Gluconeogenesis+is+an+important+metabolic+pathway+during+6mes+of+fas6ng+Lecture+16;+Chapters+17+++26+Gluconeogenesis+and+the+Pentose+Phosphate+Pathway!Outline+• Glucose+can+be+synthesized+from+noncarbohydrate+precursors+• Gluconeogenesis+and+glycolysis+are+reciprocally+regulated+• The+Cori+cycle+;+Purpose+of+the+Pentose+Phosphate+Pathway+(PPP)+; +Oxida6ve+phase+; +Nonoxida6ve+phase+;+Balancing+the+cellular+needs+for+ATP,+NADPH+and+ribose;5;P+To+the+liver+hOp://dtc.ucsf.edu/types;of;diabetes/type1/understanding;type;1;diabetes/how;the;body;processes;sugar/the;liver;blood;sugar/+Lactate+glycerol+Amino+acids+Lactate+Converted+to+glucose+Gluconeogenesis+Glycogenolysis+The+Liver+Regulates+Blood+Sugar+Levels+Gluconeogenesis++; Glucose+is+synthesized+; +ATP+is+consumed+; +NADH+is+oxidized+to+NAD+++In+some+ways,+Gluconeogenesis+is+the+reverse+of+Glycolysis+Glycolysis++; Glucose+is+catabolized+; +ATP+is+produced+++; NAD++is+reduced+to+NADH++However,+the+reac6ons+in+the+Gluconeogenesis+pathway+CANNOT+be+the+exact+reverse+of+the+reac6ons+in+the+Glycolysis+pathway.+WHY+?+Gluconeogenesis+is+not+exactly+the+reverse+of+Glycolysis+2 ∆G°’+=+;84+kJ+mol;1+∆G°’+=+;38+kJ+mol;1+++2+ATP+;+6+ATP+equivalent+Hexokinase+Phosphofructokinase+(PFK)+Pyruvate+Kinase+Glucose;6;Phosphatase+Fructose;1,6;bisphosphatase+++(F;1,6;BPase)+Pyruvate+Carboxylase+&+PEP+Carboxykinase+∆G=;33+kJ+mol;1+∆G=;22+kJ+mol;1+∆G=;17+kJ+mol;1+Glycolysis+;Reac6on+10:+ ΔG°′ = -31.7 kJ/mol after removing the energy used to phosphorylate ADP+Pyruvate+kinase+7+Gluconeogenesis+;Reac6ons+1+&+2:+Pyruvate+carboxylase+PEP+Carboxykinase+ATP!CO2!GTP!ADP!ADP!CO2!Pyruvate+is+Converted+to++Oxaloacetate+in+Mitochondria+Citric+acid+cycle+In+Mitochondria+Acetyl+CoA+Carboxybio6n+Pyruvate+carboxylase+requires+the+vitamin+bio6n+(vit+B7)+as+a+coenzyme+(proesthe6c+group).+CO2+Citric+acid+cycle+In+Mitochondria+Carboxyla6on+of+Pyruvate+(Pyruvate+Carboxylate)+∆G°’+for+the+last+step+is+;20+kJ+mol;1+carboxyphosphate+Carboxylated+bio6n+Oxaloacetate+must+move+out+to+the+cytoplasm+to+be+converted+to+PEP+mitochondria+mitochondria+Oxalacetate+can+then+be+converted+to+Phosphophenolpyruvate+kinase!(PEP)!(GAP)+Need+two+molecules+of+pyruvate+to+generate+one+glucose+++++++++++++++++++Pyruvate+++++++++++PEP++++++F1,6P+aldolase+Gluconeogenic;specific+enzymes+Gluconeogenesis+is+not+merely+(exactly)+the+reverse+of+Glycolysis+2 ∆G°’+=+;84+kJ+mol;1+∆G°’+=+;38+kJ+mol;1+++2+ATP+;+6+ATP+Hexokinase+Phosphofructokinase+(PFK)+Pyruvate+Kinase+Glucose;6;Phosphatase+Fructose;1,6;bisphosphatase+++(F;1,6;Bpase)+Pyruvate+Carboxylase+&+PEP+Carboxykinase+∆G=;33+kJ+mol;1+∆G=;22+kJ+mol;1+∆G=;17+kJ+mol;1+The+conversion+of+fructose+1,6;bisphosphate+into+fructose+6;phosphate+Gluconeogenesis+is+not+merely+(exactly)+the+reverse+of+Glycolysis+2 ∆G°’+=+;84+kJ+mol;1+∆G°’+=+;38+kJ+mol;1+++2+ATP+;+6+ATP+Hexokinase+Phosphofructokinase+(PFK)+Pyruvate+Kinase+Glucose;6;Phosphatase+Fructose;1,6;bisphosphatase+++(F;1,6;Bpase)+Pyruvate+Carboxylase+&+PEP+Carboxykinase+∆G=;33+kJ+mol;1+∆G=;22+kJ+mol;1+∆G=;17+kJ+mol;1+∆G+=+;25+kJ/mol+∆G°’+=+;16+kJ/mol+∆G°’+=+;13+kJ/mol+Need+two+molecules+of+pyruvate+to+generate+one+glucose+Gluconeogenic;specific+enzymes+The+genera6on+of+glucose+from+glucose+6;phosphate+Overall+cost+of+gluconeogenesi s+Coordinated+Reciprocal+Regula6on+of+Glycolysis+and+Gluconeogenesi s+Energy+Status+of+the+cell+And+Blood+SugarLevel+Glucose+metabolism+High+blood+[glucose]+Low+blood+[glucose]+gluconeogenesis+Glycogen+breakdown+TG+breakdown+Insulin+release+++;+glycolysis+Glycogen+synthesis+FA+synthesis+Decrease+blood+sugar+level+Glucose+metabolism+High+blood+[glucose]+Low+blood+[glucose]+Glycolysis+Glycogen+synthesis+FA+synthesis+Glucagon+release+;+++Increase+blood+sugar+level+Glycogen+breakdown+TG+breakdown+Gluconeogenesis+Reciprocal+regula6on+Acetyl!CoA!(9)!PKA!(9)!Glycolysis!Gluconeogenesis!Reciprocal+regula6on+ADP/!(PFK/PFK1)+citrate+Fructose+2,6;bisphosphate+(F2,6;BP)+Phosphofructokinase+2+(PFK2)+PFK1!Inac6vates+F1,6;BPase++The+domain+structure+of+the+bifunc6onal+regulatory+enzyme+phosphofructokinase+2+(PFK2)/fructose+2,6;bisphosphatase+The+domain+structure+of+the+bifunc6onal+regulatory+enzyme+phosphofructokinase+2+(PFK2)/fructose+2,6;bisphosphatase+X+F2,6BP!F6P!;+S6mulates+PFK1+(glycolysis)+;+Inhibits+F1,6;Bisphosphatase+(gluconeogenesis)+The+domain+structure+of+the+bifunc6onal+regulatory+enzyme+phosphofructokinase+2+(PFK2)/fructose+2,6;bisphosphatase+P+F2,6BP!X+F6P!;+Glycolysis+ê+;Gluconeogenesis+é+ADP+LOW!BLOOD!SUGAR+causes+phosphoryla6on+of+the+bifunc6onal+regulatory+enzyme+phosphofructokinase+2+(PFK2)/fructose+2,6;bisphosphatase+F2,6BP!X+é+Glucagon+PKA+ATP+P+F6P!PKA+inhibits+PFK2+HIGH!BLOOD!SUGAR+dephosphorylate++the+bifunc6onal+regulatory+enzyme+phosphofructokinase+2+(PFK2)/fructose+2,6;bisphosphatase+X+F2,6BP!F6P!Insulin/high+F6P+Phosphoprotein+Phosphatase+H2O+Pi+P+inhibits+F2,6BPase+Hormonal+Regula6on+Glucagon+Glucagon+receptor+cAMP/PKA+Enzyme+phosphoryla6on++The+ac6va6on+of+protein+kinase+A+by+a+G;protein+pathway+Chapt+13,+p218+/glucagon+/Glucagon+receptor++The+regula6on+of+protein+kinase+A.+C=+cataly6c+domain+R=+regulatory+domain+insulin+X+/glucagon+/Glucagon+receptor+S6mulates+phosphoprotein+phosphatase+Dephosphorylates+PKA+substrates+(GAP)+Gluconeogenesis+precursors+Pyruvate+++++++++++PEP++++++Lactate!Some!amino!acids!Some!amino!acids!Glycerol!The+Cori+Cycle+Fate+of+Pyruvate+under+ANAEROBIC+condi6ons+in+animals+and+other+microorganisms:+Lac6c+acid+Fermenta6on+(LDH)+Reversible+reac6on+• Generates+ATP+• Generates+anabolic+precursors+• Lowers+blood+sugar+level+• Increases+blood+sugar+level+• Uses+ATP+glycolysis+ gluconeogen esi s+Blood+sugar+too+high+Low+energy+charge+(Low+ATP)+Inhibit+s6mulates+insulin+insulin+• Generates+ATP+• Generates+anabolic+precursors+• Lowers+blood+sugar+level+• Increases+blood+sugar+level+• Uses+ATP+glycolysis+ gluconeogen esi
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