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CELLULAR METABOLISM

An introduction to pharmacy

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CELLULAR METABOLISM

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  1. CELLULAR METABOLISM Dr. Kenneth Orimma B.Sc., M.Sc., M.B.B.S, D.I.R,D.M(Doctor of Medicine)Psychiatry

  2. CELLULARMETABOLISM WhatisMetabolism? • Cellular metabolism is the process by which cells convert nutrients into energy and the building blocks needed for the synthesis of macromolecules necessary for cellular function. • This process is essential for the survival of all living organisms, including humans, and plays a crucial role in clinical pharmacology. • Why cell metabolism?Cellsengageinmetabolismtosurvive,repair,replicateandcarryouttheirfunctions

  3. CELLULARMETABOLISM • Cellular metabolism occurs in two main phases: catabolism and anabolism. • Catabolism is the process by which complex molecules are broken down into simpler molecules, releasing energy that is stored in the form of adenosine triphosphate (ATP). • Anabolism, on the other hand, is the process by which simpler molecules are synthesized into complex molecules, such as proteins, nucleic acids, and lipids. • Both phases are interdependent and regulated by a complex network of enzymes, hormones, and other cellular factors.

  4. CELLULARMETABOLISM • The energy generated by cellular metabolism is essential for the proper functioning of cells and the whole organism. • In humans, the primary source of energy is glucose, which is converted into ATP through a series of metabolic pathways, including glycolysis, the citric acid cycle, and oxidative phosphorylation. • Other nutrients, such as amino acids and fatty acids, can also be metabolized to produce ATP or used as building blocks for the synthesis of macromolecules.

  5. CELLULARMETABOLISM Energy currency of the cell: ATP(AdenosineTriphosphate): • ATPisthemainenergycarrierinthecell(OthersincludeNAD,NADH) • ATPisgeneratedinthecellbyoxidationofnutrients(Includingcarbohydrates,aminoacids,lipids) • ATPisconsumedbyanyactive/constructiveprocessundertakenbythecell

  6. CELLULARMETABOLISM

  7. CELLULARMETABOLISM

  8. CELLULARMETABOLISM • ATPformswhenaphosphateisdonatedtoADP(AdenosineDiphosphate) • ATPform-→ADP+P(inorganic)+Energy • ADPform-→AMP+P(inorganic)+ Energy

  9. CELLULARMETABOLISM AerobicMetabolism: • Oxidationofnutrientsgenerallyrequiresoxygen. • Themajorityofcellsrequireoxygenmostofthetimeinordertosurvive • Aerobicmetabolismisthemostefficientwaytoreleaseenergyfromnutrients • Canonlyoccurinthepresenceofoxygen • Requiresthecelltobeabletoexchangegaseswithitssurroundings

  10. CELLULARMETABOLISM

  11. CELLULARMETABOLISM MetabolicPathways • Burningmultiplefuels(nutrients)requiresmultiplemetabolicpathways: • Carbohydrates: • Glycolysispathway • Pentosephosphatepathway • TheCitricAcidcycle(TCA),aka:‘TheKrebsCycle’ • TheElectronTransportChain(‘Oxidativephosphorylation’) • (Glycogenesis/Glycogenolysis)–Glucosestorage&retrieval • (Gluconeogenesis)–Glucosesynthesisfromothersubstrates • AminoAcids: • AminoAcidMetabolism • TheUreaCycle • Lipids: • FattyAcidOxidation • Ketogenesis/Ketolysis • (FattyAcidSynthesis)

  12. CELLULARMETABOLISM • EachMetabolicpathwayisanorderlyseriesofreactionsdrivenbyenzymes • Enzymesarecatalysts–theylowertheactivationenergyofareaction+bindsubstrates • Differenttissue-typeshavevaryingmetaboliccapabilities: • Eg:Musclespreferentiallyburnglucose • Eg:Livercellscanhandle/transformmultiplenutrients • Eg:Heartmusclecanburnglucoseorketonebodies • Eg:Braincanburnglucoseorketonebodies

  13. HormonalRegulationofMetabolism:

  14. CARBOHYDRATEMETABOLISM OverviewofCarbohydrateMetabolism: • Energyisstoredinthechemicalbondsofcarbohydrates • EnergyisreleasedasthesechemicalbondsarebrokendownandoxidizedtoCO2andH2O • Thisenergyistransferredtoactivatedcarriermoleculeswhichserveasportableenergysources • Eg:ATP • Eg:NADP/NADPH/NADH2/NADH+ • RegulatedbyInsulin,Glucagon&‘Counter-RegulatoryHormones’: • Insulin:Promotesdecreaseinblood[glucose]byincreasinguptake(glycolysisorglycogenesis) • Glucagon:Promotesincreaseinblood[glucose]byincreasingoutput(gluconeogenesisand glycogenolysis) • *Adrenaline/Cortisol:Promotesincreaseinbloodglucose

