Biochemistry Exam 3: Glycogen Metabolism

Front 1

What is source of glycogen breakdown to glucose?

Back 1

Liver

Front 2

How long can liver supply brain with glucose via glycogen breakdown?

Back 2

Half Day

Front 3

Why is glycogen so important?

Back 3

It provides constant energy source needed in all tissues

Front 4

During fasting conditions, glucose needs are met by ___________.

Back 4

Gluconeogenesis

Front 5

In metabolism, we start with glucose. What does glucose then first turn into?

Back 5

Glucose 6 Phosphate

Front 6

What does G6P make with the pentose phosphate pathway?

Back 6

Ribose 5 phosphate

Front 7

What does it make with glycolysis?

Back 7

Pyruvate -> amino acids, lactate, or acetyl- CoA -> citric acid cycle

Front 8

What is glucneogenesis?

Back 8

Pyruvate -> G6P

Front 9

Describe the molecular structure of glycogen?

Back 9

Polymer of glucose molecules connected by alpha 1->4 linkages and by alpha 1->6 linkages every 8-14 residues. It is spheroidal molecule with 120,000 glucose units

Front 10

Where is glycogen most prominently stored?

Back 10

Muscle and Liver cells

Front 11

What do glycogen granules contain?

Back 11

Enzymes catalyzing synthesis and breakdown, and regulatory proteins

Front 12

Where does all of action that is going to take place in terms of synthesis and breakdown of glycogen occur?

Back 12

In non-reducing end of glycogen. Glucose is removed here

Front 13

Glycogen has ___ non reducing end and __ reducing end.

Back 13

Many, One

Front 14

What is the advantage of glycogen being highly branched structure?

Back 14

Permits rapid removal from multiple branched ends

Front 15

What is glycogen breakdown called? What are the three enzymes involved?

Back 15

Glycogenolysis - glycogen phosphorylase, glycogen debranching enzyme, phosphoglucomutase

Front 16

What does glycogen phosphorylase do?

Back 16

It catalyzes bond cleavage by inorganic phosphate substitution.

Front 17

What are the two forms of glycogen phosphorylase?

Back 17

a and b
a is phosphorylated form and b is dephosphorylated form

Front 18

What are allosteric inhibitors of glycogen phosphorylase?

Back 18

ATP, G6P, and gllucose

Front 19

What are allosteric activators of Glycogen phosphorylase?

Back 19

AMP

Front 20

Describe molecule of glycogen phosphorylase?

Back 20

Large N terminal with domain of 484 residues and smaller C terminal domain

Front 21

What part of Glycogen phosphorylase molecule is most important and why?

Back 21

N terminal because it contains all important sites

Front 22

What are some of the important sites in the N terminal of Glycogen phosphorylase?

Back 22

Allosteric effector site, glycogen binding site, phosphorylation site,

Front 23

What connects glycogen binding site to active site?

Back 23

30 angstrom long crevice on glycogen phosphorylase. It chops off non-reducing ends and release them to other enzyme

Front 24

How many glycogen residues at a time does the glycogen binding site of glycogen phosphoryolase accomodate?

Back 24

4-5 glucose chain residies at time. It allows several to be cleaved without unbinding/rebinding between catalytic cycles

Front 25

What is the cofactor that glycogen phosphorylase binds?

Back 25

PLP

Front 26

What is PLP's contribution to glycogen phosphorylase?

Back 26

Phosphate group which acts as acid base catalyst and it contributes it to glucose to make G1Phosphate

Front 27

What are the conformational changes that glycogen phosphorylase undergoes?

Back 27

T->R, T is inactive and R is active

Front 28

Why does T state have low substrate affinity?

Back 28

Buried active site

Front 29

What promotes T->R and how?

Back 29

AMP allosteric activator promotes this conversion by binding to R state and preventing T state substrate binding

Front 30

What binds to T state to inhibit this shift?

Back 30

ATP

Front 31

While allosteric control alters glycogen phosphorylase enzyme what else does as well?

