Lecture 26: Gluconeogenesis

Gluconeogenesis

the metabolic process of synthesizing glucose from non-carbohydrate precursors (lactate, glycerol, amino acids) primarily in the liver and kidneys during fasting or intense exercise

when does Gluconeogenesis happen

when the body does not have enough glucose

Why the body needs gluconeogenesis

The liver stores glycogen but glycogen stores last only about a day once glycogen is used up, the body still needs a way to provide glucose to the brain

gluconeogenesis and glycolysis

are reverse of each other except for the 3 irreversible steps

-exergonic reactions

steps 1, 3, and 10 are irreversible

so in gluconeogenesis those steps must be bypassed but all the other steps are reversible and can be used in gluconeogenesis

The direction of the reversible reactions depends on

concentration of intermediates and the needs of the cell/body

Gluconeogenesis is the conversion of

3-carbon pyruvate into 6-carbon glucose that consumes 6 ATP and 2 NADH -expensive

anabolic reaction

gluconeogenesis bc it consumes energy and does not release energy

Gluconeogenesis location

partly in the mitochondrial matrix and then mostly in the cytoplasm bc bypass I starts in the mitochondrial matric

3 bypass reactions

created to bypass the 3 irreversible glycolysis steps B1, B2, and B3

bypass corresponds to irreversible steps

bypass III → step 1 in glycolysis

bypass II → step 3 in glycolysis

bypass I → step 10 in glycolysis

Bypass III: Glucose-6-phosphate → glucose

irreversible rxn that removes phosphate group from carbon 6 and no ATP produced only inorganic phosphate is released by enzyme glucose-6-phosphatase

enzyme in bypass III

glucose-6-phosphatase

Bypass 2: Fructose-1,6-bisphosphate → fructose-6-phosphate

irreversible rxn where phosphate group from carbon 1 by enzyme fructose-1,6-biphosphatase

bypass 3 thermodynamics

favorable bc there is 1 good factor which is the release of inorganic phosphate stabilized by increased resonance and increased by electron localization

Bypass II thermodynamics

favorable bc release of inorganic phosphate is stabilized by increased electron localization and resonance

Bypass I : Pyruvate → PEP

is 3 steps (irreversible) where a phosphate is added and a double bond is formed that starts in the mitochondrial matrix bc the pyruvate from glycolysis is taken in mito matrix for PDH and krebs cycle

step 1 of bypass I: pyruvate → oxaloacetate

carbon dioxide is added by enzyme pyruvate carboxylase and ATP is consumed

enzyme class: carboxylase

adds CO2 to a substrate

Step 2 of bypass I: oxaloacetate → PEP

decarboxylation bc CO2 is released by enzyme phosphoenolpyruvate carboxykinase-type (not tested) and GTP is used here

Step 3 of bypass I: associated energy handling

The GDP produced is readily converted back toward GTP logic and this contributes to the ATP/GTP accounting

Overall cost of bypass I

pyruvate + 2 ATP equivalents → PEP + ADP/GDP-related products + Pi

since gluconeogenesis uses 2 pyruvate bypass 1 runs twice so 4 ATP total used

Thermodynamics of bypass I

3 bad factors but each ATP hydrolysis gives 2 good factors which 4 total good factors

net total is 1 net good factors which allows bypass I to proceed

Overall energy comparison: glycolysis

net: 2 ATP, 2 NADH, and 2 pyruvate

Overall energy comparison: gluconeogenesis

net: 6 ATP and 2 NADH

4 ATP in bypass I and 2 ATP in reverse direction

gluconeogenesis

running glycolysis and gluconeogenesis at the same time but it is inefficient bc overall result is just wasting ATP

net result of fuel cycle

you spend 4 ATP and generate heat

Glycolysis

high cell energy → inhibits glycolysis

low cell energy → activates glycolysis

Gluconeogenesis

high cell energy → activates gluconeogenesis

low cell energy → inhibits gluconeogenesis

Fructose-2,6-bisphosphate

isomer of fructose-1,6-bisphosphate, it plays an important role in regulating both pathways

Fructose-2,6-bisphosphate effect

activates glycolysis

inhibits gluconeogenesis

Activators of gluconeogenesis

pyruvate and acetyl-CoA

Inhibitors of gluconeogenesis

AMP and fructose-2,6-bisphosphate