  15. CARBOHYDRATEMETABOLISM GLYCOLYSIS: • Whatisgycolysis? • Theenergy-producingbreakdownofGlucoseintoPyruvate • Thebeginningpointofcellularcarbohydratemetabolism • Note:Othernon-glucosesugarsmustfirstbeconvertedtooneoftheglycolyticintermediates • Wheredoesgycolysisoccur? • IntheCytoplasmofallcells • Therefore,firstrequirestheuptakeofextracellularglucoseINTOthecellviatheGLUTtransporter • UptakeofextracellularglucoseisregulatedbyInsulin • Somecells(RedBloodCells)relyexclusivelyonglycolysisforenergy(nomitochondria)

  16. CARBOHYDRATEMETABOLISM Glycolysis continued Summary:Glycolysisconverts1xGlucosemoleculeinto… • 2xPyruvates (Whichthenpassintothemitochondria→TCA/KrebsCycle) • 4xATP–Netgain=2ATP’s (2spent,4produced) • 2xNADH–Netgain=2NADH’s (0spent,2produced)

  17. CARBOHYDRATEMETABOLISM THECITRICACIDCYCLE(TCA)/‘KREBSCYCLE’: • WhatisKreb’s cycle? • TheintermediatestepbetweenGlycolysis&OxidativePhosphorylation(ElectronTransportChain) • GlycolysissuppliestheTCAcyclewithPyruvate • TCACyclesuppliestheElectronTransportChainwithNADH,FADH, • WheredoesKreb’s cycle occur? • OccursintheMitochondriaofAllCells(ExceptRBCs) • RequiressufficientglucoseconcentrationinthecytoplasmtomaintainconstantsupplyofPyruvate • Note:PyruvateisconvertedtoAcetyl-CoAuponentryintotheMitochondria: • Produces1xNADH(worthapproximately 3ATP) • Consumes1xCoenzymeA • Liberates1xCO2molecule

  18. CARBOHYDRATEMETABOLISM Summary of Kreb’s cycle: TCACycleConverts1xPyruvatemoleculeinto… • 3xNADH (Whichlatermakes9ATP) • 1xFADH (Whichlatermakes2ATP) • 1xGTP (Whichlatermakes1ATP)

  19. CARBOHYDRATEMETABOLISM ELECTRONTRANSPORTCHAINS/OXIDATIVEPHOSPHORYLATION: • Whatisoxidative phosphorylation? • Aseriesofproteins,lipids&metalsthatfacilitateelectronmovement • ElectronmovementcreatesaProtongradientwithintheOuter&InnerMitochondrialMembrane • HarnessingtheflowofProtonsisusedbyATP-SynthasetogenerateATP • Wheredoesoxidative phosphorylation occur? • OccursintheInnerMitochondrialMembrane&Inter-MitochondrialMembraneSpace • Summary:OxidativePhosphorylationConverts… • NADH(producedinTCA)→NAD+3xATP • FADH(producedinTCA)→FAD+2xATP • LargeamountsofOxygen→CO2+H2O • Yieldsapproximately30-34ATPtotal(dependingoninitialfuel)

  20. PROTEINMETABOLISM: AMINO ACID UNIT OF PROTEIN AMINOACIDMETABOLISM&THEUREACYCLE • Aminoacids=NitrogenousOrganiccompoundswith–NH2&-COOHgroups • Humanscanonlymakesomeofthe20AminoAcidsrequiredbyourphysiology • Plants&microbescanmakeall20aminoacids(viatransaminationreactions) • Humansgaintheremaining‘essentialaminoacids’throughdiet • DietaryproteinsmustbebrokendownintotheirconstituentAminoAcidsinordertobemetabolized: • Oncebrokendownbydigestiveenzymes,AminoAcidsareabsorbedintheintestines • Intestinalabsorption→Portalveindeliversabsorbedaminoacids→Liver • Liver→Synthesizesnon-essentialaminoacids • Allaminoacids→deliveredtobodycellsviablood→Uptakeintocellsviaactivetransport

  21. PROTEINMETABOLISM: AMINO ACID UNIT OF PROTEIN SomeAminoAcidsare‘Glucogenic’;someare‘Ketogenic’: • GlucogenicAminoAcids: • AminoacidsthatcanbeconvertedintoGlucosethroughGluconeogenesis • (Seediagram) • KetogenicAminoAcids: • AminoacidsthatcanbeconverteddirectlyintoAcetyl-CoA(theprecursortoKetoneBodies) • (Seediagram) • Note:Leucine&Lysineareexclusivelyketogenic • Note:SomeaminoacidsarebothGlucogenic&Ketogenic: • Phenylalanine • Isoleucine • Threonine • Tryptophan • Tyrosine

