Metabolism.pdf unit 1 biochemistryb pharm 1st year

metabolism

1. Metabolism
Prepared By
Debajit Dewan
M. Pharm

2. Carbohydrate metabolism
1.Photosynthesis,inwhichC0
2isreducedtocarbohydratethroughcarbonUtilization.
2.Glycolysis,whereoxidativemetabolismofglucosemoleculesoccursincytoplasm,finallyATPand
pyruvateisformedasendproducts.
3.Citricacidcycle,wherepyruvatefromglycolysisentersintomitochondrialmatrix.
4.ThePentosePhosphatePathway,actsintheconversionofhexosesintopentosesandregenerationof
NADPHoccursthatactsasaprecursorfortheproductionofmanybiomolecules.
5.Glycogenesis,whereexcessglucoseisconvertedintoglycogenasacellularstoragetoprevent
excessiveosmotic.pressureofinsidecell,
6.Glycogenolysis,wherebreakdownofglycogenoccursintoglucoseforglucosesupplyofglucose-
dependenttissues.
7.Gluconeogenesis,wheredenovosynthesisofglucosemoleculesoccurs.

3. Glycolysis
•Thispathwayisutilizedbyallthecellsand
tissuestogetenergy,whichisstoredinthe
formofATPandNADH.
•Itoccursinbothprokaryotesandeukaryotes.
•Itisemployedinbothaerobicandanaerobic
respiration.
•Theprocessofglycolysisoccursincytosol,so
itisaveryimportantprocessofenergy
generationforthoseorganisms,whodonot
possessmitochondria.
•Theendproductofglycolysisispyruvate,
whichisanintermediateofvariousother
processessuchasgluconeogenesis,fattyacid
synthesis,fermentation,etc.

4. Glycolysis –Pathway,
energetics and
significance

5. In aerobic prokaryotes, this reaction takes place in cytosol.
•Twomoleculesofpyruvateareproducedbypartialoxidationofglucose.
•Therearetwophases;Preparatoryphase,whereATPisconsumedandPayoffphase
whereATPisproduced.Thereisanetyieldof2ATPsand2NADH.
•Itisaseriesoftenenzymaticreactions,where6CGlucoseisconvertedto2moleculesof
3Cpyruvate.
•InthefirstphaseGlucoseisphosphorylatedtoformfructose-1,6-bisphosphateinthethree-
stepprocessandthenbrokendownto3CcompoundG3P(Glyceraldehyde-3-phosphate)
andDHAP(Dihydroxyacetonephosphate).ThelattergeneratesG3P.Inthisphase2ATPs
areutilized.
•Thesecondphase,whichisanenergycapturingphase.G3Pisconvertedintopyruvatein
fivesteps.Hereweget4ATPsand2NADHareformed.
•Ineukaryoticaerobicrespiration,thepyruvateentersmitochondria,whereitundergoes
oxidativedecarboxylationtoformacetylCoA,whichentersKrebscycleorCitricacidcycle.
Inanaerobicrespiration,pyruvateisconvertedintolactate,e.g.inmusclesoracetaldehyde,
whichisconvertedintoethanolandCO
2inbacteriaandyeast.

7. Citric acid cycle
•Ineukaryotes,thecitricacidcycletakesplaceinthematrixofthemitochondria,justlikethe
conversionofpyruvatetoacetylCoA.
•Inprokaryotes,thesestepsbothtakeplaceinthecytoplasm.
•Stepsofthecitricacidcycle
➢Step1.Inthefirststepofthecitricacidcycle,acetyljoinswithafour-carbonmolecule,oxaloacetate,releasing
thegroupandformingasix-carbonmoleculecalledcitrate.
➢Step2.Inthisstepcitrateisconvertedintoitsisomer,isocitrate
➢Step3.Inthethirdstep,isocitrateisoxidizedandreleasesamoleculeofcarbondioxide,leavingbehindafive-
carbonmolecule—α-ketoglutarate.
➢Step4.Thefourthstepisα-ketoglutaratethat’soxidizedtoA,formingtheunstablecompoundsuccinylCoA.
➢Step5.Instepfive,theCoAofsuccinylCoAisreplacedbyaphosphategroupandproducedsuccinate
➢Step6.Instepsix,succinateisoxidized,forminganotherfour-carbonmoleculecalledfumarate.
➢Step7.Instepseven,waterisaddedtothefour-carbonmoleculefumarate,convertingitintoanotherfour-
carbonmoleculecalledmalate.
➢Step8.Inthelaststepofthecitricacidcycle,oxaloacetateisproducedbyoxidationofmalate.

