Sfm Glycogen Metabolism

Front 1

Nucleotide activation is involved in synthesis of complex lipids and glycoproteins (like in the substrate used for glycogenesis). Note that it is an energy-_________ process.

Back 1

requiring



Front 2

Phosphorylase can move between active and inactive forms in response to hormones. This involves ___________.

Back 2

reversible phosphorylation

Front 3

Skeletal muscle glycogen synthesis is the ______ means by which blood sugar is kept in the normal range during and just after a meal.

Back 3

primary

Front 4

A small amount of glycogen is degraded in ________ by the enzyme (1,4)glycosidase, also known as _________. The deficiency of this enzyme accounts for a fatal neonatal cardiomyopathy called Pompe Disease (Type II Glycogen Storage Disease).

Back 4

lysosomes

acid maltase

Front 5

Addition of calcium plus ATP to intact skeletal muscle glycogen particles results in “flash activation” of _____ and ________ . This is analogous to what happens in muscle during contraction (stimulated by an increase in intracellular calcium).

Back 5

phosphorylase kinase and phosphorylase




Front 6

Clinical Case: A 7 month old baby boy presents at 7 a.m. to the emergency room with a seizure. The baby has just started sleeping through the night. Developmental milestones have been normal, and the baby was thought to be healthy. Physical examination is noteworthy for massive hepatomegaly. Hypoglycemia was the presumed cause of the seizures. A liver biopsy was done, which revealed large vacuoles (fat deposits) and excess amounts of PAS-positive glycogen. The liver biopsy sample was used for enzyme determination, which showed low levels of glucose-6-phosphatase activity. This was sufficient for a diagnosis of Type I Glycogen Storage Disease. What are the implications of G-6-Phosphatase deficiency?

Back 6

Can't convert G-6-P to glucose (won't be able to do gluconeogenesis either).

Whenever the child is fasted, G-6-P accumulates, NADPH will cause a flux through the hexose monophosphate shunt = net FA synthesis.

*paradox* even though hypoglycemic and insulin levels are low, FAs are being made!
[get a fatty liver and skin lesions from circulating FAs]

He was treated with raw corn starch. By keeping him constantly “fed,” the metabolic significance of his glucose 6-phosphatase deficiency was minimized.

Front 7

Does liver synthase have a cAMP-dependent kinase site?

Back 7

NO!!!!!!!!

"Remarkable" given the central role of cAMP in regulation of liver glycogen metabolism.

Front 8

Expain the specificities of glycogenesis in the Liver vs. Muscle:


Back 8

glucose vs. insulin
export vs. local use
cAMP vsm. Ca2+
LIVER


Front 9

FASTED STATE: Short term maintenance of blood glucose levels is dependent on release from the liver of ____ derived from _______. Longer term maintenance of blood glucose depends on _________.

Back 9

GLUCOSE

GLYCOGEN

gluconeogenesis

Front 10

FED STATE: In the liver, there is net glucose uptake. This glucose is used for _______ synthesis and _________ synthesis. In skeletal muscle (not shown) insulin promotes glucose uptake and _________ synthesis.

Back 10

glycogen

triglyceride

glycogen

Front 11

Fill in the blanks for the hormonal regulation of glycogen metabolism:
 Phosphorylase is ______ when PHOSPHORYLATED.
 Synthase is _______ when phosphorylated.
 Both are substrates for phosphorylase kinase which is ____ when PHOSPHORYLATED.
 All three are substrates for _________, a major mediator of insulin action.

Back 11

ACTIVE
INACTIVE
ACTIVE
type 1 protein phosphatase (PP-1)

Front 12

For phos kinase:


Back 12



Front 13

For Phosphorylase:
glycogen-bound?
Structure
# phos. sites
allosteric reg.

Back 13

 

Front 14

For synthase:


Back 14



Front 15

Glucose release from hepatic glycogen is ____ and exquisitely regulated. It provides for the primary mechanism whereby serum glucose is kept in the _________ range during a fast and during a protein load.

Back 15

rapid

normal

Front 16

Glycogen chains are shortened by ______, not hydrolysis, which results in release of glucose-1-phosphate. This is catalyzed by PHOSPHORYLASE. Phosphorylase is specific for _____ glycosidic bonds.

Back 16

phosphorolysis

alpha-1,4



Front 17

How does glycogenin initiate glycogenesis?

Back 17

functions as an anchor

– it autocatalyzes the formation of an initial chain containing 6-10 glucose molecules.

Front 18

How is glycogen metabolism regulated?

Back 18

Allosteric regulation by metabolites and calcium.

Hormonal regulation by cAMP-mediated hormones and insulin.

Front 19

How is the glycogenesis system regulated? (five principles...)

Back 19

1. Tissue specificity of regulatory mechanisms.
2. Amplification of a hormone signal.
3. Organization into a functional unit (the glycogen particle).
4. Multiple control points (reversible phosphorylation, allosteric effects).
5. Reciprocal regulation of synthase and phosphorylase.

Front 20

If  is a reversible reaction in vitro (catalyzed by phosphorylase), why is there no effective glycogen synthesis by phosphorylase in vivo?

Back 20

In our cells, the ratio of Pi/G-1-P is very high and so it will drive the reaction to the right (glycogen degradation)

In vivo, glycogen synthase is the rate-limiting enzyme for glycogenesis.