Back 31

Phosphorylation and de phospharylation - covalent modification alters the activity

Front 32

What does the bound phosphate to the glycogen phosphorylase enzyme do?

Back 32

It is used to stabilize the inorganic phosphate that comes in

Front 33

What does phosphorylase b form need to be active?

Back 33

AMP

Front 34

What does glycogen debranching enzyme do?

Back 34

It removes the branch. Glucose removal stops within 4-5 resideus of 1-> 6 branch point and then removes and transfers trisaccharide from branch to nonreducing end of another branch. Then the remaining single glucose bond (alpha 1->6) is hydrolyzed by same debranching enzyme and yields glucose and debranched glycogen

Front 35

What happens to the glycogen residues after debranching step?

Back 35

10% are converted to glucose rather than G1P

Front 36

Why does debranching enzyme have separate active sites?

Back 36

1 for Transferase reaction and another for alpha 1->6 glucosidase reactions

Front 37

T/F Max rate of glycogen phosphorylaes is much greater than debranching enzyme.

Back 37

True

Front 38

What does phosphoglucomutase do?

Back 38

It converts G1P to G6P by transferring phosphoryl group to G1P to make G16Bisphosphate and then it is dephosphorylated to G6P

Front 39

What can G6P from glycogen breakdown do?

Back 39

It can enter glycolysis or hexose monophosphate pathway

Front 40

What can G6P do in liver?

Back 40

It can be converted to glucose for transport to other tissues

Front 41

How is G6P in cytosol imported into ER?

Back 41

G6P translocase

Front 42

What does G6Pase do?>

Back 42

It converts the G6P into glucose and inorganic phosphate

Front 43

How do the glucose and inorganic phosphate return to the cytosol after being produced in the ER?

Back 43

specific transport proteins

Front 44

How is glucose transported out of liver?

Back 44

GLUT2 transporter

Front 45

What is the difference between muscle and liver with G6P?

Back 45

Muscle and other tissues lack G6Pase so they have to retain their G6P

Front 46

What happens if there is defect in any component of G6P hydrolysis system?

Back 46

Type I Glycogen Storage Disease

Front 47

Describe the Type I glycogen Storage Disease?

Back 47

Intracellular G6P in liver increases, and glycogen in kidney increases. This results in an inability to increase blood glucose. Rresulting in hepatomegaly and hypoglycemia - failure to thrive

Front 48

Why do we need mechanism to convert G6P back to glucose?

Back 48

Because it cannot pass cell membrane

Front 49

What is the mechanism to convert the G6P resulting from the phosphoglucomutase converting G1P to G6- into glucose?

Back 49

taking G6P to ER where it reacts with G6Pase and this removes phosphate group via hydrolysis reaction. Then you are left with plain glucose and inorganic phosphate. We can transfer glucose back across cell to cytosol

Front 50

What is the standard free energy for glycogen synthesis?

Back 50

+3.1, it is spontaneous reaction and thermodynamically favored

Front 51

How did glycogen synthesis come about?

Back 51

Through study of disease called McArdle's

Front 52

What are the three new enzymes in Glycogen Synthesis?

Back 52

Phosphorylase, Synthase, Branching Enzyme

Front 53

Describe McArdle's Disease.

Back 53

It is an inherited condition that involves painful muscle cramps on exertion. There is lack of muscle glycogen phosphorylase and can not break down glycogen. Yet muscles contain normal amount of glycogen. This made it obvious that glycogen synthesis does not require glycogen phosphorylase.

Front 54

What are the three enzymes involved in Glycogen synthesis?

Back 54

Pyrophosphorylase, glycogen synthase, Glycogen branching enzyme

Front 55

What is the function of glucose pyrophosphorylase?

Back 55

It combines G1P with Uridine Triphosophate to create activated uridine diphosphate glucose (UDP - glucose)

Front 56

What is UDPG coupled with ?

Back 56

Inorganic pyrophosphatase

Front 57

How is the energy of converting G1P to UDPG driven?

