Ch. 14: CHO Metabolism II: Gluconeogenesis, Glycogen

Question 1

What are the substrates for gluconeogenesis?

Answer 1

Lactate
Pyruvate
Glycerol (fr TG in adipose)
Glucogenic a.a.
(Propionate: ruminants)

Question 2

Where does gluconeogensis occur? During starvation/metabolic acidosis?

Answer 2

85-95% in liver

Kidneys contribute up to 50%
Enterocytes not more than 5%

Question 3

How much energy needed for 2 pyruvate ➡️ 1 glucose?

Answer 3

4 ATP
2 GTP
2 NADH

Question 4

Fxns of gluconeogenesis?

Answer 4

1) Maintain [glucose]
2) Use lactate (glycolysis) & glycerol (fat breakdown)
3) Acid-base balance
4) a.a. balance
5) provision of biosynthetic precursors

Question 5

Main 4 enzymes of gluconeogenesis? (Differ from glycolysis)

Answer 5

1) Pyruvate carboxylase
2) PEP carboxykinase
3) Fructose-1,6-bisphosphatase
4) Glucose-6-phosphatase

Question 6

What is pyruvate carboxylase attached to? How attached?

Answer 6

Attached to biotin via lysine ➖charge

Question 7

3 ways oxaloacetate can get out of mitochondria?

Answer 7

1) ➡️ PEP (PEP carboxykinase in MT and cytosol)
2) ➡️ Asp
3) ➡️ Malate

Question 8

Of 2 shuttles which move oxaloacetate from MT ➡️ cytosol, which is major? Why?

Answer 8

Malate shuttle = major

Asp shuttle = minor (also need alpha-ketoglutarate in TCA cycle)

Question 9

Mechanism of activation & transfer of CO2 to pyruvate?

Answer 9

1) from HCO3- TO biotin attached to pyruvate carboxylase
2) TO pyruvate ➡️ oxaloacetate
3) oxaloacetate reduced ➡️ malate
4) malate moves into cytosol, oxidized to oxaloacetate
5) decarboxylated to PEP

Question 10

How is fructose 1,6 bisphosphatase regulated?

Answer 10

➖: AMP, fructose 2,6-bisphosphate (signaling via glucagon or epinephrine)

Question 11

Dephosphorylation of G6P occurs where? Does not occur where?

Answer 11

Liver (& kidneys?)

NOT muscle!

Question 12

4 ways gluconeogenesis is regulated?

Answer 12

1) glucagon
2) substrate availability
3) allosteric ➕ by acetyl CoA
4) allosteric ➖ by AMP

Question 13

What are the glucogenic a.a.?

Answer 13

All except Lys & Leu (KL)

Question 14

What a.a. are both glucogenic & ketogenic?

Answer 14

Trp, Ile, Phe, Thr, Tyr

Question 15

Which a.a. is most important a.a. substrate for gluconeogenesis?

Answer 15

Alanine

Question 16

Most tissues produce lactate ➡️ removed by liver & kidneys

How?

Answer 16

Actively convert lactate ➡️ glucose

Question 17

How is severe hypoglycemia defined? (Measure)

Answer 17

Glucose levels ⬇️ 40 mg/dL (adults) or ⬇️ 30 mg/dL (neonates)

Question 18

What is multiple carboxylase deficiency?

Answer 18

Genetic defect in holocarboxylase synthetase (➡️ no biotin attachment)

Question 19

Which carboxylase need biotin to function?

Answer 19

Pyruvate
Acetyl CoA
Propionyl CoA
Beta-methylcrotonyl CoA

Question 20

Effects of multiple carboxylase deficiency?

Answer 20

Develop. retardation
Ketoacidosis
Hair loss
Erythematous rash

Question 21

What is Von Gierke’s disease?

Answer 21

Genetic defect in G6Pase ➡️ G6P trapped in cell (liver)

Question 22

Effects of Von Gierke’s disease?

Answer 22

Enlarged liver
Hypoglycemia
Lactic acidosis
Hyperlipidemia
Hyperuricemia (purine ➡️ uric acid)

Question 23

What is hypoglycin A?

Answer 23

Toxin of unripe akee fruit

Question 24

How does Hypoglycin A causes hypoglycemia? (Mechanism)

Answer 24

Forms non-metabolizable esters with CoA & carnitine ➡️ ⬇️ CoA & carnitine pools ➡️ FA oxidation inhibited ➡️ gluconeogenesis inhibited (Long chain FA oxidation main source of ATP for gluconeogenesis)

Question 25

Where is glycogen stored? Fxn of glycogen at each site?

Answer 25

Muscle: greater total amt glycogen ➡️ G6P ➡️ energy Liver: greater concentration Glycogen ➡️ G6P ➡️ glucose ➡️ blood glucose

Question 26

What two bonds are formed in glycogen?

Answer 26

Alpha 1➡️4 glycosidic bonds Alpha 1➡️6 glycosidic bonds (branching)

Question 27

Glycogen synthesis pathway?

Answer 27

G6P ➡️ G1P ➡️ UDP-glucose ➡️ glycogen

Question 28

Glycogenolysis pathway?

