gluconeogenesis Flashcards
gluconeogenesis
metabolic pathway in which a precursor is converted to glucose
possible precursors to gluconeogenesis
pyruvate, lactate, glycerol (triglycerides), AAs (alanine), TCA cycle intermediates
what cannot make glucose?
acetyl-CoA
what relies on glucose as primary source of energy so its important to keep glucose levels constant?
brain, nervous system, red blood cells
what is the main site of gluconeogenesis?
liver
glycerol
supplied by adipose tissue
30% of fasting glucose from glycerol
glycerol-> glycerol 3-phosphate -> dihydroxyacetone phosphate (DHAP)
enzymes: glycerol kinase and glycerol 3-phosphate dehydrogenase
uses ATP and NAD+
alanine
supplies by muscles and is the main AA released during fasting
alanine-> pyruvate
(aketoglutarate-> L-glutamate)
enzyme: alanine amino transferase
the alanine cycle exchanges alanine and glucose between skeletal muscle and liver
lactate
supplied by red blood cells and skeletal muscle
lactate-> pyruvate
enzyme: lactate dehydrogenase
uses NAD+
the cori cycle
lactate is produced in the muscles by homolactic fermentation. lactate is released into circulation and taken up by the liver where it is used to resynthesize glucose (using liver ATP), which is returned to the muscle (for glycogen storage or energy production)
1st bypass step- synthesis of oxaloacetate from pyruvate
enzyme: pyruvate carboxylase
requires biotin (vitamin B7) cofactor and ATP
acetyl-CoA is allosteric activator
- high acetyl-coA concentrations activate the enzyme
- when oxaloacetate levels are low, acetyl-coA cannot enter the TCA cycle
occurs in mitochondria
bicarbonate + pyruvate -> __________
enzyme?
oxaloacetate
uses ATP
pyruvate carboxylase
once ____________ is produced in the mitochondria, it is transported as _________ into the cytosol, in which __________ is oxidized back to ____________
oxaloacetate; malate; malate; oxaloacetate
1st bypass step- reaction 2: synthesis of phosphoenolpyruvate (PEP) from oxaloacetate
enzyme: phosphoenolpyruvate carboxykinase (also called PEPCK)
requires GTP as energy source
mechanism is B-ketoacid decarboxylation
occurs in cytosol
2nd bypass step-dephosphorylation of fructose 1,6-bisphosphate to fructose 6-phosphate
enzyme: fructose 1,6-bisphosphatase-1, FBPase-1
highly exergonic hydrolysis– does not require ATP, is irreversible, very favorable
highly regulated
requires Mg2+
3rd bypass step- dephosphorylation of glucose-6-phosphate to glucose
enzyme: glucose 6-phosphate
highly exergonic hydrolysis
irreversible
important regulatory step
requires Mg2+
present in liver, renal, and intestinal cells
energetics of gluconeogenesis
energetically expensive, but essential
requires 6 ATP equivalents (GTP is energetically equivalent to ATP)
downstream products __________, upstream reactants _________
inhibit, stimulate
hexokinase I
high glucose affinity, but low capacity (saturation is easy)
allosterically inhibitied by their product
hexokinase 4 (aka glucokinase)
low glucose affinity but high capacity
not inhibited by product (G6P) so able to store glucose as glycogen
regulation of glycolysis and gluconeogenesis
regulation can be produced through two ways allosteric and hormonal
glucagon
signals low glucose levels
peptide hormone made in a-cells in islets of langerhans
acts as a GPCR (high camp) primarily in adipose, liver, and kidney cells
causes liver to release glucose
stimulates glycogenolysis, stops glycogenesis, stimulates gluconeogenesis, and stops glycolysis
epinephrine
works similar to glucagon
signals low glucose and/or energy required
fight or flight hormone
acts as B-adrenergic receptors (high camp) in muscle, liver, and adipose
causes liver to release glucose
stimulate glycogenolysis & inhibit glycogenesis
insulin
signals high glucose in blood
peptide hormone made in B-cells in islets of langerhans
acts as receptor tyrosine kinase in muscle, liver, and adipose
signals uptake of glucose from blood
increase glycogenesis & inhibit glycogenolysis
pyruvate kinase is activated in the liver by _________ and inhibited by __________
insulin; glucagon
only in the _______, glucagon can phosphorylate PK by PKA
phosphorylation of PK ________ its activity
liver; inhibits
only in the _________, insulin can dephosphorylate PK by PP (phosphatase)
dephosphorylation of PK ________ its activity
liver; stimulate
fructose 2,6- bisphosphatase is an allosteric activator for _______ and inhibitor for _________. F-2,6-BP is formed by the phosphorylation of F6P by PFK-2 and dephosphorylated by FBPase-2
PFK-2 & FBPase-2 exist together as a bifunctional enzyme which is under hormonal control
PFK-1; FBPase-2
low blood glucose: _________ activates PKA which phosphorylates PFK-2/FBPase-2
activates FBPase-2 & inhibits PFK-2 activity __________ F26BP levels which inhibiting ________ and activates gluconeogenesis
glucagon; decrease; glycolysis
high blood glucose: _________ activates PP1, which dephosphorylates PFK-2/ FBPase-2
activates PFK-2 and inhibits FBPase-2 _________ F26BP levels which __________ glycolysis & decreases gluconeogenesis
insulin; increase; activates