10. GlycogenmetabolismPathways(GlycogenesisandGlycogenolysis)
•Glycogenesisisthebiochemicalstepforthesynthesisofglycogenwhichisthemajorstorageformof
carbohydrateinanimalsandasstarchinplants.
•Glucoseisthemajorsourceofenergytothecellsthataresuppliedthroughthefood.Thisprocessis
activatedduringrestperiodsofCoricycle(Lacticacidcycle)intheliverandalsoactivatedbyinsulinin
responsetohighglucoselevels(aftermeal).
•Theexcesscarbohydratesarestoredintheformofglycogenwhichcouldbefurtherbrokendownto
glucosewhenneeded.

11. HMPshuntpathway:Althoughglycolysisandcitricacidcycle
arethecommonpathwaysbywhichanimaltissuesoxidiseglucoseto
CO
2andH
2OwiththeliberationofenergyintheformofATP,a
numberofalternativepathwaysarealsodiscovered.Themost
importantoneisHexoseMonophosphateShuntPathway(HMP
shunt).
Step1
Glucose6-phosphateinthepresenceofNADPandtheenzyme
glucose6-phosphatedehydrogenase,forms6-phosphoglucono-d-
lactone.ThefirstmoleculeofNADPHisproducedinthisstep.
Step2
The6-phosphogluconod-lactoneisunstableandtheester
spontaneouslyhydrolysesto6-phosphogluconate.Theenzymethat
catalysesthereactionislactonas.
Step3
6-phosphogluconatefurtherundergoesdehydrogenationand
decarboxylationby6-phosphogluconatedehydrogenasetoformthe
ketopentose,D-ribulose5-phosphate.Thisreactiongeneratesthe
secondmoleculeofNADPH.
Step4
Theenzymephosphopentoseisomeraseconvertsribulose5-
phosphatetoitsaldoseisomer,D-ribose5-phosphate.

12. Gluconeogenesis
PathwayofGluconeogenesis
1.Gluconeogenesisoriginatesintheliverorkidney’scytoplasmor
mitochondria.Tomakeoxaloacetate,twopyruvatemoleculesare
requiredtocarboxylatefirst.ThisrequiresoneATP(energy)
molecule.
2.NADHconvertsoxaloacetatetomalate,whichcanthenbe
transportedoutofthemitochondria.
3.Oncemalateleavesthemitochondria,itisoxidisedbackto
oxaloacetate.
4.TheenzymePhosphoenolpyruvatecarboxykinase(PEPCK)
convertsoxaloacetatetophosphoenolpyruvate.
5.Byreversingglycolyticprocesses,phosphoenolpyruvateis
convertedintofructose1,6-bisphosphate.
6.Fructose-1,6-bisphosphateisconvertedtofructose-6-phosphate
inthereactionreleasinginorganicphosphateandiscatalysedby
fructose-1,6-bisphosphatase.
7.Theenzymephosphoglucoisomeraseconvertsfructose-6-
phosphatetoglucose-6-phosphate.
8.Glucose-6-phosphategeneratesinorganicphosphatethatyields
freeglucose,whichenterstheblood.Glucose6-phosphataseisthe
enzymeinvolved.

13. Step1 Step2 Step3
Step4
In some tissues, the hexose phosphate pathway ends at this point, and its
overall equation is
The net result is the production of NADPH, a reductant for biosynthetic
reactions, and ribose 5-phosphate, a precursor for nucleotide synthesis.

