Gluconeogenesis Flashcards
Uses non-carbohydrates to produce glucose:
Lactate
Amino acids
Glycerol
Proprionyl CoA from Odd chain fatty acids
Gluconeogenesis occurs in
Liver 90%
Kidneys 10% major glucose producing organ in prolonged starvation
This pathway is important for
maintaining normal blood glucose levels
First step in gluconeogenesis is conversion of
by the enzyme
Happens in
Pyruvate -> oxaloacetate
Pyruvate carboxylase
Mitochondria of liver and kidney only kasi walang pyruvate carb sa muscle
Conversion of pyruvate from cytosol to oxaloacetate by pyruvate decarboxylase occurs in
mitochondria of liver and kidney
Pyruvate carboxylase in the mitochondria requires the coenzyme
Biotin B7
bound to lysine forming active biocytin
Pyruvate carboxylase is stimulated or regulated or allosterically regulated by
Inc levels of Acetyl CoA
Ex starvation and to replenish TCA
Inactive at low levels of acetyl coa and pyruvate is oxidized instead in TCA
During fasting, there is increased Acetyl Coa because fat is metabolized for energy
Fatty acids are metabolized by liver by beta oxidation with end product of Acetyl CoA
During starving, gluconeogenic amino acids and proprionyl coA (odd-chain fatty acids) can be shuttled to TCA to produce ATP
Inc ATP inhibits Kreb’s cycle and beta oxidation causing acetyl coA to rise hence activating pyruvate carboxylase
An experiment is performed on mice with knockout mutation resulting in inability to metabolize triglycerides.
After several days without food, how will the activity of the enzymes pyruvate carboxylase and glycerol kinase likely be altered in the knockout mice compared to healthy mice?
Decreased TAG metabolism leads to decreased fatty acid oxidation decreasing acetyl coA and decreasing pyruvate carboxyalse leading to decreased gluconeogenesis
Decreased TAG metabolism leads to dec glycerol leading to dec glycerol kinase
Decreased glycerol leads to a decrease in
DHAP with decreased activity Glycerol kinase
Second step:
Oxaloacetate from mitochondria is converted into this substrate to enter the cytosol
Malate by enzyme malate dehydrogenase
Oxaloacetate should be converted into Malate because in order for it to be shuttled to
cytosol because it cannot cross the mitochondrial membrane
Malate shuttle
NADH is generated each time malate is converted into oxaloacetate and is shunted by
Malate shuttle
Once in the cytoplasm, malate is convered back to
Oxaloacetate also generating
NADH
Third step: In the cytosol, oxaloacetate is converted to or decarboxylated and phosphorylated
by the enzyme
Phosphoenolpyruvate
Phosphoenolpyruvate carbokinase (PEPCK) pyruvate carboxylase
using up GTP to become GDP
Provides energetically favorable pathway from pyruvate to PEP
GTP utilized by PEPCK to convert Oxaloacetate to phosphoenolpyruvate comes from this reaction of TCA
Succinyl coa -> succinate by succinate synthase
Step 4: Phosphoenolpyruvate is converted to
By enzyme
Fructose 1,6 bisphosphate
Fructose 1,6 bisphosphatase bypasses the irreversible PFK1
*regulatory site of gluconeogenesis
Increase in fructose 1,6 bisphosphate allows conversion to frucose 6 phosphate. Fructose 6 phosphate is converted to glucose 6 phosphate.
Glucose 6 phosphate is converted to glucose by the enzyme
Glucose 6 phosphatase
Glucose 6 phosphate is converted to glucose in the
Liver and kidneys
This upregulates or increases activity of glucose 6 phosphatase
Glucagon
Deficiency of glucose 6 phosphatase is
Von Gierke’s
Type I GSD
Lactate
Gluconeogenic amino acids
enter gluconeogenesis via
Pyruvate in cytosol
Glycerol enters gluconeogenesis via
DHAP in cytoplasm
Gluconeogenic amino acids Proprionyl CoA (from odd-chain fatty acids) enter gluconeogenesis via
TCA in matrix of mitochondria
17/M
2 month history of weight loss, depression and a red blistering rash primarily affecting the leg
Two days ago, developed DVT
Rash consistent with necrolytic migratory erythema
Hyperglycemia
How will activity of fructose 1,6 bisphosphate and glucose 6 phosphatase likely be altered?
