Ch. 14: CHO Metabolism II: Gluconeogenesis, Glycogen Flashcards
What are the substrates for gluconeogenesis?
Lactate Pyruvate Glycerol (fr TG in adipose) Glucogenic a.a. (Propionate: ruminants)
Where does gluconeogensis occur? During starvation/metabolic acidosis?
85-95% in liver
Kidneys contribute up to 50%
Enterocytes not more than 5%
How much energy needed for 2 pyruvate ➡️ 1 glucose?
4 ATP
2 GTP
2 NADH
Fxns of gluconeogenesis?
1) Maintain [glucose]
2) Use lactate (glycolysis) & glycerol (fat breakdown)
3) Acid-base balance
4) a.a. balance
5) provision of biosynthetic precursors
Main 4 enzymes of gluconeogenesis? (Differ from glycolysis)
1) Pyruvate carboxylase
2) PEP carboxykinase
3) Fructose-1,6-bisphosphatase
4) Glucose-6-phosphatase
What is pyruvate carboxylase attached to? How attached?
Attached to biotin via lysine ➖charge
3 ways oxaloacetate can get out of mitochondria?
1) ➡️ PEP (PEP carboxykinase in MT and cytosol)
2) ➡️ Asp
3) ➡️ Malate
Of 2 shuttles which move oxaloacetate from MT ➡️ cytosol, which is major? Why?
Malate shuttle = major
Asp shuttle = minor (also need alpha-ketoglutarate in TCA cycle)
Mechanism of activation & transfer of CO2 to pyruvate?
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
How is fructose 1,6 bisphosphatase regulated?
➖: AMP, fructose 2,6-bisphosphate (signaling via glucagon or epinephrine)
Dephosphorylation of G6P occurs where? Does not occur where?
Liver (& kidneys?)
NOT muscle!
4 ways gluconeogenesis is regulated?
1) glucagon
2) substrate availability
3) allosteric ➕ by acetyl CoA
4) allosteric ➖ by AMP
What are the glucogenic a.a.?
All except Lys & Leu (KL)
What a.a. are both glucogenic & ketogenic?
Trp, Ile, Phe, Thr, Tyr
Which a.a. is most important a.a. substrate for gluconeogenesis?
Alanine
Most tissues produce lactate ➡️ removed by liver & kidneys
How?
Actively convert lactate ➡️ glucose
How is severe hypoglycemia defined? (Measure)
Glucose levels ⬇️ 40 mg/dL (adults) or ⬇️ 30 mg/dL (neonates)
What is multiple carboxylase deficiency?
Genetic defect in holocarboxylase synthetase (➡️ no biotin attachment)
Which carboxylase need biotin to function?
Pyruvate
Acetyl CoA
Propionyl CoA
Beta-methylcrotonyl CoA
Effects of multiple carboxylase deficiency?
Develop. retardation
Ketoacidosis
Hair loss
Erythematous rash
What is Von Gierke’s disease?
Genetic defect in G6Pase ➡️ G6P trapped in cell (liver)
Effects of Von Gierke’s disease?
Enlarged liver Hypoglycemia Lactic acidosis Hyperlipidemia Hyperuricemia (purine ➡️ uric acid)
What is hypoglycin A?
Toxin of unripe akee fruit
How does Hypoglycin A causes hypoglycemia? (Mechanism)
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)
Where is glycogen stored? Fxn of glycogen at each site?
Muscle: greater total amt
glycogen ➡️ G6P ➡️ energy
Liver: greater concentration
Glycogen ➡️ G6P ➡️ glucose ➡️ blood glucose
What two bonds are formed in glycogen?
Alpha 1➡️4 glycosidic bonds
Alpha 1➡️6 glycosidic bonds (branching)
Glycogen synthesis pathway?
G6P ➡️ G1P ➡️ UDP-glucose ➡️ glycogen
Glycogenolysis pathway?
Glycogen ➡️ G1P ➡️ G6P
Enzymes in glycogen synthesis?
