a survey of metabolism - kimika · 2010-05-18 · 3 the study of metabolism allows us to understand...
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ASURVEYOFMETABOLISM
HLeeYuJsuicoJunsay
DepartmentofChemistry
SchoolofScienceandEngineering
AteneodeManilaUniversity1
2
Whydolivingorganismsneedenergy?
1. EnergyformoEon–kineEcenergy2. Maintainhomeostasis–steadystate,potenEal
energy
3. Builduptheorganism’scomponentsfromavailablenutrients–chemicalenergy
4. Removeswaste–chemicalandkineEcenergy5. Respondstoenvironmentalchanges–chemical
energy
6. Removeandregeneratedamagedparts–chemicalenergy
3
Thestudyofmetabolismallowsustounderstandhowallthecell’sprocessaredone!
Insomeway,itisalsoastudyofhowenergyistransformedbytheorganismfromoneformtoanother!
4
AboveandbeyondallcharacterisEcs,itismetabolismthatprovidesthebestworkingdefiniEonoflife.
“ItismetabolismandnotreplicaEonthatprovidesthebestworkingdefiniEonoflife.EvoluEonarybiologistswouldsaythatweexistinordertoreproduce–butwearenot,eventhemostamorousofuse,tryingtoreproducealltheEme.Yet,ifwestopmetabolizing,evenforaminuteortwo,wearedonefor.”
» PhillipBallinStoriesoftheInvisible:AGuidedTourofMolecules,OxfordUniversityPress,2001.
METABOLISM
5
6
Organismscanbedividedtomanymetabolism‐basedclasses.
Autotrophvs.Heterotroph
7
Organismscanbedividedtomanymetabolism‐basedclasses.
Aerobesvs.Anaerobes
8
Thepathwaybywhichmoleculesdegradeandsynthesizecompoundsiscalledthemetabolicpathway
Astudyofenergytransferfromfoodtobiologicalmolecules
9
Enzymecomplexesprovidethemachineryformetabolism
10
Energyiscarriedfromoneformtoanotherbychemicalcompounds‐METABOLITES.
11
Metabolismiscarriedoutin3stages:
1. DegradaEon/Synthesisofcomplexmetabolites
2. TransformaEonofsimplemetabolites
3. Energypay‐off
12
Organismsmaintainnon‐equilibriumcondiEonsbetweentheselfandthenon‐self:steadystate.
• McKeeandMcKee(1999)Biochemistry:AnIntroducEon.Figure4.2,p.64.
System
Surroundings
EquilibriumSteadyStateNOTatequilibrium
Andwhenwetalkaboutenergyandequilibrium,weusuallylookatthermodynamics.
BIOLOGICALTHERMODYNAMICS
13
14
ThermodyamicsconsiderstheenergeLcsofa
reacLon.
FIRSTLAW:“Youcan’twin.”Energycannotbecreatedordestroyed.Itis
onlytransformedintootherforms
ΔEsystem=–ΔEsurrounding
15
ThermodyamicsconsiderstheenergeLcsofa
reacLon.
SECONDLAW:“Youalwayslose.”Thetotalentropyoftheuniverse(entropyof
system+surrounding)increasesinaspontaneousreacEon
€
ΔStotal = ΔSsystem + ΔSsurroundings > 0
16
ThermodyamicsconsiderstheenergeLcsofa
reacLon.
THIRDLAW:“Youwillnevergetthere/PerfecLonisboring”
Theentropy,S,ofapure,perfectlycrystallinesolidatabsolutezerois0.
17
Gibbsfreeenergy,ΔG,isthemaximum“useful”workthatcanbeproducedbyachemicalreacEon.
ΔG<0ThereacEonisspontaneousintheforwarddirecEon.
ΔG>0ThereacEonisnon‐spontaneousaswrinen.ThereacEonisspontaneousinthereversedirecEon.
ΔG=0ThereacEonisatequilibrium.
€
ΔG = ΔH −TΔS
18
ThermodyamicsconsiderstheenergeLcsofa
reacLon.
ΔGisthemaximum“useful”workthatcanbeproducedbyachemicalreacLon.
