GLUCONEOGENESIS

 

 

·        Net synthesis of glucose from NON-CARBOHYDRATE precursors.  [Carbohydrates are (CH2O)n]

 

·        When fasting, most of the body’s needs for glucose must be met by gluconeogenesis.

 

·        Precursors:    ¨lactate            ¨pyruvate       ¨TCA intermediates

                             ¨carbon skeletons of MOST amino acids

                               ® OXALOACETATE as common metabolite.

 

·        In animals:      ¨Leu and Lys ® ® acetyl-CoA but not oxaloacetate.                         ® inactive in gluconeogenesis.

                             ¨All other amino acids ® ® oxaloacetate.                                  ® active in gluconeogenesis.

 

·        In plants:         acetyl-CoA is active in gluconeogenesis via GLYOXYLATE pathway.

 

Differential Regulation of Biosynthesis and Degradation

 

·         Processes for biosynthesis and degradation are differentially regulated.

 

·         One is not the exact reversal of the other.

 

·         The two processes are sometimes completely different pathways (e.g. synthesis and degradation of proteins or nucleic acids).  Alternatively, they could share some common steps but some key steps in one pathway are irreversible and require new enzymes (often allosteric) to catalyze different reactions in the opposite direction (e.g. glycolysis and gluconeogenesis).

 

·         Enzymes are catalysts.  They enhance the reaction rates but do not change the equilibrium of the reactions.

 

·         In comparison to a non-catalyzed reversible reaction, a catalytic enzyme will enhance the rates in both directions to the same extent. 

 

 

 

 


·         However, if the A à C and the reverse A ß C are two different reactions catalyzed by two different enzymes, then they can be differentially regulated.

 

GLYCOLYSIS vs GLUCONEOGENESIS (Fig. 15-23)

 

·        Most of the enzymes required for gluconeogenesis are the same ones in glycolysis.

 

·        3 irreversible steps in glycolysis:  hexokinase; phosphofructokinase; pyruvate kinase.

 

·        New enzymes are needed to catalyze new reactions in the opposite direction for gluconeogenesis.

 

·        Additional needs for transport.

 

PYRUVATE (Cytosol) ® PEP (Cytosol)

 

 

1.  Pyruvate in cytosol ® mitochondria via a specific Pyruvate-H+ symport.

Text Box:

2.  Pyruvate Carboxylase (mitochondrial)

     Oxaloacetate can be INDIRECTLY transported into cytosol.

 

Text Box:

3.  Phosphoenol Pyruvate Carboxykinase (cellular location varies)

     PEP can be transported across mitochondrial membrane by a specific two-way transport system.

 

4.  The rest of enzymes required for PEP ® Glu are all cytosolic.

 

5.  Fructose-1,6-bisphosphatase

     F-1,6-bisP + H2O ® F-6-P + Pi

 

6.  Glucose-6-phosphatse

     G-6-P + H2O ® G + Pi

 

TRANSPORT OF OAA

FROM MITOCHONDRIUM TO CYTOSOL ACROSS INNER MITOCHONDRIAL MEMBRANE  (Fig. 15-28)

 

Route 1:     ¨Indirect. ¨Does not involve NADH transport.

                   ¨Involves Aspartate and Aminotransferase.

 

Route 2:     ¨Indirect. ¨Involves malate DH.

        ¨Consumes 1 NADH inside of mitochondrium and generates 1 NADH in cytosol.

                   ¨New NADH can be used by glyceraldehyde-3-P DH.

 

OVERALL

Gluconeogenesis:

2 Pyruvate + 2 NADH + 4 H+ + 4 ATP + 2 GTP + 6 H2O ®

Glu + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi

(Requires NADH and ATP/GTP as energy sources.)

 

Glycolysis:           

Glu + 2 NAD+ + 2 ADP + 2 Pi ® 2 Pyruvate + 2 NADH + 4 H+ + 2 ATP + 2 H2O

(Produces NADH and ATP.)

 

FRUCTOSE-2,6-BISPHOSPHATE

 

·        Allosteric:           Activates phosphofructokinase.

                                Inhibits F-1,6-bisphosphatase.

·        Synthesized by phosphofructokinase-2 (F-6-P + ATP ® F-2,6-bisP)

·        Degraded by fructose bisphosphatase-2 (F-2,6-bisP + H2O ® F-6-P + Pi)

·        Fig. 15-31.