Glucagonoma (Dermatitis, Depression, Declining weight, DVTs)
Glucagon dec concentration of fructose 2,6 bisphosphate by increasing activity of fructose 2,6 bisphosphate
fructose 1,6 bisphosphatase activity is increased resulting in increased conversion of fructose 6 phosphate and increases glucose 6 phosphatase hence increased gluconeogenesis
Liver glycogen can only sustain glucose in absence of carbohydrate intake within
10-18 hours
4 alternate reactions that energetically favor synthesis of glucose
(Carboxylation of pyruvate)
pyruvate -> oxaloacetate
(Transport of oxaloacetate to cytosol)
Oxaloacetate -> phosphoenolpyruvate
(Decarboxylation of cytosolic oxaloacetate)
(Dephosphorylation of fructose 1,6 bisphosphate)
Fructose 1,6 -> fructose 6
Glucose 6 phosphate -> glucose
Fructose 1,6 bisphosphatase is inhibited by
inc AMP signalling poor energy state
Fructose 2,6 bisphosphatase (allosteric) influenced by glucagon
Fructose 1,6 bisphosphatase is stimulated by
ATP
Low AMP
stimulating gluconeogenesis
Final step in gluconeogenesis
Glucose 6 phosphatase -> glucose by glucose 6 phosphatase
Deficiency of enzyme on the last step of gluconeogenesis leads to
Von Gierke Type 1 Glucose 6 Phosphatase deficiency
Affects liver, kidney and intestine Fasting hypoglycemia severe Fatty liver and hepatomegaly Hyperlactiacidemia and hyperuricemia Normal glycogen structure increased glycogen stored
Von Gierke’s Glucose 6 Phosphatase Deficiency
Type I
Most important GLUCONEOGENIC precursors
Glycerol - from hydroysis of TAG
Lactate - from RBC and skeletal muscle ; from Cori cycle (blood glucose -> lactate by muscle)
Ketoacids (pyruvate, oxaloacetate and alpha-ketoglutarate) from glycogenic amino acids forming oxaloacetate
Alpha keto acids from metabolism of glycogenic amino acids
Pyruvate
Oxaloacetate
a-ketoglutarate
Ketogenic compounds like acetyl coa from acetoacetate and ketogenic amino acids cannot give rise to synthesis of glucose because
Pyruvate to Acetyl coa by Pyruvate dehydrogenase is irreversible
Instead they give rise to ketone bodies
Hormone stimulating gluconeogenesis by
1) allosteric effect (low fructose 2,6 inc fructose 1,6 bisphosphatase and inhibition of PFK)?
2) covalent modification (inc cAMP and cAMP Protein kinase stimulates pyruvate kinase to inactive phosphorylated form) dec PEP to pyruvate
Glucagon
Gluconeogenesis is regulated by
Glucagon
Substrate availability (glycerol, lactate, a-ketoacids)
Mobilization of amino acids from muscle protein and provide carbon skeletons for gluconeogenesis
Allosteric activation of pyruvate carboxylase by acetyl coa accumulation
Glucogenic Amino acids
Glycine Serine Valine Histidine Arginine Cysteine Proline Alanine Glutamate Glutamine Aspartate Asparagine Methionine
Both glucogenic and ketogenic amino acids
Tryptophan
Tyrosine
Isoleucine
Phenylalanine
Ketogenic amino acids
Leucine
Lysine
Glycogen reserves drop after
12 hours
Inc gluconeogenesis
After 24 h, gluconeogesis is sole source
Between meals, what happens to fatty acids
oxidation of fatty acids in liver -> acetyl coa accumulates -> pyruvate carboxylase converts pyruvate to oxaloacetate and conversion of lactate and alanine to acetyl coa prevented
In the well fed state, what happens to acetyl coa
Acetyl coa accumulated is shuttled to cytoplasm for fatty acid synthesis from increased pyruvate formation (pyruvate dehydrogenase)
Alcoholics are susceptible to hypoglycemia because of
the formation of high amounts of cytoplasmic NADH from alcohol dehydrogenase and acetaldehyde dehydrogenase
Key central point of gluconeogenesis
Activated by ATP
Fructose 1,6 bisphosphate
Fructose 1,6 bisphosphate is inhibited by
AMP
Fructose 2,6 bisphosphate
Present in lumen of ER of liver
Glucose 6P is transported into ER and free glucose is transported back into cytoplasm
Absent in skeletal muscle accounting for the the fact that muscle glycogen cannot serve as source of blood glucose
Glucose-6 phosphatase
