Flashcards in Carbohydrate Metabolism Deck (48):
GLUT1 , 2 , 3 , 4
Glucose transporters to get glucose past the cell membrane into cell.
GLUT1: Ubiquitious but high in RBCs and brain. High affinity for glucose.
GLUT 2: Main transporter in liver (low affinity)
GLUT 3: Main transporter in neurons (high affinity)
GLUT4: In skeletal muscle, heart and adipose tissue (insulin dependent)
1 mol glucose —> 2 mol Pyruvate
-Generate NET 2 ATP and 2 NADH
Anaerobic respiration critical for which cells?
RBCs (no mitochondria) and overworked muscles (lacking O2)
Hexokinase and Glucokinase
Isozymes for G —> G6P (step 1 glycolysis). Traps glucose in cells via phosphorylation.
Hexokinase - all cells. High affinity, even at low [G]. Inhibited by G6P.
Glucokinase - liver, pancreatic Beta-cells. Low affinity. Sequestered in nucleus during fasting state, active during fed state. Not inhibited by G6P.
Step 3 glycolysis: F6P —> F1,6bisP
-RATE-LIMITING ENZYME OF GLYCOLYSIS
-Requires ATP (investment)
-Dephosphorylated = Active
Stimulated by AMP and F2,6bisP
Inhibited by ATP and Citrate
Glyceraldehyde 3P Dehydrogenase
3 Payoff enzymes in glycolysis
G-3P-Dehydrogenase: G3P —> 1,3Bisphosphoglycerate - 2 NADH
Phosphoglycerate Kinase: 1,3BPG —> 3-phosphoglycerate - 2ATP
Pyruvate Kinase: Phosphoenolpyruvate —> Pyruvate - 2 ATP
Pyruvate Kinase regulation in glycolysis
Catalyze irreversible reaction:
Phosphoenolpyruvate (PEP) —> Pyruvate
-Stimulated by Insulin and F1,6BP
-Inhibited by Alanine, ATP and Glucagon (PEP would then enter gluconeogenesis)
-continue the process of glycolysis —> F6P
-G6P —> G1P: Galactose metabolism or Glycogen synthesis
-Pentose Phosphate Pathway precursor
Defective Glycolysis Enzyme Consequences
Hemolytic anemia (resulting mostly from Pyruvate kinase defect)
Neurological problems (from a couple other enzymes)
RBC and Glycolysis
Glycolysis is RBCs only mechanism to make energy.
-Glycolysis failure in RBC = ATP deficiency
-Ion gradients powered by ATP disrupted (Na+/K+, etc.)
-Leads to REDUCED CELL VIABILITY ==> RBC death (HEMOLYTIC ANEMIA).
Diabetes Type 1
Hyperglycemia caused by severe insulin deficiency due to loss of Pancreatic beta-cells (possibly from immune destruction).
No insulin to trigger glucose uptake via GLUT4. Blood sugar level = HIGH
Diabetes Type 2
Insulin resistance which progresses to loss of beta-cell function
-possibly from mutations in glucokinase, aberrant conversion of pro insulting to insulin, defective insulin receptor, infection, etc.
Premature destruction of RBCs.
-Nutritional deficiencies (iron, folate, vit B12)
-Defects in glycolytic enzymes (e.g. Pyruvate kinase)
Marker: Elevated LDH (Less RBCs carrying oxygen = Less cellular respiration = increased anaerobic respiration?)
Deficiency in PFK-1
-Exercise-induced muscle weakness/cramps (muscles cannot metabolize glycogen stores)
-Hemolytic anemia (RBC’s only mech for energy compromised)
Gluconeogenesis (location, job and precursors)
Used to increase blood glucose levels converting Pyruvate —> Glucose
-3 irreversible steps of glycolysis are bypassed in gluconeogenesis
Occurs in the kidney, liver and SI
Major precursors: lactate, AAs and glycerol
Stimulated by: Glucagon, citrate, cortisol, thyroxine, acetyl-CoA
Inhibited by: ADP, AMP, F26BisP
Gluconeogenesis Bypass enzymes
Pyruvate —> Phosphoenol Pyruvate
(1) Pyruvate Carboxylase and
(2) Phosphoenolpyruvate carboxykinase
Fructose 1,6 Bisphosphatase —> F6P
(3) Fructose 1,6 Bisphosphatase
G6P —> G
Pyruvate —> oxaloacetate
First step in converting Pyruvate to Phosphoenolpyruvate in MITOCHONDRIA.
A mitchondrial enzyme, requires biotin.
Activated by: Acetyl-CoA, cortisol
Oxaloacetate —> PEP
Last step in converting Pyruvate to PEP, occurs in CYTOSOL. Bypasses Pyruvate Kinase reaction
Activated by: Cortisol, glucagon, thyroxin
Fructose 1,6 BisPhosphatase
Converting F1,6bisP —>F6P
RATE-LIMITING ENZYME, bypasses PFK-1 reaction.
Activated by: Cortisol and citrate
Inhibited by: AMP and F26BP
Converting G6P —> G
Occurs only in liver, kidney, SI and pancreas, bypasses the hexokinase/glucokinase reaction.
Muscle cells LACK this enzyme, thus cannot convert G6P to free glucose after glycogenolysis. G6P instead enters glycolysis/TCA for energy needs
Activated by: Cortisol
Links the lactate produced from anaerobic glycolysis in RBC and exercising muscle to gluconeogenesis in liver.
