte'4'Lipid'DegradaKon'+'5'6'glucose'Hydrolysis'(Lipolysis)'of'Triacylglycerols'in'an'Adipocyte'ATGL'HS'lipase'MAG'lipase'albumin'FA'Adipose'cell'7'Glycerol'can'enter'the'glycolysis/gluconeogen esi s'pathway'8'glucose'Hydrolysis'(Lipolysis)'of'Triacylglycerols'in'an'Adipocyte'ATGL'HS'lipase'MAG'lipase'albumin'FA'Adipose'cell'Muscle,'kidney'and'heart'9'Fa4y'Acid'Catabolism'1. AcKvaKon'of'Fa4y'acid'with'CoA'by'Acyl'CoA'synthase'on'outer'membrane'of'mitochondria'2. Transport'of'acKvated'fa4y'acid'into'mitochondrial'matrix'via'Translocase'3. β*oxidaKon'cycle'of'saturated'even*C'fa4y'acid'4. Catabolism'of'uneven*C'saturated'fa4y'acid'5. Catabolism'of'unsaturated'fa4y'acid'(double'bonds)'10'AcKvaKon'of'Fa4y'acids'α'β'γ'Acyl'CoA'synthase'PPi'='pyrophosphate'Pi'='orthophosphate'11'Fa4y'Acids'are'linked'to'Coenzyme'A'before'they'are'oxidized'1.'2.'12'The'Acyl*CoA'Synthetase'acKvates'fa4y'acids'for'β*oxidaKon.''Acyl*CoA'+'AMP'+'P!P!ATP!∆G°’'for''ATP!AMP'+''PP='*32.3'kJ/mol'∆G°’'for''acyl*CoA'synthesis''='+31.5'kJ/mol'Net'∆G°’' ='*0.8'kJ/mol'13'+'Fig.'23*8a,'p.'703'Transfer'of'acyl'CoA'to'inner'mitochondrial'space'Acyl'CoA'Acyl'carniKne'14'Fig.'23*8b,'p.'703'Transfer'of'Acyl'carniKne'from'inner'mitochondrial'space'to'matrix'Acyl'CoA'Acyl'carniKne'15'Reduced' Oxidized'β*oxidaKon'converts'the'β*carbon'of'Fa4y'acid'Chain'from'reduced'to'oxidized'form'C'H'H'β'O'C'β'FAD'+'NAD+'FADH2'+'NADH'β*oxidaKon'16'One'cycle'of'β*oxidaKon'–'for'saturated'FA'Acetyl'CoA'Acyl'CoA'PalmiKc'acid'(C*16)''(saturated,'even'C)'C*14'fa4y'acid'17'Each'β'cycle'of'oxidaKon'involves'four'reacKons'β oxidation oxidaKon'oxidaKon' hydraKon'cleavage'FADH2'NADH'18'ReacKons'1'&2:''DehydrogenaKon'(OxidaKon)'+HydraKon''Acyl'CoA'dehydrogenase'Enoyl'CoA'hydratase'1.'2.'19'+'3.'4.'ReacKons'3'&'4:''DehydrogenaKon'+'Cleavage'of'the'Cα'–'Cβ'bond'L*3*Hydroxyacyl'Co'A'dehydrogenase'β*ketothiolase'20'Last'round'(#7)''The'first'two'rounds'in'the'degradaKon'of'palmitate.'CoA'21'β'oxidaKon:''Total'ATP'yield'on'complete'oxidaKon'of'one'molecule'of'palmiKc'acid'(16'carbons)'Note: - * Subtracting 2 ATP equivalent that was used up for the fatty acid activation - Each round of TCA cycle produces 3 NADH, 1 FADH2 and 1 ATP 31 NADH x 2.5 ATP/NADH = 77.5 ATP 15 FADH2 x1.5 ATP/FADH2 = 22.5 ATP