1) Phosphoglucomutase (G6P ➡️ G1P)
2) UDP glucose pyrophosphorylase (G1P ➡️ UDP glucose)
3) Glycogen Synthase, branching enzyme & 4,6 transferase (UDP glucose ➡️ glycogen)
What does UDP-glucose attach to?
Glycogenin (via OH of tyr residue)
Autocatalysis (adding glucosyl units to glycogen via UDP glucose) occurs up to how many sugar residues?
7 residues ➡️ then glycogen synthase used
Enzymes in glycogenolysis?
Glycogen phosphorylase & debranching enzyme (Glycogen ➡️ G1P)
Phosphoglucomutase (G1P ➡️ G1,6P ➡️ G6P)
Glycogen-related diseases:
Type II: Pompe disease?
Lysosomal alpha 1➡️4 & 1➡️6 glucosidase deficiency
Pompe disease: main characteristics?
⬆️ [glycogen] in lysosomes
Massive cardiomegaly, heart failure
Glycogen-related diseases:
Type III: Cori/Forbes’ disease (limit dextrinosis)?
4:4 transferase deficiency
1:6 glucosidase deficiency
(Absence of debranching enzyme)
Cori/Forbes’ disease: main characteristics?
Fasting hypoglycemia
Abnormal glycogen structure
Glycogen-related diseases:
Type IV: Andersen’s disease (amylopectinosis)?
Absence of debranching enzyme
Andersen’s disease: main characteristics?
Abnormal glycogen (few branch pts) Death via cardiac/liver failure (1st year of life)
Glycogen-related diseases:
Type V: McArdle syndrome?
Skeletal muscle glycogen phosphorylase deficiency
Myophosphorylase deficiency
McArdle syndrome: main characteristics?
Muscle cramping after exercise
⬆️ glycogen content in muscles
Little/no lactate after exercise
Glycogen-related diseases:
Type VI: Hers’ disease?
Liver phosphorylase deficiency
Hers’ disease: main characteristics?
⬆️ glycogen in liver
Hypoglycemia
Glycogen-related diseases:
Type VII: Tarui’s disease?
PFK deficiency in muscle & erythrocytes
Tarui’s disease: main characteristics?
Muscle cramping after exercise
⬆️ glycogen content in muscles
Little/no lactate after exercise
Hemolytic anemia
What regulates glycogen metabolism in muscle?
Epinephrine: ➕ lysis, ➖ synthesis
Insulin: ➖ lysis, ➕ synthesis
Ca2+: ➕ lysis
What regulates glycogen metabolism in the liver?
Glucagon: ➕ adenylyl cyclase & lysis, ➖ synthesis
Insulin: ➕ synthesis
Governing force = glucagon:insulin ratio
MoA of glycogen breakdown in muscle?
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)
MoA of inhibiting glycogen synthesis during glycogen breakdown?
Epi ➡️ ➕AC, ⬆️ cAMP ➡️ ➕ protein kinase A ➡️ ➖ glycogen synthase ➡️ inactivates glycogen synthesis
MoA of glycogen synthesis in muscle?
Insulin ➡️ ➕ protein phosphatase ➡️ ➕ glycogen synthase ➡️ glycogen synthesis
Glycogen synthase also ➕ by Glucose-6-P
Inhibitors of glycogen phosphorylase in liver? In muscle?
Liver: G6P, ATP, glucose
Muscle: G6P, ATP
Activators of glycogen phosphorylase in muscle?
AMP: Anoxia & ⬇️ ATP ➡️ AMP activates glycogen phosphorylase A (w/out phosphorylation)
Ca2+
Activator of glycogen synthase in muscle & liver?
G6P
Role of inhibitor-1 in regulating glycogen metabolism in muscle?
Epi ➡️ ➕AC, ⬆️ cAMP ➡️ ➕ protein kinase A ➡️ ➕ inhibitor-1P ➡️ ➖ protein phosphatase-1 ➡️ causes:
1) ⬇️ ➖ of phosphorylase kinase A & phosphorylase A
2) ⬇️ ➕ of glycogen synthase B
