Glycogen

what is the storage form of glucose

glycogen

Role of glycogen in muscle

muscle contraction

Role of glycogen in liver

reservoir to maintain homeostasis of blood glucose

Glycogen tiered components small →large

Branched glucose chains →B glycogen granule →A glycogen granule

glycogen B granules are ___ granules

cytosolic

glycogen A granules are __ granules composed of _ B granules

protein-rich

composed of 20-40

Which releases glycogen faster: A or B granules?

B granules

What do A granules associate with

tubules of smooth ER

B granule structure

glycogenin dimer = primer

tiers of glucose residues + branches

Benefits of tiered branched glucose

many free nonreducing ends

Draw glucose a1→4 linkage

Draw glucose a1→6 linkage

What enzymes are involved with glycogenolysis

1. Glycogen phosphatase

2. Branching enzyme

3. Phosphoglucomutase

Glycogen phosphorylase

Catalyzes phosphorolytic cleavage at nonreducing ends

• requires pyridoxyl phosphate cofactor

• acts repeatedly until 4 glucose away from branch point

Draw glycogen phosphorylase steps

phosphorylates, removes glucose until 4 away from branch

Debranching enzyme

1. Transfers branch onto main chain (transferase activity)

2. releases residue at the a1→6 branch as free glucose (glucosidase)

Draw what the debranching enzyme does

1. transfers branch to main chain

2. removes branch point glucose

What happens to glucose 1 phosphate after glycogenolysis?

Is converted to glucose 6P for glycolysis (muscle) or converted to glucose in ER to replenish blood glucose (liver)

Phosphoglucomutase

Converts glucose 1 P ←> glucose 6P

Draw phosphoglucomutase steps

1. Ser-O-P transfers P to C6

2. Glucose 6-P transfers P to Ser-OH

What are the fates of glucose 6P

Muscle: enters glycolysis

liver: glucose 6 phosphatase converts it to glucose in ER for transport to replenish blood glucose

Glucose 6 phosphatase

glucose 6P →glucose

What are sources of glycogen 6P for glycogenesis

1. Hexokinase isozymes catalyze glucose + ATP ←> glucose 6P + ADP

2. Lactate taken up by the liver converted to glucose 6P by gluconeogenesis

What is the first step of glycogenesis

glucose 6P ←> glucose 1P

• catalyzed by phosphoglucomutase

What is the 2nd step of glycogenesis

Glucose 1P + UTP → UDP-glucose + PPi

What enzyme converts glucose 1P to UTP glucose?

UTP glucose pyrophosphorylase

What is a sugar nucleotide

anomeric carbon is activated by attachment of a nucleotide

Draw UDP

= glucose w PPi attached at C1, linked to ribose-uridine

Why are sugar nucleotides suitable for biosynthetic reactions

• formation metabolically irreversible

• nucleotide moiety has many groups that can undergo noncovalent int w enzymes

• nucleotidyl group (UDP, ADP) = excellent leaving group, facilitates nucleophilic attack

• “tagging” w nucleotidyl groups distinguishes hexoses destined for other purposes

How is a sugar nucleotide made?

sugar phospahte attacks alpha P on NTP

—> NDP sugar + PPi

What makes the formation of a sugar nucleotide irreversible

Hydrolysis of PPi to 2 Pi

How is the glycogen chain elongated?

glycogen nonreducing end attacks UDP-sugar, transfering glucose to chain, releasing UDP

Draw how glycogen chain is extended

What enzyme catalyzes glycogen chain elongation

glycogen synthase

What enzyme catalyzes the formation of (a1→6) bonds

glycogen branching enzyme

What is the role of glycogenin

The primer on which new chains are assembled and the enzyme that catalyzes their activity

How does glycogenin make a primer?