19
EnergeEcallyunfavorablereacEonsarecoupledtofavorableonestodrivethemforward.(thisishoworganismswin!)
20
ΔG=+17kJ/mol
ΔG=‐30kJ/mol
EnergeEcallyunfavorablereacEonsarecoupledtofavorableonestodrivethemforward.
CoupledreacEonspassesthroughadifferentmechanismwhoseoverallyieldgiveΔG<0
21
CHEMICALSTRATEGIES
22
Organismsusecommonchemicalstrategiesinenergymanagement.
23
PhosphoryltransferreacEonsyieldverynegaEveΔGmakingthemidealforcouplingwithotherreacEons
24
PhosphoryltransferreacEonsyieldverynegaEveΔGmakingthemidealforcouplingwithotherreacEons
25
ATPhasintermediatephosphoryltransferpotenEal.
26
LessreacLvethanPEP,kineLcallystable.
ATPhasintermediatephosphoryltransferpotenEal.
27
Why do we need an intermediate metabolite as energy carrier?
28
Phophoryl transfer molecules are used up in the cells depending on certain conditions
29
Phophoryl transfer molecules are used up in the cells depending on certain conditions
30
OxidaEon‐reducEonreacEonsneedredoxpartners.
31
OxidaEon‐reducEonreacEonsneedredoxpartners.
32
Theseredoxpartnersareusuallyelectroncarriers..Toothermoleculesortorespiratoryenzymes
33
CASESTUDY:GLYCOLYSISANDTHEFATESOFPYRUVATE
34
Glycolysisandthecitricacidcycleareatthecenterofthemetabolicprocessesinlivingorganisms
35
Glucosemetabolisminvolvesbothenergyproducing(catabolic,orange)andenergyconsuming(anabolic,green)processes
36
WHYGLUCOSE?!
37
Theonlyfuelthebrainusesinnon‐starvaEoncondiEons
Theonlyfuelredbloodcellscanuse WHY?
EvoluEonary:probablyavailableforprimiEvesystems(fromformaldehyde)
Lowtendencytoglycosylateproteins,strongtendencytoexistinringform(recall:allequatorial!)
GlycolysisturnsglucosetopyruvatewhichthencanbeuElizedinfermentaEonorthrucompleteoxidaEon.
38
Glycolysisoccursinthreemajorstages:
1. INVESTMENT:Glucosefructose‐1,6‐biphosphate
2. MULTIPLIER:Fructose‐1,6‐biphosphateglyceraldehyde‐3‐phosphate
3. PAYBACK:Glyceraldehyde‐3‐phosphatePyruvate
39
STEP1:PhosphorylaEonofglucoseusinghexokinase(orglucokinase)toglucose‐6‐phosphate(G6P)
40
• Thisstepisaprimingstep–usesATPtogetmoreATPlater,–VerynegaEveΔG
• Donetokeepglucoseinthecytoplasm
O
OH
OH
OH
HO
OH
hexokinase
ATP ADP
O
OH
OH
OH
-2O3PO
OH
Glucose Glucose-6-phosphate
STEP1:PhosphorylaEonofglucoseusinghexokinase(orglucokinase)toglucose‐6‐phosphate(G6P)
41
• Thisstepisaprimingstep–usesATPtogetmoreATPlater,–VerynegaEveΔG
• Donetokeepglucoseinthecytoplasm
STEP2:IsomerizaEonofG6Ptofructose‐6‐phosphate
42
• 3rdstepwillbeeasieronaprimaryOH,ratherthanahemiacetal
• ReadiesthecompoundforlatercleavagebetweenC3‐C4
O
OH
OH
OH
-2O3PO
OH
O
OH
OH-2O3PO
HO
OH
phosphogluycoisomerase