Back 57

By using energy of PPi hydrolysis

Front 58

What prevents reverse of reaction of converting G1P to UDGP?

Back 58

Removing all of inorganic pyrophsphatase PPi

Front 59

What does glycogen synthase do?

Back 59

glucosyl unit of UDPG transferred to glycogen nonreducing C4-OH forming alpha 1->4 glycosidic bond

Front 60

What is the combination of the first two enzymatic reactions to make glycogen?

Back 60

Glycogen + G1P + UTP -> Glycogen + UDP + 2Pi

Front 61

How is UTP replenished?

Back 61

Phosphoryl transfer mediated by nucleotide diphosphate kinase

Front 62

What is UTP consumption in glycogen synthesis energetically equivalent to?

Back 62

ATP consumption

Front 63

What are the two forms of glycogen synthase?

Back 63

Form a is the dephosphorylated but active form and form b is the phosphorylated form

Front 64

Glycogen synthase is under what kind of control and affected by concentrations of what?

Back 64

Allosteric, atp and ADP

Front 65

What activates the dephosphorylated a form of glycogen synthase?

Back 65

G6P

Front 66

What affects glycogen synthase activity in cell?

Back 66

G6P concentration and fraction in dephosphorylated form a

Front 67

Why is this glycogen synthase difficult to study?

Back 67

Because it has multiple different phosphorylation sites

Front 68

Glycogen _________ glycogen synthase.

Back 68

Primes

Front 69

If you do not have glycogen, how is the glycogen synthesis reaction initiated?

Back 69

Protein called glycogenin

Front 70

Describe the function of glycogenin?

Back 70

It is a small protein which you can attach glucose molecules to and start linking them through glycogen synthase and form alpha linkages. It forms a glycogen primer Once primer is created glycogen synthase starts glycogen synthesis by adding to primer

Front 71

What is contained in glycogen granules?

Back 71

1 Glycogenin and 1 glycogen synthase

Front 72

How is a branch created with branching enzyme?

Back 72

A 7 residue segment from end of 11 residue chain is transferred to C6-OH of glucose on same or different chain

Front 73

How do we control pathways of synthesis and breakdown of glycogen?

Back 73

Allosteric control and hormonal control via covalent modification

Front 74

How is glycogen phoshorylase directly controlled?

Back 74

It is activated by AMP and inhibited by ATP and G6P

Front 75

When ATP demand is high what does that mean about other molecules?

Back 75

ATP concentration is going to be low and G6P low and AMP high

Front 76

What is turned on when ATP demand is high?

Back 76

Phosphorylase so this inhibits the synthase and will favor the glycogen breakdown

Front 77

What is activated when there is increase in ATP and G6P?

Back 77

Glycogen synthase and synthesis is favored

Front 78

In allosteric control of glycogen metabolism, allosteric control is superimposed on ____________.

Back 78

Covalent modification

Front 79

When is phosphorylase activated and when is synthase activated?

Back 79

Phosphorylase is activated in a form meaning it is phosphorylated and synthase is active dephosphorylated form and G6P present

Front 80

What is the net result of phosphorylation?

Back 80

Phosphorylase activated: b->a
Synthase activated: a->b

Front 81

What is net result of dephosphorylation?

Back 81

Phosphorylase inactivated: a -> b
Synthase activated: b->a

Front 82

Describe the process of activate glycogen phosphorylase.

Back 82

Phosphoryl kinase is made more active by protein kinase a. Then phosphorylase kinase makes glycogen phosphorylase b active into phosphorylase a. This is done by hydrolysis reaction mediated by phosphatase

Front 83

What are the four different forms of enzyme phosphorylase?

Back 83

R form - are both active whether a or b. If b, AMP present to make it active.

T forms are inactivated. ATP or G6P will convert R unphosphorylated form to inactive. Glucose will convert R phosphorylated form to T phosphorylated form which spontaneously undergos hydrolysis reaction

Front 84

What are the hormonal controls of glycogen metabolism in the liver?

