Lect 4 CHO Metabolism Flashcards Preview

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Flashcards in Lect 4 CHO Metabolism Deck (66):
1

What is the only fuel RBCs can use?

Glucose (no mitochondria)

2

What energy forms does the Brain use?

Glucose (non-starvation)

Switch to Ketones (starvation)

3

Where is GLUT1?

Ubiquitous, but high in RBC and brain

High affinity Km 1 mM

4

Where is GLUT2?

Main transporter in Liver

Low Affinity Km 10 mM

5

Where is GLUT3?

Main transporter in neurons

High Affinity Km 1 mM

6

Where is GLUT4?

Skeletal muscle, heart, adipose tissue

Regulated: Insulin Dependent

7

How is GLUT4 brought to the plasma membrane?

GLUT4 sequestered in vesicles in cells

Insulin signaling --> fusion of vesicles with PM

Enables GLUT4 induced glucose uptake

8

Glycolysis is _ process

Anaerobic (no O2)

9

Where does Glycolysis occur?

Cytoplasm

10

What is Glycolysis's Net Yield

2 ATP

2 NADH

2 Pyruvate

11

Describe Glycolysis Phase 1 (Investment Phase)

  • Phosphorylation of Glucose --> G6P (Regulatory Step)
    • Hexokinase (all cells) & Glucokinase (liver, pancreatic B-cells)
      • ATP --> ADP
  • Isomerization of G6P to F6P
  • Phosphorylation of F6P --> Fructose 1,6-Bisphosphate  (F1,6-BP) (RATE LIMITING STEP​)
    • Phosphofructokinase-1 (PFK-1)
      • ​ATP --> ADP

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12

How is Hexokinase Regulated?

What is its affinity?

Inhibited by G6P

High Affinity (functional even at low [glucose])

13

How is Glucokinase Regulated?

What is its affinity?

Activated: Glucose, F1P, Insulin

Inhibited: Glucagon, F6P

Low affinity for glucose

Most active when high [glucose]

14

How is PFK-1 Regulated?

Activate: AMP, F2,6-BP (formed by PFK-2)

Inhibit: ATP, Citrate

 

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15

How is PFK-1 Hormonally Regulated with Insulin?

  • Fed State: 
    • High insulin/low glucagon
    • Activate protein phosphatases, Dephosphorylate PFK-2/FBPase-2 (Kinase activity) produces F2,6BP --> activating PFK-1

16

How is PFK-1 Hormonally Regulated with Glucagon?

  • Fasting State
    • High glucagon/low insulin
    • Induces high [cAMP] --> activate PKA, phosphorylates PFK-2/FBPase-2 (phosphorylation activity) --> Reduces PFK-1 activity

17

Describe Glycolysis Phase 2 (Splitting)

  • Cleavage of F1,6-BP --> Dihydroxyacetone Phosphate (DHAP) + Glyceraldehyde 3P (G3P)
    • Aldolase A
  • Isomerization of DHAP --> G3P (Now have 2 G3P)
    • Triose Phosphate Isomerase

18

Describe Glycolysis Phase 3 (Payoff)

  • G3P (2) --> 1,3-Bisphosphoglycerate (2)
    • Glyceraldehyde 3P Dehydrogenase
      • Reduces NAD+ (2) --> NADH (2)
  • ​​1,3-BPG (2) --> 3-Phosphoglycerate (3PG) (2)
    • Phosphoglycerate Kinase
      • ADP (2) --> ATP (2)
  • 3PG --> 2PG --> PEP
  • PEP (2) --> Pyruvate (2)
    • Pyruvate Kinase
      • ADP (2) --> ATP (2)

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19

Describe Pyruvate Kinase Regulation

  • Activated: Insulin, F1,6-BP
  • Inhibit: Alanine, ATP, Glucagon

20

Describe PK Hormonal Regulation

  • High Insulin: Stimulate protein phosphotase --> Dephosphorylation of PK --> Activate
  • High Glucagon: cAMP activates PKA --> Phosphorylation of PK --> Inhibition

21

3 Regulation Checkpoints of Glycolysis

Hexokinase/Glucokinase (Glu --> G6P)

PFK-1 (F6P --> F16BP)

Pyruvate Kinase (PEP --> Pyruvate)

22

What are the other fates of G6P?

  • Pentose Phosphate Pathway: G6P --> Ribose and NADPH Synthesis
  • Converted to G1P: Gylcogen synthesis, Gal metabolism

23

Defective Glycolytic Enzymes = _ 

What cells most affected?

Most common enzyme defective?

Ineffective glycolysis

Cells w/o Mitochondria impacted most (RBC)

Pyruvate Kinase

24

Most Glycolytic Enzyme Defects cause this condition

Hemolytic Anemias

25

Failure of glycolysis results in _ leading to disruption of ion gradients.

This causes what to happen and what condition?

ATP Deficiency --> Reduced cell viability

RBC destruction causes hemolytic anemia

26

Why is the brain particularly dependent on glucose?

