Metabolic Breakdown of Individual Amino AcidsProducts of Amino Acid BreakdownAnimals cannot carryout net synthesis of precursors of gluconeogenesis from acetyl-CoA or acetoacetateConversion of Pyruvate and Oxaloacetate to PEP (Gluconeogenesis)Degradation to PyruvateAlanineCysteineGlycine, Threonine and SerineGlycine —> SerineFormation of Glycine-PLP Schiff BaseFormation of KetimineFormation of SerineThreonine —> SerineFormation of Threonine-PLP Schiff BaseSlide 15Slide 16SummaryN5, N10-Methylene TetrahydrofolateSource of N5, N10-Methylene TetrahydrofolateGlycine Cleavage SystemGlycine Cleavage System (Formation of Glycine-PLP Schiff Base)Glycine Cleavage System (Decarboxylation and Transfer of 1-Carbon Unit)Glycine Cleavage System (Formation of N5, N10-Methylene THF)Slide 24Elimination of Water from SerineSerine Dehydratase (Formation of Serine-PLP Schiff Base)Serine Dehydratase (Formation of Aminoacrylate)Non-Enzymatic Step (Conversion of Aminoacrylate to Pyruvate)Slide 29Degradation to OxaloacetateAsparagine —> Aspartate —> OxaloacetateDegradation to a-KetoglutarateArginine and ProlineHistidineN5-Formimino TetrahydrofolateGlutamate and GlutamineMetabolic Breakdown of Individual Amino AcidstoCitric Acid Cycle Intermediatesortheir PrecursorsProducts of Amino Acid Breakdown•Glucogenic–Pyruvate– -Ketoglutarate–Succinyl-CoA–Fumarate–Oxaloacetate•Ketogenic –Acetyl-CoA–AcetoacetateAnimals cannot carryout net synthesis of precursors of gluconeogenesis from acetyl-CoA or acetoacetateConversion of Pyruvate and Oxaloacetate to PEP(Gluconeogenesis)COOHCH2COCOOHH3C C COOHOHCO3–(CO2)ATPH2C C COO–OPCOOHCH2COCOOHOxaloacetateADP + Pi+PyruvatePyruvateCarboxylaseOxaloacetatePhosphoenolpyruvate(PEP)GlucosePEPCarboxykinase"Gluconeogenesis"GTP GDP + CO2Degradation to PyruvateAlanine, Cysteine, Glycine, Serine and ThreonineAlanine+H3N CHC H3C O O–H3C C C O O–Oα K G G l uA l a n i n eP y r u v a t eA l a n i n e A m i n o t r a n s f e r a s eCysteine(Various Routes)Glycine, Threonine and SerineN C H3HPCH NHO–C C O O–HT h r e o n i n eG l y c i n eS e r i n e" C H2" + H2O P L PSerine ——> PyruvateGlycine —> SerineSerine Hydroxymethyl TransferaseFormation of Glycine-PLP Schiff BaseN C H3HPCH NHO–( C H2)4E n z y m e – B :N C H3HPCH NHO–C C O O–HE n z y m e – B :L y sC C O O–+H3NHH+G l y c i n eE n z y m e - P L P ( S c h i f f B a s e ) G l y c i n e - P L P S c h i f f B a s eα" T r a n s i m i n a t i o n "HFormation of KetimineN C H3HPCH NHO–C C O O–HE n z y m e – B :L y sαHN C H3HPCH NHO–C C O O–HE n z y m e – B H+L y sN C H3HPCH NHO–C C O O–HE n z y m e – B H+L y sFormation of SerineN C H3HPCH NHO–CC O O–HE n z y m e – B H+L y s+H3N CHC O O–C H2O HN5, N1 0- M e t h y l e n e - T H F+H2OE n z y m e - P L P+T H FS e r i n eThreonine —> SerineSerine Hydroxymethyl Transferase(PLP and C–C Bond Cleavage)Formation of Threonine-PLP Schiff BaseN C H3HPCH NHO–( C H2)4E n z y m e – B :N C H3HPCH NHO–C C O O–HCHH3COHE n z y m e – B :L y sC C O O–+H3NHH CC H3O H+T h r e o n i n eE n z y m e - P L P ( S c h i f f B a s e ) T h r e o