Back 84

Insulin, glucagon, glucose synthesized in pancrease, epinephrine

Front 85

What are the hormonal controls in muscle and other tissues of glycogen metabolism?

Back 85

Insulin, epinephrine and norepinephrine,

Front 86

How do hormones affect target tissue?.

Back 86

Through covalent modification of regulatory enzymes. They bind to transmembrane receptors and this triggers 2nd messengers, usually either Cyclic AMP or Calicum

Front 87

What occurs when intracellular cAMP concentration increases?

Back 87

Protein kinase A activity increases and this increases phosphorylation rates and decreasing dephosphorylation rates

Front 88

What is a characteristic of this cascade nature of regulatory enzymes?

Back 88

Small changes in hromone concentration result in dramatic changes in control of enzyme

Front 89

What happens when large fraction of glycogen metabolism enzymes are phosphorylated?

Back 89

Metabolic flux towards glycogen breakdown since phosphorylase active and synthase inactive

Front 90

What happens when cAMP decreases?

Back 90

Phosphorylation rate decreases and Dephosphorylation rate increases so synthase activated and metabolic flux towards glycogen synthesis

Front 91

How does glucagon affect glycogen metabolism?

Back 91

When there is not enough glucose in body, glucagon binds to liver cell to generate intracellular cAMP whigh results in glucose mobilization from glycogen. THe glucagon is released from pancreas

Front 92

When is glucagon released from pancreas

Back 92

When glucose concentration is low and exercise or hours between meals

Front 93

Why don't muscle cells respond to glucagon?

Back 93

They have no receptors

Front 94

What do adrenal glands release in response to stress?

Back 94

Epi and Norepi

Front 95

What are the two types of adrenal hormone receptors and describe the,.

Back 95

Alpha - adrenergic recptors release Ca as second messenger

B adrenergic receptors produce cAMP

Front 96

Which adrenal hormone receptors does liver have? Muscle?

Back 96

Liver - both a and B
Muscle - only B

Front 97

What happens when we have high circulatory glucose?

Back 97

Insulin produced by pancreas causes glucose to be brough back into cell and synthesizing glycogen into liver

Front 98

What does pancreas respond to?

Back 98

Glucose concentrations in circulation by either taking up glucose or releasing it

Front 99

What is the response of muscle cells to epinephrine?

Back 99

They break down glycogen for glycolysis and generate ATP. This helps muscle cope with stress

Front 100

How do liver cells respond to epinephrine?

Back 100

Directly and Indirectly. Epinephrine promotes release of glucagon from pancreas which binds to liver cell and stimulates glycogen breakdown. It also binds to alpha and beta receptors on liver and results in release of cAMP which also leads to glycogen breakdown. Binding to alpha receptor also stimulates increase in Ca which reinforces cells response to cAMP. The Ca inactivates glycogen synthase by catalyzing phosphorylation.

Front 101

What cells have both insulin receptors and insulin sensitive GLUT4?

Back 101

Fat and muscle, liver and brain do not

Front 102

What happens with increase in insulin concentration?

Back 102

cAMP increases and this causes glycogen metabolic shift from breakdown to synthesis

Front 103

What does insulin do in muscle?

Back 103

It promotes glucose storage as glycogen and stimulation of synthesis and inhibition of breakdown

Front 104

What does insulin do in liver?

Back 104

Promotes glycogen synthesis

Front 105

What does glucsoe do in liver?

Back 105

It inhibits phosphorylase a by binding to enzyme's inactive T state. This promotes dephosphorylation and promotes inactivation of glycogen phosphorylase through conversion to b form.

Front 106

What are glycogen storage diseases?

Back 106

Inherited disorders affecting glycogen metabolism and producing abnormal glycogen in either quality or quantity. They mainly affect liver by producing large liver and low blood sugar.

Front 107

What do glycogen storage diseases do to muscles?

Back 107

Cramps and weakness

Front 108

When does gluconeogenesis occur?