  22. PROTEINMETABOLISM: AMINO ACID UNIT OF PROTEIN AminoAcidMetabolismProducesAmmonia(NH4): • Ammonia(NH4)isTOXIC&thereforemustbedetoxifiedtoUrea(Non-toxic) • UreaCycleisresponsibleforthisdetoxification

  23. PROTEINMETABOLISM: AMINO ACID UNIT OF PROTEIN THEUREACYCLE: • Whatisit? • ThecriticaldetoxificationpathwayofAmmonia(NH4)→Urea(NH2)2CO • Consistsof4xenzymaticreactions(1xmitochondrialreaction&3xcytosolicreactions) • Whereinthebodydoesitoccur? • PrimarilyoccursintheLiver→Ureareleasedintobloodstream→Excretedintourinebykidneys • Also,inkidneystolesserextent • Whereinthecelldoesitoccur? • Mitochondria(1ofthe4reactions) • Cytosol(3ofthe4reactions) • Summary: • Costs3xATP→2xADP+1xAMP

  24. PROTEINMETABOLISM: AMINO ACID UNIT OF PROTEIN TheAspartate-Arginino-succinateShunt’(UreaCycle’sRelationshipwiththeTCACycle): • TheUreaCycle&TCAcycleareindependentbutcanfeedintoeachother • TransaminationofaTCA-producedOxaloacetate→suppliesUreaCyclewithAspartate • FumarateproducedbyUreaCycle→Malate→EnterstheTCAcycle

  25. FATTYACIDMETABOLISM OverviewofFattyAcidMetabolism: • FattyAcids=TheSimplestLipidform • ConsistofaCarboxylicAcid o+aLongCarbon + Hydrogenchain • ChainLengthVaries: • DietaryFats:Short-MediumChainFattyAcids • In-VivoFats(Synthesizedbythebody;Liver&Adipose):LongChainFattyAcids • Functions: • Fuel:Fattyacidsaremetabolizedtoproduceenergy(ATP)via‘Beta-Oxidation’ • EnergyStorage:Thehighestenergy-densityofallnutrientclasses(mostATPpergram) • Precursors:FattyacidsareprecursorsforTriglycerides,Phospholipids,Hormones&Ketones

  26. FATTYACIDOXIDATION: • 1:Lipolysis(Adiposetissue): • Lipase→RemovesthefattyacidchainfromtheGlycerolonatriglyceride • StimulatedbyGlucagon&Epinephrineinresponsetodecliningbloodglucoselevels • 2:FattyAcidsenterBloodstream: • Fattyacidsarenotwater-soluble,soaretransportedbyplasmaAlbumin • 3:FreeFattyAcidsenterMetabolizingCells: • EnterviaSpecifictransportproteins(eg:SLC27) • 4:FattyAcidisreactedwithCoenzymeAtogiveFatty-Acyl-CoA • 5:Fatty-Acyl-CoAentersMitochondrionviathe‘CarnitineShuttle’ • 6:BetaOxidation→TCACycle: • Beta-Oxidationcutslongcarbonchainsofthefattyacidsintomultiple2-carbon(Acetate)units • EachAcetateunitcombinewithCo-Enzyme-AtoformAcetyl-CoA • Acetyl-CoA→combineswithOxaloacetate→Citrate • Citrate→FeedsdirectlyintotheTCACycle

  27. CLINICAL APPLICATIONS • Understanding cellular metabolism is essential in pharmacology, as drugs can interfere with the metabolic pathways involved in the synthesis and degradation of various molecules, including drugs themselves. • For example, many drugs are metabolized by the liver enzymes known as cytochrome P450 (CYP) enzymes. • These enzymes are involved in the metabolism of many endogenous and exogenous compounds, including drugs. • Alterations in CYP activity can affect the pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics (drug-receptor interactions) of drugs. • Therefore, understanding the metabolic pathways involved in drug metabolism can help predict and prevent potential drug interactions and adverse drug reactions.

  28. CLINICAL APPLICATIONS • Another example of the clinical relevance of cellular metabolism is the use of pharmacogenomics. • Pharmacogenomics is the study of how an individual's genetic makeup affects their response to drugs. • Many genes involved in drug metabolism and transport, such as CYP enzymes, are polymorphic, meaning they can have different versions or alleles. • These genetic variations can affect drug efficacy and toxicity and contribute to inter-individual variability in drug response

  29. CLINICAL APPLICATIONS • Cellular metabolism is a fundamental process in all living organisms, including humans, and plays a crucial role in clinical pharmacology. • Understanding the metabolic pathways involved in drug metabolism and the genetic factors that affect drug response can help predict and prevent potential drug interactions and adverse drug reactions, leading to safer and more effective drug therapy.

  30. THE END THANK YOU

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