n i n e - P L P S c h i f f B a s eαβ" T r a n s i m i n a t i o n "Formation of KetimineN C H3HPCH NHO–C C O O–HCHH3COHN C H3HPCH NHO–C C O O–HH3C COHE n z y m e – B H+L y sE n z y m e – B :L y sN C H3HPCH NHO–C C O O–HE n z y m e – B H+L y sFormation of SerineN C H3HPCH NHO–CC O O–HE n z y m e – B H+L y s+H3N CHC O O–C H2O HN5, N1 0- M e t h y l e n e - T H F+H2OE n z y m e - P L P+T H FS e r i n eSummaryN CH3HPCH NHO–C COO–HThreonineGlycineSerine"CH2" + H2O PLPN5, N10-Methylene TetrahydrofolateHNNNHNH2CNOH2NCONHCHCOO–n510CH2CH2COOHGlutamateSource ofN5, N10-Methylene TetrahydrofolateGlycine Cleavage SystemGlycine Decarboxylase Multienzyme ComplexorGlycine Synthase (reverse direction)Glycine Cleavage System•P-Protein: PLP-dependent glycine decarboxylase•H-Protein: lipoamide-containing protein•T-Protein: THF-requiring enzyme•L-Protein: NAD+-dependent FAD-requiring dihydrolipoyl dehydrogenaseGlycine Cleavage System (Formation of Glycine-PLP Schiff Base)N C H3HPCH NHO–( C H2)4E n z y m e – B :N C H3HPCH NHO–C C O O–HE n z y m e – B :L y sC C O O–+H3NHH+G l y c i n eE n z y m e - P L P ( S c h i f f B a s e ) G l y c i n e - P L P S c h i f f B a s eα" T r a n s i m i n a t i o n "HGlycine Cleavage System(Decarboxylation and Transfer of 1-Carbon Unit)N C H3HPCH NHO–C C O O–HHN C H3HPCH NHO–C HHSS HHSS HHCH2N H2C O2H2OHSSαE n z y m e — P L PGlycine Cleavage System(Formation of N5, N10-Methylene THF)SSHHCH2NH2T • THFSHSHHT • N5, N10-Methylene–THFNAD+ NADH + H+SSHL-proteinNH3N5, N10-Methylene TetrahydrofolateHNNNHNH2CNOH2NCONHCHCOO–n510CH2CH2COOHGlutamateElimination of Water from SerineSerine DehydrataseSerine Dehydratase(Formation of Serine-PLP Schiff Base)N CH3HPCH NHO–Enzyme–PLP+SerineC COO–H2COHHH+N CH3HPCH NHO–C COO–H2COHResonance-stabilizedSerine Dehydratase(Formation of Aminoacrylate)C C O O–H2CN C H3HPCH NHO–C C O O–H2COHN C H3HPCH NHO–O H–H2C C C O O–N H2A m i n o a c r y l a t eH2O P L P + H+Non-Enzymatic Step(Conversion of Aminoacrylate to Pyruvate)H2C C COO–NH2AminoacrylateH3C C COO–NH2H2O NH4+H3C COCOO–PyruvateTautomerizationHydrolysisH+[Imine]SummaryN CH3HPCH NHO–C COO–HThreonineGlycineSerine"CH2" + H2O PLPSerine ———> PyruvateDegradation to OxaloacetateAsparagine and AspartateAsparagine —> Aspartate —> Oxaloacetate+H3N C COO–HH2C CONH2H2O NH4+Asparaginase+H3N C COO–HH2C COO–Asparagine Aspartateα KG GluGlutamate–AspartateAminotransferaseO C COO–HH2C COO–OxaloacetateDegradation to -KetoglutarateArginine, Glutamate, Glutamine, Histidine and ProlineArginine and Proline+H3N C COO–H(CH2)3NHCH2NNH2Arginine+H3N C COO–H(CH2)3NH3+OrnithineH2OUreaArginase+H3N C COO–H(CH2)2CHONHCOO–Prolineα KG GluOrnithine- δ -AminotransferaseGlutamate-5-SemialdehydeNH2COO–Pyrroline-5-CarboxylateSpontaneous1/2 O2H2OProlineOxidaseNAD(P)+ + H2ONAD(P)H + H++H3N C COO–H(CH2)2COO–GlutamateGlutamateSemialdehydeDehydrogenaseH2OHistidineH2C COO–H2CNHNO4-Imidazolone-5-PropionateH2O H+NHC COO–CH2CH2COO–HCHHNN -FormiminoglutamateImidazolonePropionaseTHF N5-Formimino-THF+H3N C COO–CH2CH2COO–HGlutamateGlutamate FormiminoTransferase+H3N