Gluconeogenesis

Gluconeogenesis

pathway that converts pyruvate and related 3-4 carbon compounds to glucose

Step 1 of first bypass rxn

pyruvate is transported from the cytosol into mitochondria or generated from alanine w/in mitochondria by transmit

Step 2 of first bypass rxn

pyruvate carboxylase converts pyruvate to oxaloacetate

- requires the coenzyme biotin

Step 3 of first bypass rxn

malate dehydrogenase uses NADH to reduce oxaloacetate to malate

Step 4 of first bypass rxn

malate leaves the mitochondria through a malate transporter in the inner mitochondria membrane, then reoxidized to oxaloacetate

Step 5 of first bypass rxn

phosphoenolpyruvate carboxykinase converts oxaloacetate to PEP

- requires Mg2+ and GTP

Second bypass rxn

fructose1,6-bisphosphatase (FBPase-1) converts fructose 1,6-bisphosphate to fructose 6-phosphate by hydrolysis of the C-1 phosphate

- requires Mg2+

Third bypass rxn

glucose 6-phosphate catalyzes the simple hydrolysis of glucose 6-phosphate to glucose

- requires Mg2+

- only found in the lumen of the ER of hepatocytes, renal cells, and epithelial cells of the small intestine

Equation of gluconeogenesis

2 pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 4H2O -----> glucose + 4ADP + 2GDP + 6Pi + 2NAD+

Glucogenic amino acids

amino acids able to undergo net conversion to glucose

Glyceroneogenesis

conversion of pyruvate to dihydroxyacetone phosphate via the early reactions of gluconeogenesis, followed by a reduction of glycerol 3-phosphate

- carries out of adipocytes

How are glycolysis and gluconeogenesis reciprocally regulated?

simultaneous operation of both pathways at each point of the 3 bypass points would consume ATP w/out accomplishing chemical or biological work. regulation prevents wasteful operation of both pathways at the same time

How are hexokinases affected by glucose 6-phosphate?

- hexokinase 1,2, and 3 are all inhibited by their product

- hexokinase 4 in the liver is not inhibited

Kinetic properties of hexokinase 4

Km is higher than the usual glucose concentration

Citrate

key intermediate in the aerobic oxidation of pyruvate, FAs, and AAs

How does citrate allosterically regulate PFK-1?

- high concentrations increase the inhibitory effect of ATP

- serves as an intracellular signal that the cell is meeting its current needs for energy-yielding metabolism by the oxidation of fats and proteins

How is FBPase-1 allosterically inhibited by AMP?

- high AMP corresponds to low ATP, slows glucose synthesis

- high ATP glows glycolysis and speeds gluconeogenesis

Glucagon

hormone that signals the liver to produce and release more glucose and to stop consuming it

- released when blood glucose level decreases

insulin

hormone that signals the liver to use glucose as a fuel and as a precursor for the storage of glycogen and triacylglycerol

fructose 2,6-bisphosphate

mediates the rapid hormonal regulation of glycolysis and gluconeogenesis

- binds to PFK-1 and increases its affinity for fructose 6-phosphate

- binds to FBPase-1 and reduces its affinity for its substrate

phosphofructokinase-2

(PFK-2) catalyzes the formation of fructose 2,6-bisphosphate

fructose 2,6-bisphosphate

(FBPase-2) catalyzes the breakdown of fructose 2,6-bisphosphate

xylulose 5-phosphate

an intermediate of the pentose phosphate pathway that activates phosphoprotein phosphatase 2A

phosphoprotein phosphatase 2A

dephosphorylates the bifunctional PFK-2/FBPase-2 enzyme

- causes an increase in fructose 2,6-bisphosphate

Role of acetyl-CoA in gluconeogenesis

- allosterically stimulates pyruvate carboxylase

- allosterically inhibits pyruvate dehydrogenase

ChREBP (carbohydrate response element binding protein)

transcription factor expressed in liver, adipose tissue, and kidney

- acts in the nucleus to regulate gene expression for genes coding for enzymes needed for carbohydrate and fat synthesis