Carbohydrate Metabolism Flashcards Preview

MCM - Rusheil > Carbohydrate Metabolism > Flashcards

Flashcards in Carbohydrate Metabolism Deck (48):
1

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)

2

Glycolysis yield

1 mol glucose —> 2 mol Pyruvate
-Generate NET 2 ATP and 2 NADH

3

Anaerobic respiration critical for which cells?

RBCs (no mitochondria) and overworked muscles (lacking O2)

4

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.

5

Phosphofructokinase-1 (PFK1)

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

6

Glyceraldehyde 3P Dehydrogenase

Phosphoglycerate Kinase

Pyruvate Kinase

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

7

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)

8

G6P pathways

G6P could:
-continue the process of glycolysis —> F6P
-G6P —> G1P: Galactose metabolism or Glycogen synthesis
-Pentose Phosphate Pathway precursor

9

Defective Glycolysis Enzyme Consequences

Hemolytic anemia (resulting mostly from Pyruvate kinase defect)

Neurological problems (from a couple other enzymes)

10

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).

11

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

12

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.

13

Hemolytic Anemia

Premature destruction of RBCs.

Cause(s):
-Nutritional deficiencies (iron, folate, vit B12)
-Defects in glycolytic enzymes (e.g. Pyruvate kinase)
-Elevated cholesterol

Marker: Elevated LDH (Less RBCs carrying oxygen = Less cellular respiration = increased anaerobic respiration?)

14

Tarui Disease

Deficiency in PFK-1

-Exercise-induced muscle weakness/cramps (muscles cannot metabolize glycogen stores)
-Hemolytic anemia (RBC’s only mech for energy compromised)

15

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

16

Gluconeogenesis Regulation

Stimulated by: Glucagon, citrate, cortisol, thyroxine, acetyl-CoA

Inhibited by: ADP, AMP, F26BisP

17

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
(4) Glucose-6-Phosphatase

18

Pyruvate Carboxylase

Pyruvate —> oxaloacetate

First step in converting Pyruvate to Phosphoenolpyruvate in MITOCHONDRIA.
A mitchondrial enzyme, requires biotin.

Activated by: Acetyl-CoA, cortisol

19

Phosphoenolpyruvate Carboxykinase

Oxaloacetate —> PEP

Last step in converting Pyruvate to PEP, occurs in CYTOSOL. Bypasses Pyruvate Kinase reaction

Activated by: Cortisol, glucagon, thyroxin

20

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

21

Glucose-6-Phosphatase

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

22

Cori Cycle

Links the lactate produced from anaerobic glycolysis in RBC and exercising muscle to gluconeogenesis in liver.

-Prevents lactate accumulation
-Regenerates glucose

23

F1,6bisPhosphatase Deficiency

Hypoglycemia, lactic acidosis, Ketosis

24

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

25

Fanconi-Bickel syndrome

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)

26

Hereditary Fructose Intolerance

Inability to metabolize fructose from F1P to Glyceraldehyde and DHAP

27

Galactosemia

Galactose metabolism disorder, deficiency in either two enzymes: GALT or Galactokinase

GALT deficiency:
-Accumulation of galactitol
-CLASSIC galactosemia: failure to thrive, liver failure, sepsis

Galactokinase deficiency:
-Accumulation of galactose and galatitol in blood/urine. Accumulation of galactitol in lens of eye = cataracts in infancy

28

Pentose Phosphate Pathway

Glucose-6-P from glycolysis enters PPP. Phagocytic cells have VERY high PPP activity, high in lung and liver tissue.

Oxidative phase:
-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

29

G6P Dehdrogenase (G6PD)

RATE LIMITING ENZYME of PPP oxidative phase

NADP+ reduced —> NADPH
G6P oxidized
NADPH inhibits G6P (Feedback inhibition from product)

G6PD Deficiency: Hemolytic Anemia due to elevated NADPH need
-Requires oxidizing medication

30

Glutathione

An important antioxidant (G—SH) that detoxifies hydrogen peroxide with glutathione reductive

Regenerated by NADPH from PPP

31

6-Phosphogluconate Dehydrogenase

Last enzyme in oxidative phase of PPP—> ribulose-5P formation

Produces NADPH and CO2

32

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

33

Glycogen storage

In liver, muscle and other tissue.

Stored as granules, which contain glycogen and other enzymes required for glycogen metabolism.

34

Glucokinase/hexokinase regarding glycogen

First enzyme of Glycogenesis:

Traps Glucose in hepatocyte or muscle cells BYU phosphorylation to G6P.

35

Phosphoglycomutase

Glycogenesis enzyme, step 2

G6P —> G1P

(Moves the phosphate group)

36

UDP-glucose pyrophosphorylase

Enzyme in Glycogenesis

G1P —> UDP-glucose

Transfers UTP on to G1P releasing a phosphate

37

Glycogen Synthase

RATE-LIMITING ENZYME in Glycogenesis

Catalyzes glucose from UDP-glucose onto non-reducing end of glycogen
(Alpha-1,4 glycosidic bond)

Dephosphorylated = ACTIVE

38

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

39

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

40

Debranching enzyme

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

41

Pompe Disease

Defect in lysosomal alpha-1,6-glucosidase (acid maltase)

Lysosomes contain small amount of branched glycogen

42

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.

43

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)

44

GSD 0

Deficiency in glycogen synthase
-cannot synthesize glycogen
-muscle cramps (lack of glycogen in muscle)
-vulnerable to hypoglycemia when fasting
-must eat frequently

45

Cori Disease

Deficiency in alpha-1,6-Glucosidase (DEBRANCHING enzyme)
-Many short branches in glycogen
-light hypoglycemia and hepatomegaly

46

Anderson Disease

Deficiency in glucosyl (4:6) transferase (BRANCHING enzyme)
-long chain glycogen, few branches
-enlarged liver and spleen, scarring of liver tissue
-death

47

McArdle Disease

Deficiency in muscle glycogen phosphorylase
-Patient unable to supply muscle with enough glucose
-weakness, muscle cramps

48

Hers Disease

Deficiency in liver glycogen phosphorylase. Prevents glycogen breakdown in liver —> accumulates in liver —> hepatomegaly

-low blood glucose levels