Glucose-6-phosphateFructose-6-phosphate
STEP2:IsomerizaEonofG6Ptofructose‐6‐phosphate
43
• 3rdstepwillbeeasieronaprimaryOH,ratherthanahemiacetal
• ReadiesthecompoundforlatercleavagebetweenC3‐C4
STEP3:PhosphorylaEonofF6Ptofructose‐1,6‐bisphosphate(usingPhosphofructokinase,PFK)
44
• Thisisanotherprimingstep–UsesATPtogetmoreATPlater,–VerynegaEveΔG
• Thisisthecommibedstep:F‐1,6‐BPisveryreacEve!• PFK,InhibitedbylotsofATP.(ifyoudon’tneedenergy,yourstepwillnotoccur)
O
OH
OH-2O3PO
HO
OH
O
OH
OPO3-2-2O3PO
HO
OH
phosphofructokinase
Fructose-6-phosphate Fructose-1,6-bisphosphate
ATP ADP
RecallSTAGE1:INVESTMENT
45
STEP4:Cleavingthe6Cmoleculetotwo3Cmolecules
46
• Donebyaldolase(areversealdolcondensaEonreacEon)
O
HO
-2O3PO OPO3-2
OH
Fructose-1,6-bisphosphate
Aldolase
H2C
C O
CH2OH
O P
O
O-
O-
Dihydroxyacetonephosphate(DHAP)
HC
HC OH
CH2O
O
P
O
O-
O-
1
2
3
4
5
6+
Glyceraldehyde-3-phosphate (G-3-P)
1
2
34
5
6
STEP4:Cleavingthe6Cmoleculetotwo3Cmolecules
47
• Donebyaldolase(areversealdolcondensaEonreacEon)
STEP5:ConvertsDHAPtoG‐3‐P
48
• UsesTriose‐phosphateisomerase• ThisreacEonyieldsanoveralltwo(2)G‐3‐Ppermoleculeofglucose
H2C
C O
CH2OH
O P
O
O-
O-
Dihydroxyacetonephosphate(DHAP)
HC
HC OH
CH2O
O
P
O
O-
O-
Glyceraldehyde-3-phosphate (G-3-P)
Triose-phosphate isomerase
STEP5:ConvertsDHAPtoG‐3‐P
49
• UsesTriose‐phosphateisomerase• ThisreacEonyieldsanoveralltwo(2)G‐3‐Ppermoleculeofglucose
RecallSTAGE2:MULTIPLIER
50
CHECKLIST:
51
We’veUSEDUP2ATPmoleculestoprocess1glucosemolecule
Weareleswith2G3Pnow
Timeforenergypayback,thusSTAGE3!
Recallthatstage3happensinparalleltothetwoG3Pmolecules
STEP6:G‐3‐Pisoxidizedto1,3‐bisphosphateglycerate(1,3‐BPG)
52
• YieldsNADH,anelectroncarrier!• YieldsahighlyreacEve1,3‐BPG,aphosphorylcarrier!
C
HC OH
CH2O
O
P
O
O-
O-
Glyceraldehyde-3-phosphate (G-3-P)
H
C
HC OH
CH2O
O
P
O
O-
O-
1,3-bisphosphate glycerate(1,3-BPG)
OPO3-2
NAD+ NADH
HPO4-2+
H++G-3-P dehydrogenase
STEP7:1,3‐BPGistransformedto3‐phosphoglycerate(3‐PG)
53
• YieldsATPpaybackEme!(rememberforeverystephere,twoareactuallyyieldedduetothetwoG‐3‐Pmoleculesthatwemadeearlier!)
C
HC OH
CH2O
O
P
O
O-
O-
1,3-bisphosphate glycerate(1,3-BPG)
OPO3-2
C
HC OH
CH2O
O
P
O
O-
O-
OH
3-phosphoglycerate(3-PG)
phophoglycerate kinase
ADP ATP
STEP8:3‐PGisconvertedto2‐PG
54
• PlacesphosphatefromC3toC2..ReadiesthemoleculetomakePhosphoenolpyruvate,anotherhighlyreacEvecompound!
C
HC OH
CH2O
O
P
O
O-
O-
OH
3-phosphoglycerate(3-PG)
C
HC O
CH2OH
O
P
O
O-
O-
OH
2-phosphoglycerate(2-PG)
phophoglycerate mutase
STEP9:2‐PGisre‐arrangedtophosphoenolpyruvate(PEP)
55
• EnolasecreatesanenollikefuncEonalgroup.
