Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Lipid metabolism, Pentose phosphate pathwayand integration of energy metabolismYue [email protected] Lineberger Cancer CenterFour major physiological roles of fatty acids As fuel molecules to store energy Complete oxidation: 38 kJ (or 9 kcal) / g for fatty acids 17 kJ (4 kcal) / g carbohydrates or protein A 70 kg man: 100,000 kcal store of triacylglycerol, 600 kcal of glycogen, 40 kcal of glucose Serving as building blocks of phospholipids and glycolipids for the membrane synthesis  Used to covalently modify proteins for localizing them to membrane  Serving as hormones and intracellular messengers in cell signaling hibernation ~ 7 months 30 miles / hours x 60 hoursFatty acids are stored as triacylglycerol in adipocytes of fat tissues Adipocytes Fat droplet Fat tissue Fat mice(triglycerides)Why was fatty acid, not glycogen, evolved as the major energy reservoir? Complete oxidation of 1 g fatty acid: ~38 kJ (9 kcal) Complete oxidation of 1 g carbohydrate (or protein): ~17 kJ (4 kcal)Fatty acids are non-polar and are stored as anhydrous form1 g dry glycogen binds to 2 g water1 g fatty acids stores 6.7 times more energy as 1 g of hydrated glycogenHormones stimulate glycogen degradationactiveGlycogen degradationGlycogenPhosphorylase GlycogenphosphorylaseKinaseactiveGlycogenphosphorylaseKinaseinactiveinactiveFastingExercisingGlucagon(liver)Epinephrine (adrenaline)(muscle, liver)Adenylyl cyclasecAMPactive inactivecAMP-dependentProtein kinase AcAMP-dependentProtein kinase AGlycogenPhosphorylaseHormones stimulate fatty acid degradationFastingExercisingGlucagon(liver)Epinephrine (adrenaline)(muscle, liver)Adenylyl cyclasecAMPactive inactivecAMP-dependentProtein kinase AcAMP-dependentProtein kinase AactiveTriacylglycerollipaseinactiveTriacylglycerollipaseFree fatty acidsTriacylglycerol(stored fatty acids)Glycerol+GlycolysisAc-CoA TCAFatty acid synthesis and degradation each consists four steps and are reverse of each other8 Ac-CoA + 7 ATP + 14 NADPH + 6 H+  palmitate + 14 NADP+ + 8 CoA + 6H2O + 7 ADP + 7 Pi Fatty acid synthesis 14 NADPHs are used for the synthesis of one molecule of fatty acid (palmitate)8 NADPHs are shuttled out mitochondrial6 more NADPHs are needed Occur in the cytoplasmCholesterol: ‘a Janus-faced molecule’ Required to build and maintain membrane and modulates membrane fluidity Used as precursor for steroid synthesis  Water-insoluble: is useful cell membrane and also makes it lethal.Cholesterol synthesis also uses a lot NADPH18 Ac-CoA + 36 ATP + 16 NADPH + 4 O2 + 5 H2O + 16H+  clolesterol + 16 NADP+ + 18 CoA + 9 CO2 + 36 ADP + 24 Pi + 6 PPi  16 NADPH are used for the synthesis of one molecule of cholesterolPentose phosphate pathwayHeinz bodies & hemolytic anemia Also known as pentose shunt or PPP Occurs in the cytosol Two primary functions: Produce NADPH for biosynthesis and protection against oxidative damageProduce ribose-5-phosphate (R5P) for nucleotide biosynthesis  Includes two phases: oxidative and non-oxidative, each involving 3 enzymesPentose phosphate pathway includes two phases and produces two important metabolitesNonoxidativephaseTransaldolaseTransketolaseNucleotidesDNA, RNAG6P + 2 NADP+ + H2O  R5P + 2 NADPH + 2H+ + 2 CO2Glucose 6-phosphate (G6P) 6-phosphogluconateRibulose 5-phosphateRibose 5-phosphate (R5P)OxidativephaseGlucose 6-phosphatedehydrogenaseNADPHNADPHNADP+ NADPHGSSG2 GSHNADP+ NADPHPrecursorsFatty acidsSterolsNADH and NADPH are structurally similar, but used differentlyUsed by the respiratory chain to generate ATP Used as a reductant in biosynthetic processes and detoxificationReduced nicotinamide adenine dinucleotide (NADH)Reduced nicotinamide adenine dinucleotide phosphate (NADPH)Km of G6PD for NAD+ is 1000 times higher than for NADP+III IVIIIToxic reactive oxygen species (ROS) are produced during oxidative phosphorylation O2 O2- O22-e-e-Superoxide dismutaseGlutathione peroxidaseAntioxidantssuperoxide peroxideReactive oxygen species (ROS)Oxidative stressAging and other diseasesNADPH is used for protecting against ROS  Reactive oxygen species (ROS) causes damage to DNA, proteins, lipidsNADPH is also used for other biological processesDetoxification Phagocytosis Nitric oxide synthesisG6PD deficiency causes hemolytic anemia  Confers resistance to malaria whose optimal growth require reduced glutathione and the products of PPPMalaria landingHeinz bodies & hemolytic anemia Affect many cell types, most severe in RBCs (because of lack of mitochondria, which also produces NADPH)  The most common disease-causing enzyme abnormality, affecting ~400 million worldwide Caused by point mutations in G6PD and reduced enzyme activityWhy are red blood cells particularly susceptible to G6PD deficiency?RBCGUTLIVERBRAINADIPOSEMUSCLEglucoseGLUCOSEFATGFed StateInsulinGLUCOSEGLYCOGENG6PAc-CoA + NADPH DIET:GlucoseFat (TG)Protein (aa)GLYCOGENG6PGLUCOSEATPATPRBCGUTLIVERBRAINADIPOSEMUSCLE DIET:CH2O (glc)Fat (TG)Protein (aa)glucoseGLC-6-PGLUCOSEFastingStateGlucagonFFA(albumin)CO2ATPFFACO2ATPFFAGLYCOGENTGGLUCONEO-GENESISGLYCOGENUse of stored fuels(glc + fatty acids)FAhormone-sensitivelipaseFree Fatty Acid (FFA)Breakdown of triglyceride gives rise to unesterified fatty acids that are insoluble in water and are transported (i.e. solubilized and circulated) by plasma protein albumin)Pathway integration: hormone control of glycogen degradationFASTING: low glucose EXCISE: need energyBRAINBrain: the constant userLiver: the makerMuscle: the burner1. Glycogen degradation2. Gluconeogenesis3. Glycolysis4. TCA5. Oxidative phosphorylationThink what should happen, it could happen and it