Metabolism 1 and 2 Flashcards
Why don’t skeletal muscles export glucose?
They don’t have Glucose-6-Phosphatase so can’t convert glucose-6-P –> Glucose. During states of high glucose (resting), they convert to glycogen to store
What enzymes convert Glucose –> G-6-P? (Glucose metabolism)
Hexokinase (Skeletal muscle)
Glucokinase (Hepatocytes)
What is caused by deficiency in glycolytic enzymes?
Hemolytic Anemia (RBCs burst, lose Hb)
What reaction do HK/GK catalyze? What is important about the product?
Glucose –> G-6-P
G-6-P is more polar and impermeable so cannot leave the cell
This rxn is irreversible phosphorylation and ATP used with Mg as a cofactor
Where is Hexokinase located? Glucokinase?
HK: all cell types
GK: liver and pancreas
What is the regulator of Hexokinase?
Allosteric inhibition by G-6-P (feedback inhibition)
What are the regulators of Glucokinase?
- Fructose-6-P promotes translocation to nucleus (decreases activity)
- Glucose promotes translocation to cytosol (increases activity)
- Insulin promotes enzyme synthesis (inducible enzyme)
List differences between Hexokinase and Glucokinase
Hexokinase:
- All cell types
- Constitutive enzyme (present in constant amount independent of activation)
- Low Km for glucose (saturates at low conc.), High affinity
Glucokinase:
- Liver and pancreas
- Inducible enzyme (insulin)
- High Km for glucose (not saturated at normal conc.), Low affinity
What reaction is catalyzed by PFK-1?
F-6-P –> F-1,6-bisP
What is the main regulator of PFK-1? What are the conditions that increase or decrease the regulator’s concentration?
Fructose-2,6-bisP is the major physiological activator of hepatic PFK-1
- High F-2,6,-bisP when insulin and blood glucose high
- Low F-2,6,bisP when glucagon and epi high (Glucagon/Epi –> cAMP –> active PKA –> phosphorylates kinase domain of PFK-2 –> F-2,6-bisP not formed)
What is the reaction catalyzed by PFK-2?
Fructose-6-P –> Fructose-2,6-bisP
What are the 2 isoforms of PFK-2 and how are they influenced?
- In liver, glucagon/epi –> inhibit/phosphorylate PFK-2 kinase domain, promote phosphatase –> block F-2,6,bisP –> block glycolysis
- In heart/skeletal muscle, Epi only –> inhibit/phosphorylate PFK-2 phosphatase domain, promote kinase –> made F-2,6-bisP –> promote glycolysis
What reaction is catalyzed by Pyruvate Kinase?
PEP (phosphoenolpyruvate) –> Pyruvate
How is Pyruvate Kinase regulated (2 activators 2 inhibitors)
Activate PK:
- Fructose-1,6-bisP
- Insulin: promotes dephosphorylation of PK (active)
Inhibit PK:
- ATP and Alanine
- Glucagon/Epi: promote phosphorylation (via PKA) of PK (inactive)
What are the 3 main enzymes of glycolysis?
- Hexokinase/Glucokinase
- PFK-1
- Pyruvate Kinase
What 2 enzymes do glucagon/epinepherine modify in hepatic glycolysis?
- Indirectly inhibits PFK-1 by phosphorylating kinase domain of PFK-2 (less F-2,6-bisP)
- Directly phosphorylating Pyruvate Kinase
What are the 4 fates of Pyruvate post-glycolysis?
- Transamination –> Alanine
- Pyruvate Carboxylase (caboxylation) –> Oxaloacetate
- LDH (reduction) –> Lactate –> Cori Cycle
- PDH (oxidation)–> Acetyl-CoA –> TCA –> ETC
What happens with Pyruvate Carboxylase deficiency?
(Converts pyruvate –> oxaloacetate)
- Will cause increased alanine, lactate, pyruvate concentrations
- Symptoms: developmental delay, recurrent seizures, metabolic acidosis
What happens with PDH deficiency?
(allows pyruvate to enter TCA cycle)
- Will cause increased pyruvate and lactate concentrations
- Symptoms: micocephaly, poor muscle coordination, mental retardation
What are the 3 ways NAD+ can be regenerated in the cytoplasm?
- LDH
- Malate-Aspartate Shuttle
- Glycerol-Phosphate Shuttle
What reaction does the PHD complex catalyze?
Pyruvate + Coenzyme A (CoASH) + NAD+ –> Acetyl-CoA + NADH
What vitamins/cofactors are needed for PDH?
Vitamin B1 (Thiamine-TPP) Vitamin B2 (Riboflavin-FAD) Vitamin B3 (Niacin-NAD) (and Vitamin B5)
What occurs during LDH-A?
LDHA is lactate dehydrogenase A deficiency
- Patient can’t maintain exercise because can’t do glycolysis to make ATP needed for muscle contraction anaerobically
- NAD+ becomes limiting during exercise and flux through glyceraldehyde-3-P-dehydrogenase reaction inhibited
What regulates PDH?
Acetyl-CoA and NADH:
- allosterically inhibit PDH
- Promote phosphorylation/inhibition of PDH
What 2 enzymes metabolize galactose?
- Galactokinase
2. Galactose-1-P-uridyltransferase
What occurs in Galactosemia? Which enzyme deficient?
Most commonly Galactose-1-P-uridyltransferase
- causes accumulation of galactose
- causes cataracts (among other problems)
How is Hereditary Fructose Intolerance caused? What is effect?
Aldolase B deficiency
- Fructose-1-P trapping of Pi –> cannot make ATP –> ATP levels fall quickly
- Hypoglycemia, Vomiting, Jaundice, Hepatic failure