C
HC O
CH2OH
O
P
O
O-
O-
OH
2-phosphoglycerate(2-PG)
C
C O
CH2
O
P
O
O-
O-
OH
Phosphoenol pyruvate(PEP)
enolase
H2O
STEP9:PEPisconvertedtoPyruvate
56
• YieldsATPanotherpaybackstep!
C
C O
CH2
O
P
O
O-
O-
OH
Phosphoenol pyruvate(PEP)
ADP + H+ ATP
pyruvate kinase C
C
OHH2C
OHO
C
C
OH3C
OHOketo-enoltautomerization
pyruvate
RecallSTAGE3:PAYBACK
57
CHECKLIST:
58
Made2NADH(onefromeachG‐3‐P)
Made4ATP(twofromeachG‐3‐P)
OVERALLMassbalance:
Glucose+2Pi+2ADP+2NAD+
2Pyruvate+NADH+2ATP+2H++2H2O
59
NADHhastwopossiblefates:fermentaEonorrespiraEon
FermentaLon:IntheabsenceofO2,NADHisusedasachemicalreductantofpyruvatetomakelactate
60
NADHhastwopossiblefates:fermentaEonorrespiraEon
RespiraLon:InthepresenceofO2,NADHisusedasaelectroncarriertoharnessenergyinthemitochondria.
61
Pyruvatehasthreepossiblefates:lactatefermentaEon,alcoholfermentaEonandcompleteoxidaEon
LactateFermentaLon:IntheabsenceorshortsupplyofO2,pyruvateisconvertedtolactate(vialactatedehydrogenase).Reverseisdonebythesameenzyme.
62
Pyruvatehasthreepossiblefates:lactatefermentaEon,alcoholfermentaEonandcompleteoxidaEon
LactateFermentaLon:IntheabsenceorshortsupplyofO2,pyruvateisconvertedtolactate(vialactatedehydrogenase).Reverseisdonebythesameenzyme.
63
Pyruvatehasthreepossiblefates:lactatefermentaEon,alcoholfermentaEonandcompleteoxidaEon
EthanolFermentaLon:Inanaerobicbacteria/yeast,pyruvateisdecarboxylatedthenreducedtoethanol
O
H3C
O
OH
O
H3C
H
H3C C
OH
H
H
CO2
alcoholdecarboxylase
pyruvate acetaldehyde
NADH + H+ NAD+
alcohol dehydrogenase
ethanol
64
Pyruvatehasthreepossiblefates:lactatefermentaEon,alcoholfermentaEonandcompleteoxidaEon
RespiraLon:InthepresenceofO2,pyruvateisconvertedtoAcetyl‐CoAwhichwillbefedontothetricarboxylicacidcycle.
O
H3C
O
OH
pyruvate Acetyl-CoA
O
H3C
SCoA
HSCoANAD+
NADH + H+CO2
pyruvate dehydrogenase complex (E1 + E2 + E3)
65
TheenergeEcsofglycolysisrevealsthreeimportantthings:
1. Mostoftheprocessisnotenergyintensiveandarethusreversible
2. Therearethreeirreversiblesteps:1,3and10.
3. ThesestepsarepossiblywhereregulaEoncanhappen
66
67
68
Othermonosaccharidescanalsoenterglycolysis.
69
70
Thesynthesisofglucosefrompyruvate,lactate,aminoacidsorothermetabolites,iscalledgluconeogenesis.
Occursmainlyinliverandkidneys
Notthemerereversalofglycolysisfor2reasons: EnergeEcsmustchangetomakegluconeogenesisfavorable(deltaGofglycolysis=‐74kJ/mol
ReciprocalregulaEonmustturnoneonandtheotheroff‐thisrequiressomethingnew!
71
Sevenstepsofglycolysisareretained: Steps2and4‐9
Threestepsarereplaced: Steps1,3,and10(theregulatedsteps!)