Answer 28

Glycogen ➡️ G1P ➡️ G6P

Question 29

Enzymes in glycogen synthesis?

Answer 29

1) Phosphoglucomutase (G6P ➡️ G1P) 2) UDP glucose pyrophosphorylase (G1P ➡️ UDP glucose) 3) Glycogen Synthase, branching enzyme & 4,6 transferase (UDP glucose ➡️ glycogen)

Question 30

What does UDP-glucose attach to?

Answer 30

Glycogenin (via OH of tyr residue)

Question 31

Autocatalysis (adding glucosyl units to glycogen via UDP glucose) occurs up to how many sugar residues?

Answer 31

7 residues ➡️ then glycogen synthase used

Question 32

Enzymes in glycogenolysis?

Answer 32

Glycogen phosphorylase & debranching enzyme (Glycogen ➡️ G1P) Phosphoglucomutase (G1P ➡️ G1,6P ➡️ G6P)

Question 33

Glycogen-related diseases: Type II: Pompe disease?

Answer 33

Lysosomal alpha 1➡️4 & 1➡️6 glucosidase deficiency

Question 34

Pompe disease: main characteristics?

Answer 34

⬆️ [glycogen] in lysosomes Massive cardiomegaly, heart failure

Question 35

Glycogen-related diseases: Type III: Cori/Forbes' disease (limit dextrinosis)?

Answer 35

4:4 transferase deficiency 1:6 glucosidase deficiency (Absence of debranching enzyme)

Question 36

Cori/Forbes' disease: main characteristics?

Answer 36

Fasting hypoglycemia Abnormal glycogen structure

Question 37

Glycogen-related diseases: Type IV: Andersen's disease (amylopectinosis)?

Answer 37

Absence of debranching enzyme

Question 38

Andersen's disease: main characteristics?

Answer 38

``` Abnormal glycogen (few branch pts) Death via cardiac/liver failure (1st year of life) ```

Question 39

Glycogen-related diseases: Type V: McArdle syndrome?

Answer 39

Skeletal muscle glycogen phosphorylase deficiency | Myophosphorylase deficiency

Question 40

McArdle syndrome: main characteristics?

Answer 40

Muscle cramping after exercise ⬆️ glycogen content in muscles Little/no lactate after exercise

Question 41

Glycogen-related diseases: Type VI: Hers' disease?

Answer 41

Liver phosphorylase deficiency

Question 42

Hers' disease: main characteristics?

Answer 42

⬆️ glycogen in liver Hypoglycemia

Question 43

Glycogen-related diseases: Type VII: Tarui's disease?

Answer 43

PFK deficiency in muscle & erythrocytes

Question 44

Tarui's disease: main characteristics?

Answer 44

Muscle cramping after exercise ⬆️ glycogen content in muscles Little/no lactate after exercise Hemolytic anemia

Question 45

What regulates glycogen metabolism in muscle?

Answer 45

Epinephrine: ➕ lysis, ➖ synthesis Insulin: ➖ lysis, ➕ synthesis Ca2+: ➕ lysis

Question 46

What regulates glycogen metabolism in the liver?

Answer 46

Glucagon: ➕ adenylyl cyclase & lysis, ➖ synthesis Insulin: ➕ synthesis Governing force = glucagon:insulin ratio

Question 47

MoA of glycogen breakdown in muscle?

Answer 47

Epi ➡️ ➕AC, ⬆️ cAMP ➡️ ➕ protein kinase A ➡️ ➕ phosphorylase kinase A ➡️ ➕ phosphorylase A (glycogen phosphorylase) ➡️ glycogen breakdown Ca2+ also ➕phosphorylase kinase A (binds to it's calmodulin)

Question 48

MoA of inhibiting glycogen synthesis during glycogen breakdown?

Answer 48

Epi ➡️ ➕AC, ⬆️ cAMP ➡️ ➕ protein kinase A ➡️ ➖ glycogen synthase ➡️ inactivates glycogen synthesis

Question 49

MoA of glycogen synthesis in muscle?

Answer 49

Insulin ➡️ ➕ protein phosphatase ➡️ ➕ glycogen synthase ➡️ glycogen synthesis Glycogen synthase also ➕ by Glucose-6-P

Question 50

Inhibitors of glycogen phosphorylase in liver? In muscle?

Answer 50

Liver: G6P, ATP, glucose Muscle: G6P, ATP

Question 51

Activators of glycogen phosphorylase in muscle?

Answer 51

AMP: Anoxia & ⬇️ ATP ➡️ AMP activates glycogen phosphorylase A (w/out phosphorylation) Ca2+

Question 52

Activator of glycogen synthase in muscle & liver?

Answer 52

G6P

Question 53

Role of inhibitor-1 in regulating glycogen metabolism in muscle?

Answer 53

Epi ➡️ ➕AC, ⬆️ cAMP ➡️ ➕ protein kinase A ➡️ ➕ inhibitor-1P ➡️ ➖ protein phosphatase-1 ➡️ causes: 1) ⬇️ ➖ of phosphorylase kinase A & phosphorylase A 2) ⬇️ ➕ of glycogen synthase B