14. Glycogenstoragedisease(GSD)Glucoseisthemainsourceoftheenergy
forthebodyandthroughtheactionofenzymes,thebodyjuststoredtheglucoseinthe
formofglycogenwhichisthenreleasedintothebloodwheneverthebodyneedsit.
•GSDexistsinmanytypes,butallpeoplewhohavetheconditionwerebornwithit.
SymptomsofGSDincludeBecauseofalackofenzymes,theliverisunableto
controlglucoseandglycogenuse,asglucosecannotbeturnedintoglycogenor
releasedfromglycogen.
•Hypoglycemiaisaconditioninwhichthereisnotenoughglucoseintheblood.
•Sugarsofferenergytothebodyandhencesugarsaswellasglucoseisfoundinfoods.
Thebloodsugarlevelincreasesafterfoodconsumption.
•Glycogenisthereforenotneededimmediatelyforthebodyandhenceitisthestorage
formofglucose.
•Eventually,thebodywillusethisstoredenergyasthelevelsofbloodglucosebegin
todrop.Alivercanaccumulateglycogenoroneofitsrelatedstarchesiftheenzymes
requiredtoprocessthemarenotpresent

15. Hormonal regulation of blood glucose:
•Thepancreassecretesglucagon,apeptidehormonethatelevatesbloodglucoselevels.
•Itsactionisdiametricallyopposedtothatofinsulin,whichreducesbloodglucoselevels.
•Glucagonincreasesglycolysis,thebreakdownofglycogen,andtheexportofglucoseintothe
circulationonceitreachestheliver.

16. Lipid metabolism

17. •Lipids are fats which are essential for the body for certain functions.
•They are synthesized by liver and absorbed by the food in the body.
•Triglycerides (TGs) and cholesterol are the main lipids in living things.
•Triglycerides act as storing of energy in adipocytesand muscle cells whereas cholesterol is ubiquitous
constituent of cell membranes, steroids, bile acids and signaling molecules and produce steroid hormones like
sex hormones.
•All lipids are hydrophobic and mostly insoluble in blood.
•They require transport within hydrophilic, spherical structures called lipoproteins.
•Lipoproteins are particles made up of droplets of fats surrounded by a single layer of phospholipidmolecules.

18. Lipolysis:Lipolysisistheprocessbywhichfatsarebrokendownin
bodiesthroughenzymesandwater,orhydrolysis.Thatmeansitisthe
biochemicalpathwayresponsibleforthehydrolysisoftriglyceridesinto
non-esterifiedfattyacidsandglycerolwiththehelpoflipasesenzymes.
Differenttypesoflipolysisare-
Gastrointestinallipolysisisresponsibleforthecatabolismandthe
subsequentabsorptionofdietarytriacylglycerol.Theinvolvedenzymes
arelingual,gastricandpancreaticlipases
Vascularlipolysismediatesthehydrolysisoflipoproteinassociated
triacylglycerolsinthecapillarybed.Theinvolvedenzymesare
lipoproteinlipase(LPL),andhepaticlipase.
Intracellularlipolysisisresponsibleforthehydrolysisof
triacylglycerolsstoredinintracellularlipiddroplets.Itinvolvesneutral
andacidlipases.
Lipolysisisveryimportantinthefastingstate,ofmetabolism.The
majorenzymeinvolvedinthisprocessareadiposetriglyceridelipase
(AGTL),hormone-semsitivelipase(HSL)andmonoglyceridelipase
(MGL).Theendproductofliposysisisfattyacidandglycerol.

