Lecture 9 and 10: Carb Metabolism (Glycogen Metabolism and Gluconeogenesis)

What form and where is glucose stored in the body?

as glycogen in the liver

when is glycogen used

when glucose is needed

what is glycogen directly broken to

glucose-6-phosphate

what does glycogen breaking down into glucose-6-phosphate allow it to do

enter the ribose-5-phosphate pathwayw

what does the body do at high levels of pyruvate

break it down to convert it back to glucose-6-phosphate via gluconeogenesis

what are the main linkages of glycogen

alpha 1-4 linkages

what are the branched linkages in glycogen

alpha 1-6 linkages

what is the reducing end of glycogen

only one reducing end in each animal/person, cannot use this glucose

what is the nonreducing end of glucose

lots of nonreducing ends, broken for the generation of glucose

function of the glycogen debranching enzyme

when the branch has 4 remaining glucose molecules the first 3 get debranched and added to the linear end of the nearest branch, the 4th glucose gets hydrolyzed

what kind of polymer is glycogen

a branched polymer

steps of glucose mobilization

conversions from glycogen to glucose-1-phosphate to glucose-6-phosphate and finally to glucose

steps to remove a glucose from glycogen

1. debranching enzyme if necessary (4 remaining glucose molecules)

2. Glycogen phosphorylase converts glycogen → glucose-1-phosphate

3. Phosphoglucomutase converts glucose-1-phosphate → glucose-6-phosphate

steps to add a glucose to glycogen

1. Phosphoglucomutase turns glucose-6-phosphate → glucose-1-phosphate

2. UTP + UDP-glucose pyrophosphorylase converts glucose-1-phosphate → UDP-glucose

   1. two PPi high energy bonds interact with inorganic pyrophosphatase

3. Glycogen synthase breaks UDP-glucose into glucose and adds the polysaccharide to the chain

   1. branching enzyme is used if the polysaccharide branch is at 13 glucose molecules

what is the glycogen synthase inhibitor

1,5-gluconolactone

what does the glycogen branching enzyme do

• glucose is added to the polysaccharide until it reaches 13 glucose molecules

  • the branching enzyme removes 7 molecules to make a new branch that is separated by 3 glucose molecules, placing the new chain on the 4th glucose

what kind of genetic disorder is equine glycogen branching enzyme deficiency (GBED)

autosomal recessive

what does GBED prevent

the storage of glucose as glycogen

what does GBED result in

• late term abortion or stillbirth

• muscle weakness, too weak to stand

• foals develop seizures, high respiratory rate

• typically die by week 18 of age

common breeds and GBED prevention

• common in quarter horse and related breeds (~10%)

• testing performed to remove carriers from breeding pool

what kind of molecule is UDP-glucose

an activated molecule

what protein builds the primer and extension of glycogen

glycogenin

downstream affects of phosphorylation of protein kinase A

1. cAMP is a secondary signaling molecule activated by glucagon or epinephrine

2. this activates protein kinase A

3. protein kinase A phosphorylates and activates phosphorylase kinase a and glycogen phosphorylase a

   1. it also phosphorylates phosphoprotein phosphatase inhibitor-1, which inhibits phosphoprotein phosphatase-1 and inhibits its ability to dephosphorylate

4. protein kinase A phorphorylates and deactivates glycogen synthase B

Phosphorylation = glycogen is broken down (making free glucose available)

downstream affects of dephosphorylation of protein kinase A

1. PKA stays in the inactive form because cAMP drops

2. inhibitor 1-a gets dephosphorylated

   1. can no longer block PP1

3. PP1 becomes activated

   1. removes phosphate group from glycogen synthase b

      1. this activates it and allows glycogen synthesis

when is insulin secreted

in response to high glucose levels by the pancreas

insulin regulating phosphoprotein phosphatase-1 in muscle

• insulin reduces high glucose level by converting extra free glucose into glycogen