ThenewreacEonsprovideforaspontaneouspathway(ΔGnegaEveinthedirecEonofsugarsynthesis),andtheyprovidenewmechanismsofregulaEon
MakesureyouknowtheTHREEBYPASSSTEPSofGluconeogenesis!!!
Thesynthesisofglucosefrompyruvate,lactate,aminoacidsorothermetabolites,iscalledgluconeogenesis.
72
Thesynthesisofglucosefrompyruvateiscalledgluconeogenesis.
Occursmainlyinliverandkidneys
Notthemerereversalofglycolysisfor2reasons: EnergeEcsmustchangetomakegluconeogenesisfavorable(deltaGofglycolysis=‐74kJ/mol
ReciprocalregulaEonmustturnoneonandtheotheroff‐thisrequiressomethingnew!
73
Thesynthesisofglucosefrompyruvate,lactate,aminoacidsorothermetabolites,iscalledgluconeogenesis.
74
Thesynthesisofglucosefrompyruvateiscalledgluconeogenesis.
75
76
Asidefrom(+)and(‐)effectors,hormonescontrolgeneexpression.
77
Asidefrom(+)and(‐)effectors,hormonescontrolgeneexpression.
CASESTUDY:TRICARBOXYLICACIDCYCLEANDELECTRONTRANSPORTCHAIN
78
79
Acetyl‐CoAentersacyclethatconvertsittoCO2
andlotsofelectroncarriers
80
Acetyl‐CoAentersacyclethatconvertsittoCO2
andlotsofelectroncarriers
81
Acetyl‐CoAreactwithOxaloacetateandisconvertedtoCitrate.Thecycleregeneratestheoxaloacete,disposesoftheCO2andyieldlotsofenergycarriers.
82
Acetyl‐CoAreactwithOxaloacetateandisconvertedtoCitrate.Thecycleregeneratestheoxaloacete,disposesoftheCO2andyieldlotsofenergycarriers.
83
Acetyl‐CoAreactwithOxaloacetateandisconvertedtoCitrate.Thecycleregeneratestheoxaloacete,disposesoftheCO2andyieldlotsofenergycarriers.
84
Acetyl‐CoAreactwithOxaloacetateandisconvertedtoCitrate.Thecycleregeneratestheoxaloacete,disposesoftheCO2andyieldlotsofenergycarriers.
85
NADHandFADH2carrieshighenergyelectronwhichcreatesahydrogenpotenEalwhichinturncreatesATP
86
NADHandFADH2carrieshighenergyelectronwhichcreatesahydrogenpotenEalwhichinturncreatesATP.1NADH=3ATP,1FADH2=2ATP.
87
Glycolysis+Pyruvatedehydrogenase+TCA=lotsofenergy
CASESTUDY:BETA‐OXIDATIONOFFATS
88
89
FatsaredegradedbycuungthemupintoC2fragments:Acetyl‐CoAandfedintotheTCA.
90
FatsaredegradedbycuungthemupintoC2fragments:Acetyl‐CoAandfedintotheTCA.
SUMMARY
91
92
Metabolismofnutrientsinvolve
Breakdownfrombiomoleculestosimplemolecules
Simplemoleculesareconvertedtofeedermolecules
Glycolysis, Pyruvatedehydrogenase, B‐oxidaEon
Feedermoleculesarefedtoacyclethatproduceslotsofenergycarriers
TCANADH+FAH2
EnergycarriersareprocessedandcanreleaselotsofATP ElectrontransportChain
THESEPROCESSESARETIGHTLYREGULATED
93
AboveandbeyondallcharacterisEcs,itismetabolismthatprovidesthebestworkingdefiniEonoflife.
“ItismetabolismandnotreplicaEonthatprovidesthebestworkingdefiniEonoflife.EvoluEonarybiologistswouldsaythatweexistinordertoreproduce–butwearenot,eventhemostamorousofuse,tryingtoreproducealltheEme.Yet,ifwestopmetabolizing,evenforaminuteortwo,wearedonefor.”
» PhillipBallinStoriesoftheInvisible:AGuidedTourofMolecules,OxfordUniversityPress,2001.
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