BVMS1

• synthesis of glucose from non-carbohydrate sources (requires E from metabolism of fats and source of carbons)
• essential for maintaining blood glucose concentrations
• meets the body's demands for glucose when carbohydrate stores are limited (fasting and starvation)
• occurs primarily in the liver (90%) and kidney (10%)
• liver and kidney have G-6-phosphatase activity: allows release of glucose into blood stream

• Lactate produced by anaerobic glycolysis (in RBC's and exercising skeletal muscle)
• Glucogenic aminoacids (from muscle)
• glycerol
• TCA intermediates

• Lactate from exercising muscle diffuses into the blood stream
• in the liver lactate is converted to pyruvate by lactate dehydrogenase
• produces NADH in the cytoplasm

Glycerol from breakdown of Triglycerides

• amino acids can undergo transamination rxns
• amino group transferred to a-ketoglutarate
• end product is pyruvate or TCA intermediates
• (pyruvate, oxaloacetate, fumarate, succinyl CoA, a-ketoglutarate, acetoacetate and acetyl CoA)

NO

• Gluconeogenesis is NOT the reversal of glycolysis
• GNG:
• 2 pyruvate + 4 ATP + 2 GTP + 2 NADG + 2 H+ + 4 H2O --> Glucose + 4 ADP + 2 GDP + 2 NAD+ + 6 Pi

• Glycolysis:
• Glucose + 2 ADP + 2 Pi + 2 NAD+ --> 2 pyruvate + 2 ATP + 2 H+ + 2 NADH + 2 H2O

• Glucose + ATP ----hexokinase---> glucose 6-phosphate + ADP
• Fructose 6-phosphate + ATP ---PFK---> fructose 1,6-bisphosphate + ADP
• Phosphoenolpyruvate + ADP --Pyruvate kinase--> pyruvate + ATP

**these 3 reactions have a large -delta G (free energy change) and must be bypassed**

• 1) pyruvate carboxylase & PEP carboxykinase bypass pyruvate kinase step
• 2) Fructose 1,6 biphosphatase bypasses phosphofructokinase step
• 3) glucose 6 phosphatase bypasses hexokinase step

• these provide for a spontaneous pathway in the direction of glucose synthesis
• -delta G is in the direction of sugar synthesis

• pyruvate is first converted to oxaloacetate
• carboxylation rxn requiring energy
• CO2 is added by pyruvate carboxylase (a mitochondrial enzyme)
• *most enzymes for GNG are cytoplasmic* this is an exception
• pyruvate + ATP + CO2 + H2O --> oxaloacetate + ADP + Pi + 2H+
• Oxaloacetate is shuttled into the cytosol and converted to phosphoenol pyruvate (PEP)

• OAA is synthesized in the mitochondria
• OAA cannot diffue out of the mitochondria
• converted to malate and shuttled into the cytoplasm then converted back to OAA
• uses a specific malate transport system

Fructose 1,6 biphosphatase bypasses phosphofructokinase step

• Glucose 6 phosphatase bypasses hexokinase stem
• G-6-Pase is pimarily an enzyme of liver (and kidneys)
• in hepatocytes the glucose-6-phosphatase reactions allows the liver to supply the blood with free glucose
• muscle cells lack G-6-Pase and direct G-6-P to glycogen sunthesis
• G-6-Pase is located on the membrane of the ER
• hydrolysis of G-6-P released glucose into the lumen of the ER
• Glucose is packaged into vesicles for transport

• GNG expends 6 P bonds of ATP and GTP
• Glycolysis yields 2 P bonds of ATP
• if 2 pathways runs concurrently becomes a futile cycle: must be regulated!!
• when GNG is on, glycolysis should be off
• when energy stores are high, glycolysis should be off
• when energy stores are low, glucose should be rapidly degraded to provide energy
• Regulation occurs at the sites of the irreversible reactions!!!

• GNG (Fructose 1,6 bisphosphatase) is inhibited by AMP
• stimulated by citrate (signaling the cell to store energy as glucose)
• Glycolysis (phosphofructose kinase) is inhbited by ATP, citrate and stimulated by AMP (indicates low energy)
• Fructose 2,6-bisphosphate reciprocally controls these 2 enzymes
• levels are controlled by glucagon and insulin
• levels are low during startvation-stimulates GNA
• levels are high during the fed state accelerates glyc.

Glucose enters liver after meal--> insulin mediates dephosphorylation of PFK-2--> GNG is inhibited

• PEP to pyruvate: pyruvate kinase (glycolysis)
• enzyme inhibited by acetyl-CoA, ATP and alanine
• signals that energy levels are high
• also controlled by phosphorylation by glucagon and insulin (pyruvate kinase is inhibited during starvation)
• Pyruvate to oxaloacetate: pyruvate carboxylase (GNG)
• stimulated by acetyl CoA and inhibited by ADP (more GNG when energy levels are high)
• PEP carboxykinase is similarly inhibited by ADP levels