  • activates insulin stimulated protein kinase → affects phosphatase which → removes phosphorus → makes glycogen

what secretes epinephrine

secreted by the adrenal gland in fight or flight response to make free glucose available

how does epinephrine make free glucose available

activates protein kinase A → downstream impacts to increase phosphorylation and increase glycogen breakdown

relationship between epinephrine and insulin

they work against each other, but epinephrine is more powerful than insulin

secretion of glucagon

secreted by the pancreas in response to low glucose levels, low glucose levels = break down of glycogen stores

relationship between glucagon and insulin

work in seesaw

hormonal control of glycogen metabolism in muscle

• In the muscle

  • GLUT4 glucose transporter

  • Insulin

    • Excretion from pancreas → insulin receptor on muscle → glycogen synthesis (does not store)

      • Allows for movement of glucose in the cell

    • Excretion from pancreas → insulin receptor on muscle

  • Epinephrine

    • Adrenal glands → epinephrine → receptor → cAMP → glycogen degradation → glycolysis

hormonal control of glycogen metabolism in the liver

• In the liver

  • GLUT2 glucose transporter

  • Insulin

    • Insulin receptor → glycogen synthesis

  • Epinephrine

    • Receptor → cAMP → glycogen degradation → glucose

  • Glucagon 

    • Receptor → cAMP → glycogen degradation → glucose 

what regulates glycogen breakdown and synthesis

allosteric interactions and covalent modification of key enzymes

what is glycogen metabolism ultimately controlled by

the hormones such as insulin, glucagon, and epinephrine

what is gluconeogenesis

the making of glucose from non-carb sources

what must non-carb precursors be converted to for gluconeogenesis

oxaloacetate

gluconeogenesis and energy

uses extra energy in the form of GTP to convert oxaloacetate to PEP, two high energy bonds broken to get from pyruvate → oxaloacetate → PEP

what can oxaloacetate be converted to to move across mitochondrial membrane

malate or aspartate

why must oxaloacetate be converted

becuse it cannot move across the membrane as is to get to the cytosol for gluconeogenesis

what enzymes are used to convert oxaloacetate to malate or aspartate

malate dehydrogenase or aspartate aminotransferase

bottleneck affect of malate and aspartate

process can only move so quickly based on availability of the enzymes and how much malate/aspartate the body already has

rate controlling preference for glucose and glucose-6-phosphate

heoxkinase > glucose-6-phosphatase

rate controlling preference betweek F6P and FBP

PFK > FBPase

rate controlling preference between PEP and pyruvate

comparable between pyruvate kinase and pyruvate carboxylase + PEPCK

what impacts if you go all the way up from pyruvate → glucose

the level of substrate because the preference is for the enzymes to go glucose → pyruvate

relationship between F2,6P and F1,6P

F26P tries to activate PFK and stop FBPase (in favor of glycolysis), F16P tries to stop PFK and activate FBPase (speed up gluconeogenesis)

formation and degradation of F2,6P

• This process only takes place in the liver because the F2,6P enzyme is liver specific

• F6P → F2,6P

  • Occurs when there is a high level of ATP and F6P

    • You do not want to run glycolysis to you convert it to a localized storage form

metabolic events linking low [glucose] and gluconeogenesis in liver

low blood [glucose] → increased glucagon secretion → increased [cAMP] → increased enzyme phosphorylation → activation of FBPase-2 and inactivation of PFK-2 → decreased [F2,6P] → inhibition of PFK and activation of FBPase → increased gluconeogenesis

metabolic events linking high [glucose] and glycolysis

high blood [glucose] → increased insulin secretion → decreased [cAMP] → decreased enzyme phosphorylation → activation of PFK-2 and inhibition of FBPase → increased [F2,6P] → activation of PFK and inhibition of FBPase → inhibition of gluconeogenesis → glycolysis runs

how does alanine get converted to pyruvate

via alpha-keto acid

what can the liver and kidney synthesize glucose from

lactate, pyruvate, and amino acids

gluconeogenesis versus glycolysis

gluconeogenesis is mostly the reverse of glycolysis with the pyruvate kinase reaction bypassed by the pyruvate carboxylase and phosphoenolpyruvate carboxykinase reactions, and the phosphofructokinase and hexokinase reactions bypassed by the phosphatase reactions

• receprocally regulated by allosteric effects, phosphorylation, and changes in enzyme synthesis rates

what does the formation of glycosidic bonds in carbs require

energy of activated nucleotide sugars

O-linked oligosaccharides

synthesized by sequential addition of sugars to a protein

N-linked oligosaccharides

first assembled on dolichol carrier