19. Beta Oxidation of Palmiticacid
β-oxidationofsaturatedfattyacyl-CoA(ncarbons)occurswithinthe
mitochondriainfivestepsasdiscussedbelow:
Step1:Infirststep,longchainfattyacid(palmiticacid,C-16)is
convertedintofattyacylCo-Awiththehelpofthiokinaseenzyme.
Mg2+actsasacoenzyme,ATPisutilizedandconvertedintoAMPand
PPi.
Step-2:Acyl-CoAisoxidizedtotrans-Δ
2
-enoyl-CoAwithatrans
doublebondbetweenαandβcarbonatoms(C-2andC-3)withanacyl-
CoAdehydrogenaseenzyme.FADactsasanelectronacceptorandis
convertedintoFADH
2whichultimatelyentersintotherespiratorychain.
Step-3:Inthisstep,betahydroxyacylCoAisproducedfromtrans-A2-
enoyl-CoAwhichisL-stereoisomer,byhydrationmethodwiththehelp
ofenolCoAhydrataseenzyme.
Step-4:InthisstepoxidationofbetahydroxyacylCoAtakesplace.β
hydroxy-acyl-CoAisdehydrogenatedtoformβ-ketoacyl-CoAwiththe
helpofβhydroxy-acyl-CoAdehydrogenaseenzyme.NAD+actsasan
electronacceptorandconvertedintoNADH.
Step-5:Thisisthefinalstepofthereactionwherethecleavageofβ-
ketoacyl-CoAtakesplacebythethiolgroupofasecondmoleofCoA,
whichyieldsacetyl-CoAandanacyl-CoA.Thisthiolyticcleavageis
catalysedbyacyl-CoAacetyltransferaseenzyme.Thisenzymeisalso
knownasβketo-thiolaseorthiolase.

21. Ketogenesis:
•Ketogenesisisacatabolicpathwayofmetabolismthrough
whichketonebodiesareproduced.
•Fattyacidsundergooxidationinthelivermitochondriato
generatehighamountofenergyandformthreeketone
compounds(Acetoacetate,D-3-hydroxybutyrate,andAcetone).
•Ketogenesishappensatahigherratewhen
1.Underlowbloodglucoselevel,e.g.duringfastingor
starvation.
2.Onexhaustionofcarbohydratereserve,e.g.glycogen.
3.Thereisinsufficientinsulin,e.g.Type-Idiabetes.
Theketogenesisprocessoccursprimarilyinmitochondriaofliver
cells.Belowarethestepsintheprocessofketogenesis.
1.Transferoffattyacidsinmitochondriabycarnitine
palmitoyltransferaseCPT-1
2.β-oxidationoffattyacidtoformacetylCOA.
3.Acetoacetyl-CoAformation:2acetylCOAform
acetoacetylCOAThereactioniscatalyzedbytheenzymethiolase.
4.3-hydroxy-3-methyIgIutaryl-CoA(HMG-CoA)
synthesis:ThestepiscatalyzedbyHMG-CoAsynthase.
5.Acetoacetateformation:HMG-CoAisbrokendown
toacetoacetateandacetyl-CAbytheactionofHMG-CoAIyase.

22. Ketolysisistheoppositeprocesstoketogenesis.Itencompassesasetof
reactionsthataimtoregainenergyviaoxidationofketonebodies,which
takesplaceinmitochondriaduetothepresenceofhighactiveenzymes
acetoacetatethiokinaseandthiophorase.Ketolysisprocessnotoccurinliver,
duelackingofabovetwoenzymes.Heart,skeletalmuscleunderexertion
andbraininstarvationconditionsuseketonebodiesasamajorenergy
storagemolecule.
Process-
➢Beta-hydroxybutyrateisdehydrogenatedtoformacetoacetateinthepresence
ofbetahydroxy-butyratedehydrogenaseenzyme.
➢ActivationofacetoacetatetoacetoacetylCoAoccursbytwowayseithervia
formationofsuccinylCOAwiththeenzymesuccinylCoAacetoacetateCoA
transferase(COAtransferase)orviaactivationofacetoacetatewithATPin
thepresenceofCoA-SHcatalysedbythiokinase(AcetoacetylCoAsynthase).
➢Thereafter,acetoacetylCoAsplitstoacetylCoAbythiolaseenzymeand
oxidizedviacitricacidcycletoCO
2andH
2O.

