Chapter 17 Flashcards
(18 cards)
Gluconeogenesis
- The ability to make glucose from noncarbohydrate precursors
- Pyruvate tends to be the main source
- Liver is main gluconeogenic tissue
- Important during fasting or starvation
- Primary fuel for the brain and the only fuel for red blood cells
Gluconeogenesis: non-carbohydrate precurosors
- Pyruvate: can be formed from muscle-derived lactate in the liver by lactate dehydrogenase
- The carbon skeletons of some amino acids; can be converted into gluconeogenic intermediates
- Glycerol, derived from the hydrolysis of triacylglycerols; can be converted into dihydroxyacetone phosphate, which can be processed by gluconeogenesis or glycolysis
Gluconeogenic Pathway
Pyruvate to glucose
- Reversal of glycolysis
- Reversible enzymes are shared
- Gluconeogenesis is not a complete reversal of glycolysis
- irreversible steps
Irreversible Enzymes of Gluconeogenesis
- pyruvate carboxylase
- phosphoenolpyruvate (PEP) carboxykinase
- fructose 1,6-bisphosphatase
- glucose-6-phosphatase
Pyruvate Carboxylase
- pyruvate (3-C) into oxaloacetate (4-C)
3 stages: - Bicarbonate phosphorylated
- CO2 transferred to biotin arm of enzyme, which is called “carboxybiotin”
- requires the vitamin biotin (B7) as a cofactor
- CO2 added to pyruvate
Biotin as an Enzyme Swing Arm
- Pyruvate carboxylase requires the vitamin biotin
(B7) as a cofactor - Biotin serves as the carrier of activated CO2
- The carboxylate group of biotin is linked to lysine
- Biotin is covalently attached to the biotin
carboxyl carrier domain - Biotin transports CO2 from the biotin carboxylase
active site to the pyruvate carboxylase active site
of an adjacent subunit - Biotin acts as a swing arm, or tether
- requires Acetyl CoA to be present (allosteric regulation)
Pyruvate Carboxylase is in the Mitochondria
mitochondria: location of pyruvate carboxylase
- Pyruvate to Oxaloacetate
- Oxaloacetate is reduced to malate
- Mate transported into the cytoplasm
- malate re-oxidized to oxaloacetate
- generates cytoplasmic NADH
- NADH utilized in subsequent steps of gluconeogenesis
Phosphoenolpyruvate Carboxykinase
- generates phosphoenolpyruvate from oxaloacetate in a phosphorylation and decarboxylation reaction
- phosphoryl donor is GTP (considered an ATP equivalent)
- adding the phosphoryl group to pyruvate is very unfavourable
- decarboxylation reactions are favorable and used to power the phosphorylation
- CO2 that was added by pyruvate carboxylase comes off in this step
Fructose 1,6-bisphosphatase
- Conversion of fructose 1,6-bisphosphate into fructose 6-phosphate is an irreversible step
- Enzyme: fructose 1,6-bisphosphatase
- highly regulated allosteric enzyme
- irreversible step
Glucose 6-phosphatase
- Free glucose is generated from glucose 6-phosphate via glucose 6-phosphatase
- glucose 6-phosphatase in ER membrane anchored
- takes place in the liver on the inner surface of the endoplasmic reticulum
- reverse activity of glucokinase in liver
- allows phosphate to be removed and glucose to move out GLUT transporters
- other tissues (e.g., muscle) lack this phosphatase: glucose 6-phosphate used for glycogen synthesis
Net Reaction of Gluconeogenesis
- Six high-transfer-potential phosphoryl groups are required in synthesizing glucose from
pyruvate: 4-ATP and 2-GTP- Evidence of coupling (ATP/decarboxylation) drives the unfavourable reactions
- Glycolysis: net 2-ATP generated
- Need to tightly regulate these reciprocal pathways
General Liver Regulation
- The interconversion of fructose 1,6-bisphosphate and fructose 6-phosphate is a key regulatory site
- Additional regulation at the interconversion of phosphoenolpyruvate and pyruvate
- Regulatory energy signals:
- ATP vs. AMP and ADP
- Citrate (build up indicates CAC cycle busy/overloaded)
- Acetyl CoA (build up indicates CAC cycle busy/overloaded) - Others: F-1,6-BP and F-2,6-BP
Liver Glycolysis/Gluconeogenesis Regulation
- Key regulator: fructose 2,6-bisphosphate
- activator of phosphofructokinase
- inhibitor of fructose 1,6-bisphosphatase
- bifunctional enzyme: one domain is phosphofructokinase 2 (PFK2); one domain is fructose 2,6-bisphosphatase (FBPase2)
Bifunctional enzyme regulation
- by glucagon signal
- phosphorylation of serine residue via
- turning off kinase automatically turns on phosphatase and vice versa
Liver PFK2-FBPase2 Regulation
Low blood glucose (fasting)
- Glucagon signaling results phosphorylation and
inactivation of PFK2 and activation of FBPase2
- F-2,6-bP gets converted to F-6-P and PFK stimulation
removed so glycolysis is inhibited
Liver PFK2-FBPase2 Regulation (after feeding)
When blood glucose increases
- Insulin signal replaces glucagon signal
- G-6-P in cell increases and F-6-P accumulates
- F-6-P activates phosphoprotein phosphatase to
remove phosphate from PFK2-FBPase2 that activates
PFK2 and inhibits FBPase2
- F-2,6-bP is made that activates PFK which stimulates glycolysis
Hormonal Control of Glycolysis and Gluconeogenesis in
Liver and Muscle is Different
- both have different isoforms of PFK2/FBPase2
- Muscle PFK2 isoform does not have the serine residue for phosphorylation
- Glucagon/epinephrine signaling has no effect on muscle PFK2/FBPase2
Liver Carries a Metabolic Burden
- Liver supports glucose needs of other tissues
- Convert lactate from other tissues to glucose
- Muscle and erythrocytes big sources of lactate
- Muscle-liver lactate exchange called → Cori Cycle