• OH on glycogenin’s tyrosine residue attacks UDP at anomeric carbon

• Repeats 7 more times (8 total times)

How many times does the OH end on glycogenin attack UDP’s anomeric carbon

8x

Glycogen phosphorylase a vs. glycogen phosphorylase b

• glycogen phosphorylase a=active (is phosphorylated)

• glycogen phosphorylase b= less active (dephosphorylated)

Where is epinephrine located

muscle

Where is glucagon located

liver

What enzyme catalyzes glycogen phosphorylase b → a?

phosphorylase b kinase

What activates phosphorylase b kinase

glucagon (liver), epinephrine (muscle)= inc Ca2+, AMP

How is glycogen breakdown regulated?

Epinephrine + glucagon activate adenyl cyclase: ATP → cAMP

increased cAMP activates PKA

PKA + Ca2+ activate phosphorylase b kinase

phosphorylase b kinase phosphorylates glycogen phosphorylase b →a

glycogen phosphorylase a (active) + AMP: glycogen →glucose 1P

Role of Ca2+ in regulation

Signal for muscle contraction

binds to and activates phosphorylase b kinase

Role of AMP in regulation

accumulates in vigorously contracting muscle

binds to and activates glycogen phosphorylase a to speed up glucose 1P release

Role of ATP in regulation

Blocks allosteric site, inactivates glycogen phosphorylase

What is PP1 (phosphoprotein phosphatase 1), what does it do

Catalyzes glycogen phosphorylase a (active) → b (less active)

• removes phosphate

How is glycogen phosphorylase a a glucose sensor

Glucose binds to allosteric site on phosphorylase a, makes it more susceptible to dephosphorylation by PP1

phosphorylase a (allosteric empty) + 2 glu → exposes P groups →phosphorylase b

What enzyme in glycogenesis is regulated

glycogen synthase

Glycogen synthase a vs. glycogen synthase b

—>how does it differ from glycogen phosphorylase

Glycogen synthase b: phosphorylated—inactive unless glucose 6P

glycogen synthase a: dephosphorylated-active

What enzyme catalyzes glycogen synthase b→a

PP1

What enzyme catalyzes glycogen synthase a→b

GSK3—catalyzes phosphorylation

GSK3

catalyzes phosphorylation of glycogen synthase a → b

What does insulin do for regulation?

Insulin (liver): inactivates GSK3

Activates PP1

→activates glycogen synthase = makes glycogen

What does glucose 6P do for regulation

Acts allosterically to make glycogen synthase b a better substrate for PP1

How is GSK3 regulated

GSK3 can’t phosphorylate glycogen synthase a until CKII has phosphorylated the glycogen synthase on a neighboring residue

= a priming event

glycogen targeting protein

regulatory subunit of PP1, serves as scaffold

• binds glycogen, phosphorylase kinase, glycogen phosphorylase, glycogen synthase

Summary of regulation in the liver vs. muscle

Liver:

• glucagon: leads to glycogen breakdown by activating glycogen phosphorylase

  • stim glycogen breakdown and gluconeogenesis, block glycolysis

• insulin: activates glycogen synthase by inhibiting GSK3 and activating PP1

Muscle:

• epinephrine: provides ATP by stimulating glycogen breakdown and glycolysis

How is carbohydrate metabolism regulated in liver?

High blood glucose:

• increase insulin = activate PP1= inactivate phosphorylase a, activate synthase

• = synth hexokinase II, pyruvate kinase, PFK1

= decrease glycogen breakdown

=increase glycogen synth

=increase glycolysis

Low blood glucose

• increase glucagon= increase cAMP = activate PKA = activate glycogen synthase

• =increase phosphorylase kinase, inc glycogen phosphorylase

• =increase FBP-2, decrease PFK2 = decrease F26BP= decrease PFK-1

=increase glycogen breakdown

=decrease glycogen synth

=decrease glycolysis

How is glycogen regulated in skeletal muscle

• uses stored glycogen only for own needs

• undergoes very large changes in demand for ATP

• lacks enzymatic machinery for gluconeogenesis