23. Utilization of ketonebodies
Theketonebodies,beingwater-soluble,areeasilytransportedfromthelivertovarious
tissues.Thetwoketonebodies-acetoacetateandβ-hydroxybutyrateserveasimportant
sourcesofenergyfortheperipheraltissuessuchasskeletalmuscle,cardiacmuscle,renal
cortexetc.Thetissueswhichlackmitochondria(e.g.erythrocytes)however,cannot
utilizeketonebodies.Theproductionofketonebodiesandtheirutilizationbecomemore
significantwhenglucoseisinshortsupplytothetissues,asobservedinstarvation,and
diabetesmellitus.Duringprolongedstarvation,ketonebodiesarethemajorfuelsource
forthebrainandotherpartsofcentralnervoussystem.Itshouldbenotedthattheability
ofthebraintoutilizefattyacidsforenergyisverylimited.Theketonebodiescanmeet
50–70%ofthebrain'senergyneeds.Thisisanadaptationforthesurvivaloftheorganism
duringtheperiodsoffooddeprivation.

24. De novo synthesis of fatty acids (Palmiticacid)
1.Biosynthesisoffattyacidsoccursinallorganismsandinmammalsitoccurs
mainlyinadiposetissue,mammaryglands,andliver.
2.Fattyacidsynthesistakesplaceinthecytosolintwosteps
I)Formationofmediumchainfattyacidofchainlength16carbonatoms.
II)Lengtheningofthiscarbonchaininmicrosomesforlargerfattyacids.
3.AcetylCoAservesasasourceofcarbonatomsforsaturatedaswellas
unsaturatedfattyacids.AcetylCoAcanbeformedfromexcessivedietaryglucose
andglucogenicaminoacids(aminoacidswhichcanbeconvertedtoglucose).
Carbohydratesandaminoacidsinthepresenceofoxygenisconvertedtopyruvate
whichinturncanbeconvertedtoacetylCoA
Conversion of Acetyl CoAto MalonylCoA
The acetyl -CoAis carboxylatedin the cytoplasm in the presence of
acetyl CoAcarboxylase, a vitamin Biotin containing enzyme, which
helps in carbondioxidefixation. Acetyl CoAcarboxylaseis the
regulatory enzyme in the fatty acid biosynthesis.

25. Conversion of Malonyl CoA to Palmitic acid
Acyl-carrier protein (ACP) acetyl-CoAcarboxylase(ACC)

27. Biologicalsignificanceofcholesterol
•Itisastructuralcomponentofcellmembrane.
•Cholesterolisprecursorforsynthesisofallothersteroidsinthebody.Theseincludessteroid
hormones,vitaminDandbileacids.
•Itisanessentialingredientinthestructureoflipoproteininwhichformthelipidsinthe
bodyaretransported.
•Fattyacidsaretransportedtoliverascholesterylestersforoxidation.
•ItconvertssunshinetovitaminD.
•Itisimportantforthemetabolismoffatsolublevitamins,includingvitaminsA,D,E,andK.
•Itinsulatesnervefibers.
•Maintenanceofourbodytemperature.Protectionofinternalorgans.
•Modulationthefluidityofcellmembranes.
•Highplasmacholesterolpromotesatherosclerosis

29. VitaminDisaderivedproductofcholesterol
duetoultravioletlightactionontherings(ring
B)resultinginsplittingofthering.Cholesterol
servesasaprecursorofVitaminDviaits
intermediateproductofprovitaminD3(7-
Dehydrocholesterol)duringcholesterol
synthesis.The generationof7-
Dehydrocholesterolisduetoelectron
movementbyresonanceinringB.The
previtaminD3isconvertedintheskinto
VitaminD3(cholecalciferol)byphotolytic
actionofultravioletrays.Subsequently,the
active hormone, 5, 25 –
dihydroxycholecalciferol(Calcitriol)is
producedfromcholecalciferolinthekidneys
andliverviahydroxylationreaction