BIOC 203 - midterm 4 / glycogen, gluconeogenesis

what is the overall structure of glycogen?

chains consisting of 12-14 glucose residues

• a1-a4 linkage

branch point at every 5-6 glucose residues

• a1-a6 linkage

what is the chain structure of glycogen?

• reducing end = linkage at C4

• non-reducing end = free OH group on C4

what is step 1 of glycogen synthesis?

glucose phosphorylation

• glucose → glucose-6-phosphate

  • by hexokinase (muscle) or glucokinase (liver)

what is step 2 of glycogen synthesis?

isomerization

• glucose-6-phosphate → glucose-1-phosphate

  • by phosphoglucomutase

what is step 3 of glycogen synthesis?

activation

• glucose-1-phosphate → UDP-glucose

  • by UDP-glucose phosphorylase

what is step 4 of glycogen synthesis?

primer synthesis

• glycogenin = enzyme / primer

• attaches several glucose residues to itself, forms short chain

what is step 5 of glycogen synthesis?

chain elongation

• glucose units from UDP-glucose transferred to non-reducing end of glycogen chain

  • forms a1-4 linkages

  • by glycogen synthase

what is step 6 of glycogen synthesis?

branching

• 7 residue segment from non-reducing end of chain transferred to different glucose

  • forms a1-6 linkages

  • creates many non-reducing ends, increases solubility

  • by glycogen branching enzyme

summary of glycogen synthesis?

• costs 2 ATP equivalents / glucose added

• glycogen synthase requires a primer of at least 4 glucose residues

  • provided by glycogenin

what is step 1 of glycogen breakdown?

phosphorolysis

• breaking of a1-4 linkages at non-reducing ends of chain by addition of Pi

  • releases glucose 1-phosphate

  • by glycogen phosphorylase

what is step 2 of glycogen breakdown?

debranching

• bifunctional debranching enzyme acts in 2 steps

  • transferase - moves 3 glucose residues from C1-linked to C6-linked side

  • a1-6 glucosidase activity - hydrolyzes final a1-6 glucose residue, releases free glucose

what is bypass pathway 1 of gluconeogenesis?

pyruvate → phosphoenolpyruvate (PEP)

• pyruvate → oxaloacetate

  • by pyruvate carboxylase

  • uses 1 ATP / pyruvate

  • ATP hydrolysis drives carboxylation

• oxaloacetate → phosphoenolpyruvate

  • by PEP carboxykinase

  • uses 1 GTP / pyruvate

  • decarboxylation drives phosphorylation

what is bypass pathway 2 of gluconeogenesis?

fructose-1,6-bisphosphate → fructose-6-phosphate

• removal of phosphate group from fructose-1,6-bisphosphate

  • by fructose-1,6-bisphosphatase

  • key regulatory step

what is bypass pathway 3 of gluconeogenesis?

glucose-6-phosphate → glucose

• removal of phosphate group from glucose-6-phosphate

  • by glucose-6-phosphatase

what is the overall reaction of gluconeogenesis?

2 pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O → glucose + 4 ADP + 2 GDP + 2 NAD+ + 6 Pi

what are the 3 sources of carbon / fuel for gluconeogenesis?

lactate / pyruvate

• during high muscle activity, glucose is fermented to lactate

• lactate can be taken up by liver and converted back to glucose by gluconeogenesis

amino acids

• used particularly during fasting / starvation

• can be broken down into pyruvate or Krebs cycle intermediates

• oxaloacetate used in gluconeogenesis

glycerol

• backbone of triacylglycerides (TAGs)

• can be converted into DHAP (glycolysis intermediate)

what is gluconeogenesis reciprocally regulated with?

glycolysis

• one activated, other deactivated

• ensures both pathways are not open at the same time

how is gluconeogenesis allosterically regulated?

• low cellular energy inhibits pathway

• high citrate and acetyl-CoA up-regulate

• fructose-2,6-bisphosphate controlled by insulin and glucagon

  • important regulatory molecule

how is fructose-2,6-bisphosphate regulated?

insulin increases F2,6BP

• activates glycolysis, inhibits gluconeogenesis

glucagon decreases F2,6BP

• inhibits glycolysis, activates gluconeogenesis

what is healthy fasting blood glucose?

~5mM

why is hyperglycemia?

• >= 7mM

• moderate hyperglycemia chronically can lead to type II diabetes

  • cardiovascular, vision, venal, and neurological damage

what is acute blood glucose?

• ~20-30mM

• acute hyperglycemia lack of insulin can lead to type I diabetes

  • dehydration and loss of consciousness

  • glucose pulls water out of cells

what is hypoglycemia?

• <= 4mM

• too much insulin for a diabetic, or starvation hypoglycemia

  • loss of consciousness

  • brain not getting glucose

what hormones regulate blood glucose?

• insulin

• glucagon

• epinephrine (adrenaline)

how does insulin regulate blood glucose?

released when glucose is high

• produced by B-islets in pancreas

• promotes glucose uptake by most cells

• promotes glycolysis and inhibits gluconeogenesis in liver

how does glucagon regulate blood glucose?

released when glucose is low

• produced by a-islets in pancreas

• promotes glucose release by liver

how does epinephrine regulate blood glucose?

released when glucose is needed in stress situations

• synthesized from tyrosine

• promotes glycogen breakdown in muscles

what is the fed state of the fed / fast cycle?

increase in dietary fuels

• insulin : glucagon ratio increases

• signals to cells to consume glucose

• excess glucose stored as glycogen in muscles and liver, or as fatty acids

• low levels or no gluconeogenesis happening

what is the short-term fast state of the fed / fast cycle?

decrease in dietary fuels

• insulin : glucagon ratio decreases

• signals to cells to stop consuming glucose and start using fatty acids for fuel

• glycogen breakdown in liver to maintain blood glucose

• low levels of gluconeogenesis using lactate and glycerol as carbon sources

what is the long-term fast state of the fed / fast cycle?

glycogen stores run out

• main source of fuel for cells is fats

• increase in gluconeogenesis with protein breakdown

~2 days of fasting

• brain retools metabolism to use ketone bodies produces by liver as fuel

• reduces need for glucose, gluconeogenesis and protein breakdown slow

weeks - months of fasting

• fatty acid stores run out, cannot make more ketone bodies

• body consumes its own proteins

• leads to eventual death