Front 21

If you digest glycogen straight chains as far as possible,the result is a ________.

Back 21

limit dextrin.

Front 22

In glycogenolysis, the action of phosphorylase stops 3 or 4 glucose residues before branch point. The glycogen resulting from maximum degradation by phosphorylase is a _______.

Back 22

limit dextrin

Front 23

Is phosphorylase subject to allosteric regulation?

Back 23

Oh yes, take a look at this table (though he says don't memorize...but know that there is direct allosteric regulation that reflects the energy level of the cell)


**Gruppuso says the most important inactivator in liver will be glucose - because with lots of glucose around, you want to synthesize glycogen, not break it down.
**Also, you do less break down when energy is high (ATP) and more break down when energy levels are low (AMP).

Front 24

Phosphorylase is a _____enzyme (heterodimer/heterotetramer).

Back 24

multisubunit

Front 25

Quick histo reference- what does this image tell you about co-localization of glycogen and its regulatory enzymes?


Back 25

hmmm, well...
That glycogen particles are associated with microsomal membranes (associated with G-6-phosphatase).

They contain the enzymes of glycogen metabolism (synthase, phosphorylase, debrancher, brancher, phosphorylase, kinase, and type-1 phosphatase), all of which have glycogen binding sites.

Front 26

Since debranching enzyme plays two roles in the degradation of glycogen (catalyzes two different reactions), it is referred to as a _________ enzyme.

Back 26

bifunctional

Front 27

Skeletal and cardiac muscle use ___ as a store for energy used for muscle contraction.

Back 27

glycogen

Front 28

The primary cause of hyperglycemia in adult onset diabetes is impaired ______ disposal in _________. The glycogen storage diseases are inborn metabolic defects resulting from mutations in the enzymes involved in glycogen metabolism.

Back 28

glucose in skeletal muscle (as glycogen)

Front 29

What are the four key points in glygocen metabolism regulation?

Back 29

-cascade amplification
-reciprocal regulation (synthesis and breakdown)
-complex intra- and intermolecular interactions allow for fine tuning...
-multiple and complex allosteric regulation (effects of Ca-muscle and cAMP-liver)

Front 30

What are the three main steps in glycogen degradation?

Back 30

a) phorphorolysis (catalyzed by phosphorylase) releases 8 glucose molecules

b) transferase (catalyzed by debranching enzyme) moves 3 glucose molecules from one branch to another

c) alpha 1,6 glucosidase (also catalyzed by debranching enzyme) releases one glucose

= straight chain that can be degraded by phosphorylase...



Front 31

What are the two pathways of regulation of glycogen synthase by insulin?

Back 31

1) inacativation of GSK-3
2) activation of glycegen-bound PP-1 (functions as synthase phosphatase, phosphorylase phosphatase and phosphorylase kinase phosphatase)

these are // activities that both lead to the activation of glycogen synthesis


Front 32

What characteristic of glycogenolysis makes it a reversible reaction in a test tube?

Back 32

The reaction is isoenergetic (K~1.0)

Front 33

What goes in/comes out of glycogen metabolism?

Back 33

What goes in: GLUCOSE
What comes out: GLUCOSE (6-phosphate)

Front 34

What is glycogenin?

Back 34

Core primer protein of glycogen



Front 35

What is the biochemical structure of glycogen?

Back 35

 Straight chains, alpha-1,4 linkage - withn linkages - helical
 Branches, alpha-1,6.
 In contrast, beta-linkage results in flat, tightly packed chains (cellulose).



Front 36

What is the dual purpose of glycogen?

Back 36

storage depot

structural scaffold for the enzymes that regulate glycogen metabolism.

Front 37

What is the location for glycogen metabolism? Where, and also where inside of cells?

Back 37

Most (virtually all) cells.

Within cells, in the form of glycogen particles in the cytosol.

Front 38

What is the purpose of glycogen metabolism?

Back 38

Acute storage of glucose in the fed state. [Glucose-6-P release from glycogen is used for different purposes depending on the tissue].

-For most tissues, use is local (skeletal muscle, brain, leukocytes …) amount stored is small.

The liver breaks down glycogen for glucose export to other tissues.

Front 39

What is the purpose of Triglyceride synthesis?

Back 39

represents a mechanism for a long-term form of calorie storage.

Front 40

Describe the structure of glycogen.

Back 40

 Highly branched.
 Core primer protein – glycogenin.
 Molecular weight ca. 3,000,000 Da. - large
 Exists as dense particles.



Front 41

What is the substrate for glycogen synthase-catalyzed glycogenesis?

Back 41

nucleotide-activated glucose



Front 42

Why use glycogen and not glucose as a carbohydrate storage form?

Back 42

 High density (doesn’t take up much space; can provide for a lot of carbohydrate storage).
 Low osmolar load for the cell storing it.
 Its synthesis and breakdown are exquisitely regulated by machinery intrinsic to the glycogen particle. This contributes to the precise regulation of blood glucose concentration.

Front 43

Why is the regulation of glycogen synthase so complex?

Back 43

There are 9 phosphorylation sites for at least 7 kinases.
Critical sites are 3a-c and 4, which are substrates for “GSK-3.”

**important for type II diabetes**


Front 44

 __________ is not a substrate for PK-A (cAMP-dependent protein kinase).

Back 44

Phosphorylase