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Gluconeogenesis is the synthesis of glucose from:
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Non-carbohydrate precursors: most amino acids (except lys and leu), lactate, and glycerol
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Role of gluconeogenesis
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To help maintain adequate levels of glucose in the blood because not all cells can use serum fatty acids as fuels (brain cells and RBCs)
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Glycolysis and Gluconeogensis
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The 7/10 reversible glycolysis reactions are the same in gluconeogensis, and the enzymes that catalyze the reactions in glycolysis also catalyze the reactions in gluconeogenesis
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Glucose-6-Phosphate -> Glucose
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Glucose-6-P Phosophatase (liver enzyme), H20 -> Pi , Glucose-6-P cannot cross cell membranes, but Glucose can
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Fru-1,6-bis P -> Fru-6-P
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Fructose-1,6-bis P Phosphatase, H20 -> Pi
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Pyruvate -> PEP
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Pyruvate -> Oxaloacetate (Pyruvate Carboxylase) add CO2, ATP -> ADP + Pi; Oxaloacetate -> PEP (PEP Carboxykinase) lose CO2, GTP -> GDP
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Lactate -> Pyruvate
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LDH = lactate dehydrogenase; NAD+ -> NADH **Produce cytosolic NADH
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Alanine -> Pyruvate
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ALT = Alanine amino transferase; alpha-ketoglutarate -> Glu
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Oxaloacetate
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Cannot cross inner membrane once made from pyruvate in the mitochondrial matrix
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PEP Carboxykinase
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Catalyzes conversion of oxaloacetate (OAA) to PEP. Mitochondrial isoform: more important when lactate is the main gluconeogenic substrate. Cytosolic isoform: more important when Ala (or related amino acids) are the main gluconeogenic substrate.
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Pyruvate -> PEP when lactate is the gluconeogenic substrate
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Cytosolic NADH is made upon conversion of lactate to pyruvate, pyruvate diffuses to mitochondrial matrix, Pyruvate -> OAA (Pyruvate carboxylase), OAA -> PEP (PEP Carboxykinase (mitochondrial isoform)) PEP diffuses out of mitochondrial matrix
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Pyruvate -> PEP when Ala is the gluconeogenic substrate
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No cytosolic NADH is made upon conversion of Ala to Pyr. Pyr in mitochondrial matrix -> OAA (Pyruvate carboxylase), OAA -> Malate (malate dehydrogenase MDH), Malate diffuses out of mitochondrial matrix, Malate -> OAA (MDH), OAA -> PEP (PEP Carboxykinase (cytosolic isoform))
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[NADH] during gluconeogenesis
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Gluconeogenesis consumes NADH in the cytosol, cytosolic [NADH} decreases when Ala (but not when lactate) is the main gluconeogenic substrate. Low cytosolic [NADH] promotes conversion of cytosolic malate to OAA, which decreases cytosolic [malate] causing malate to diffuse out of the matrix into the cytosol. This decreases matrix [malate], promoting the conversion of OAA to malate in the matrix.
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2 Pyr -> 1 Glc requires ? NTPs and ? NADH
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6 NTPs and 2 NADH
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Amino acids that are broken down to pyruvate:
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Ala, Cys, Ser, Gly, Trp, Thr (other amino acids are converted into OAA via citric acid cycle intermediates
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