Total'ATP'yield''='77.5'+'22.5'+'8'*2*'''''='106'''''+''123'H2O'22'Fa4y'Acid'OxidaKon'is'an'Important'Source'of'Metabolic'Water'for'Some'Animals'23'How'Are'Odd*Carbon'Fa4y'Acids'Oxidized?'Some'of'the'intermediate'steps'require'bioKn'and'B12'derivaKves'TCA'Can'be'used'to'regenerate'OAA'24''Fa4y'acids'can'be'Saturated'or'Unsaturated'One'or''more'C*C'bonds'in'the'tail'are'double'bonds'Saturated' Mono*'or'poly*Unsaturated'Tail'has'only'single'C*C'bonds'16:0'18:2'25'β&oxida,on!of!fa/y!with!double!bond!on!ODD!carbon!!1.'OxidaKon'è'FADH'2.'HydraKon'çH2O'3.'OxidaKon'è'NADH'4.'Cleavage'of'AcetyCoA'2!2!2!3!3!3!X'Acyl'CoA'dehydrogenase'26'β&oxida,on!of!fa/y!with!double!bond!on!Even!carbon!!2.'HydraKon'çH2O'3.'OxidaKon'è'NADH'2!3!4!1.'OxidaKon'è'FADH'Acyl'CoA'dehydrogenase'3!2!4!reductase'NADPH'NADP+'3!2!4!X'27'β&oxida,on!of!fa/y!with!double!bond!on!Even!carbon!!2.'HydraKon'çH2O'3.'OxidaKon'è'NADH'2!3!4!1.'OxidaKon'è'FADH'Acyl'CoA'dehydrogenase'3!2!4!3!2!4!28'Fa4y'acid'breakdown'(lipolysis)'TGè''FA''(lipase)'sKmulated'by'glucagon'and'epinephrine,'inhibited'by'insulin'FA'''1) Coupled'to'CoA'(acyl'CoA')'needs'ATP'+'PPi''(Acyl'CoA'synthetase)'2) Transported'into'mitochondrial'matrix'(carniKne'transporter)'3)'''β*oxidaKon:'(separate'enzymes'in'mitochondrial'matrix)''''oxidaKon+'FADH2''''hydraKon''''oxidaKon'''+'NADH''''cleavage:''acetyl'CoA'+'acyl'CoA'TCA'Another'round'of'β*oxidaKon'∆odd'double*bond:'(one'step)'cis*∆3*enoyl'CoA'isomerase'∆even'double'bond:'(two'steps)''2,4*Dienoyl'CoA'reductase'29'Fat'burns'in'the'flame'of''carbohydrates'30'Ketone'and'diabetes'h4p://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html'catabolism'In'the'liver'31'h4p://www.elmhurst.edu/~chm/vchembook/623acetylCoAfate.html'Ketone'Bodies'Acetyl'CoA'Acetyl'CoA'AcetoaceKc'acid'3*hydroxybutanoic'acid'acetone'CO2'+'2'CoA''+'H+'32'Diabe,c!ketosis!results!when!insulin!is!absent'33'Fa4y'acid'catabolism'''''''''''''''''''''''''''''''Fa4y'acid'anabolism''1. Intermediates'are'linked'covalently'to'the'–SH'group'of'CoA'2. Occurs'in'the'mitochondrial'matrix'3. Enzymes'of'fa4y'acid'breakdown'are'all'separate'proteins''4. The'coenzyme'for'oxidaKon*reducKon'reacKons'is'the'NAD+/NADH'couple'1. Intermediates'are'linked'covalently'to'the'–SH'group'of'Acyl'Carrier'proteins'(ACPs)'2. Occurs'in'the'cytosol'3. All'enzymes'(except'for'one)'required'to'synthesize'a'molecule'of'fa4y'acid'are'components'(different'domains)'of'one)long)polypep,de)chain,'called'Fa4y'Acid'Synthase'(FAS)'4.
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