Back 108

When glucose is unavailable through glycogen breakdown or dietary sources

Front 109

How is glucose made via gluconeogenesis?

Back 109

Noncarbohydrate precursors such as lactate, pyruvate, TCA cycle intermediates, glycolysis products, and carbon skeletons of most amino acids

Front 110

What do we convert amino acids and pyruvate to in glucneogensis?

Back 110

Oxaloacetate, except for leucine and lysine do not convert to this because they break down to acetyl CoA

Front 111

What is the pathway of gluconeogenesis?

Back 111

Pyruvate to glucose

Front 112

Which glycolytic reactions of gluconeogenesis are not reversible?

Back 112

Hexokinase, phosphofructokinase, pyruvate kinase

Front 113

How do we convert pyruvate to oxaloacetic acid and then to PEP?

Back 113

Pyruvate Carboxylase catalyzes it to convert to oxaloacetate and then PEPCK converts it to PEP and GTP used as phosphoryl group donor

Front 114

Describe pyruvate carboxylase.

Back 114

It is a tetramer protein with biotin prosthetic group on each subunit. This acts as CO2 carrier

Front 115

What happens when TC metabolite increases?

Back 115

Activates pyruvate carboxylase and increases amount of oxaloacetate that participate in TCA cycle

Front 116

Oxaloacetate is an intermediate in what two processes?

Back 116

Gluconeogenesis and TCA cycle

Front 117

Describe PEPCK.

Back 117

Monomeric and requires GTP as enzyme for decarboxylation and phosphorylation of oxalacetate to PEP. It eliminates the CO2 to make PEP

Front 118

T/F PEP can be transported across membrane by specific membrane transport proteins while oxaloacetate has no transport system.

Back 118

True

Front 119

What are two mechanisms for PEP transport across mitochondrial membrane?

Back 119

Conversion to aspartate or malate

Front 120

What is the difference between both Malate dehydrogenase route and aspartate aminotransferase route?

Back 120

Malate moves reducing equivalents from mitochondria to cytosol. It uses mitochondrial NADH and produces cytosol NADH

Front 121

Gluconeogenesis requires _____.

Back 121

NADH

Front 122

Since transport systems are reversible what else can it be used to transport?

Back 122

Reducing equivalents into mitochondria for oxidative phosphorylation

Front 123

How does PEP become glucose?

Back 123

PEP IS CONVERTED TO fbp, fbp -> F6P by FBPase, and then F6P - > G6P which makes glucose via G6Pase

Front 124

What is the net energetic loss of converting 2 pyruvate to 1 glucose?

Back 124

6 ATP equivalents lost

Front 125

T/F glycolysis and gluconeogensis do not operate simultaneously in vivo.

Back 125

True

Front 126

How does low glucose stimulate gluconeogenesis flux?

Back 126

Low glucose -> glucagon stimulates cAMP in liver cells -> cAMP activates PKA to phosphorylate the bifunctional enzyme at specific Ser residue -> deactivates PKF2 activity -> activates FBPase 2 activity -> decrease in F26P and shifts balance in factor of FBP hydrolysis so this increases gluconeogenesis and releases glucose

Front 127

What happens when there is an increase in glucose conversely to producing gluconeogenesis?

Back 127

This causes decrease in cAMP, increase in F26P, and leads to glycolysis

Front 128

What allosterically inhibits Pyrucate kinase in liver?

Back 128

Alanine - major glucneogenetic precursor that converts to pyruvate. In activation of pyruvate kinase increases glucnoegenic flux

Front 129

What activates pyruvate carboxylase?

Back 129

Acetyl CoA

Front 130

How does insulin affect glucose metabolism?

Back 130

It inhibits the transcription of the gene for PEPCK

Front 131

How does increase in cAMP affect glucose metabolis,?

Back 131

It promotes transcription of PEPCK gene and FBPase gene and G6P gene but represses Glucokinase gene PFK gene and PFK-2/FBPase 2 bifunctional gene