-Prevents lactate accumulation
Hypoglycemia, lactic acidosis, Ketosis
Von Gierke Disease
Deficiency in Glucose-6-Phosphatase
Inefficient release of glucose into blood by liver in gluconeogenesis
Hypoglycemia, lactic acidosis, hepatomegaly due to buildup of glycogen.
Diet management is therapy
Autosomal Recessive disorder - mutation in GLUT2 transporter (which takes up fructose, glucose and galactose).
Failure to thrive, hepatomegaly, abdominal bloating. Fasting hypoglycemia and post-meal hyperglycemia.
Treatment: Vitamin D and uncooked cornstarch (prevents spikes in blood sugar and provides sustained release of glucose)
Hereditary Fructose Intolerance
Inability to metabolize fructose from F1P to Glyceraldehyde and DHAP
Galactose metabolism disorder, deficiency in either two enzymes: GALT or Galactokinase
-Accumulation of galactitol
-CLASSIC galactosemia: failure to thrive, liver failure, sepsis
-Accumulation of galactose and galatitol in blood/urine. Accumulation of galactitol in lens of eye = cataracts in infancy
Pentose Phosphate Pathway
Glucose-6-P from glycolysis enters PPP. Phagocytic cells have VERY high PPP activity, high in lung and liver tissue.
-Produce sugar for DNA and RNA formation: ribulose-5P
-Produce 2 NADPH via oxidation of Glucose-6-P and 1 CO2
Non-oxidative phase produces nucleotide precursors and glycolysis intermediates that cycle back to glycolysis or gluconeogenesis (F6P and Glyceraldehyde-3-P)
Oxidative steps = Irreversible
Non-oxidative steps = reversible
G6P Dehdrogenase (G6PD)
RATE LIMITING ENZYME of PPP oxidative phase
NADP+ reduced —> NADPH
NADPH inhibits G6P (Feedback inhibition from product)
G6PD Deficiency: Hemolytic Anemia due to elevated NADPH need
-Requires oxidizing medication
An important antioxidant (G—SH) that detoxifies hydrogen peroxide with glutathione reductive
Regenerated by NADPH from PPP
Last enzyme in oxidative phase of PPP—> ribulose-5P formation
Produces NADPH and CO2
Reducing/non-reducing ends of Glycogen
Non-reducing ends each contain terminal glucose with C4 hydroxyl group. Glycogen degraded/extended from non-reducing end
Reducing ends consist of glucose monomer connected to GLYCOGENIN protein.
-glycogenin creates short glycogen polymer on itself—> primer for glycogen synthesis
In liver, muscle and other tissue.
Stored as granules, which contain glycogen and other enzymes required for glycogen metabolism.
Glucokinase/hexokinase regarding glycogen
First enzyme of Glycogenesis:
Traps Glucose in hepatocyte or muscle cells BYU phosphorylation to G6P.
Glycogenesis enzyme, step 2
G6P —> G1P
(Moves the phosphate group)
Enzyme in Glycogenesis
G1P —> UDP-glucose
Transfers UTP on to G1P releasing a phosphate
RATE-LIMITING ENZYME in Glycogenesis
Catalyzes glucose from UDP-glucose onto non-reducing end of glycogen
(Alpha-1,4 glycosidic bond)
Dephosphorylated = ACTIVE
Glucosamine (4:6) transferase
Glycogen gets to 11 residues, stops, breaks off last 7 residues from alpha-1,4-glycosidic linkage and reattached somewhere with alpha-1,6 linkage.
BRANCHING ENZYME of Glycogenesis
-branching increases solubility of glycogen
Glycogen Phosphorylase (GP)
RATE LIMITING ENZYME of Glycogenolysis
Cleaves G1P residue from non-reducing end of glycogen.
Utilizes Vitamin B6 (Pyridoxal) as CO-FACTOR
Takes glucose residues off until about 4 residues of next branch (alpha-1,6 linkage)
Phosphorylated = INACTIVE
Glycogenolysis debranching enzyme uses transferase (4:4) activity, taking 3 glucose residues close to a branch site and attaching them to non-reducing end with alpha-1,4 linkage
Debranching enzyme cleaves the last residue with the alpha-1,6 link producing a free glucose residue
Defect in lysosomal alpha-1,6-glucosidase (acid maltase)
Lysosomes contain small amount of branched glycogen
Why muscle cells cannot hydrolyzed G6P to glucose
Livers take G1P and convert to G6P after glycogenolysis. Then they use GLUCOSE-6-PHOSPHATASE to confer G6P to free glucose to enter blood.
Muscle cells LACK glucose-6-phosphatase thus cannot convert it to free glucose. Instead G6P in muscles enter glycolysis and TCA.
Blood Glucose Criteria
Normal: 70-100 ml/dL (fasting) , = 140 mg/dL (fed)
Prediabetic (at risk): 100-125 mg/dL (fasting) , >140 mg/dL (fed)
Diabetes mellitus: > 125 mg/dL (fasting) , > 199 mg/dL (fed)
Deficiency in glycogen synthase
-cannot synthesize glycogen
-muscle cramps (lack of glycogen in muscle)
-vulnerable to hypoglycemia when fasting
-must eat frequently
Deficiency in alpha-1,6-Glucosidase (DEBRANCHING enzyme)
-Many short branches in glycogen
-light hypoglycemia and hepatomegaly
Deficiency in glucosyl (4:6) transferase (BRANCHING enzyme)
-long chain glycogen, few branches
-enlarged liver and spleen, scarring of liver tissue
Deficiency in muscle glycogen phosphorylase
-Patient unable to supply muscle with enough glucose
-weakness, muscle cramps