What happens during starvation?

Glucose only fuel molecule to cross blood brain barrier (BBB)

Starvation: obtain glucose from liver via gluconeogenesis

Also utilize ketone bodies (extreme starvation/ketogenic diet)

27

Diabetes is characterized by _ 

Differences between Type I and Type II

Fasting glucose levels in prediabetic and diabetic

  • Characterized by hyperglycemia
    • Type I: insulin deficiency due to loss of pancreatic B-cells
    • Type II: insulin resistance progresses to loss of B-cell function
  • Prediabetic = 100-125
  • Diabetic = > 125

28

How much Glucose does the body need? the brain?

How much is availabel in body fluids? glycogen stores?

Needs 160 g glucose/day

Brain requires 120 g

Glucose in body fluids 20 g

Glucose available from glycogen 190 g

29

Gluconeogenesis Location, Function, Precursors

Location: Liver, Kidney, SI

Function: Pyruvate --> Glucose

Precursors: Lactate, AAs, Glycerol

30

What is Pyruvate Carboxylase (PC)

  • Mitochondrial Enzyme that catalyzes 1st Step: 
    • Pyruvate carboxylated to form OAA

31

Pyruvate Carboxylase cofactor?

Biotin

32

Pyruvate Carboxylase Regulation

Activated: Acetyl CoA and Cortisol

Inhibited: ADP

33

How is Pyruvate transported out of Mitochondria

  • OAA reduced --> Malate via Malate Dehydrogenase (NADH dependent)
  • Transported to cytoplasm via Malate shuttle
  • Re-oxidized to OAA via cytosolic malate dehyrogenase (NADH dependent)

34

What is the function of Phosphoenolpyruvate Carboxykinase (PEPCK)

OAA --> PEP

Activated: Cortisol, Glucagon, Thyroxine

35

Fructose 1,6-Bisphosphatase

F1,6-BP --> F6P

Rate Limiting Step

Activated: Cortisol and Citrate

Inhibited: AMP and F26BP

36

What does Glucose 6 Phosphatase do?

G6P --> Glucose

Activated by Cortisol

37

Glucose 6 Phosphatase Location and Structure

Lumen of ER in Liver, Kidneys, SI, and Pancreas

Catalytic Unit; G6P/Pi antiporter; glucose transporter (GLUT7)

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38

What is the Function of Cori Cycle?

Lactate from anaerobic glycolysis in RBC/exercising muscle    --> Liver (gluconeogenesis)

39

F1,6-Bisphosphatase Deficiency Consequences

Hypoglycemia, lactic acidosis, ketosis, apnea, hyperventilation

40

What is Von Gierke Disease (GSD1a)?

Deficiency in glucose 6 phosphatase

41

Fructose Uptake Transporter?

GLUT5 (Facilitated Diffusion)

42

Galactose/Glucose Uptake Transporter?

SGLT1 (Secondary Active Transport w/ Na)

43

Fanconi Bickel Syndrome Cause and Defects

Mutation in GLUT2 transporter (liver, pancreatic B cell, enterocytes, renal tubular cells)

Unable to uptake Glu, Fru, Gal

44

Conversion of Glucose  to Fructose via Polyol Pathway

Glucose --> Sorbitol (Aldose reductase) --> Fructose (Sorbitol dehydrogenase)

Cells lacking sorbitol dehydrogenase (kidney, retina) accumulate sorbitol (water influx/swelling) and manifest as retinopathy, cataracts

45

High Fructose Corn Syrup (HCFS) and Obesity

 

Bypasses PFK-1, more efficiently converted to Fat

46

How is Galactose Metabolism

Galactose --> Galactose 1P (galactokinase) --> Glucose 1P (Glucose 1P Uridyltransferase/GALT)

47

Galactosemia is caused by what?

  • Deficiency in GALT
  • Deficiency in Galactokinase

48

PPP Location and Products

Occurs in cytosol

Oxidation of G6P --> Ribulose 5P

Reduction of NADP+ --> NADPH (2)

49

Irreversible Oxidative Step (Catabolism)

G6P --> 6PLactone (G6P Dehydrogenase) --> 6PGluconate --> Ribulose 5P

Produces 2 NADPH

G6PDH Inhibited by NADPH

50

PPP Rate Limiting Enzyme

G6P Dehydrogenase

51

NADPH regenerates _

Glutathione (antioxidant, detoxifies H2O2)

52

PPP - Nonoxidative phase is series of _ reactions. 

These end products are shunted to glycolytic, gluconeogenic, and nucleotide synthesis pathways.

Reversible

Ribose 5P, G3P, F6P

53

Where there is a high demand of ribose 5P (nucleotide syn), _ phase is favored to produce _  

When there is high demand for NADPH, _ phase products channeled into gluconeogenesis for re-entry into PPP

Oxidative - Ribulose 5P

Non - oxidative

54

Glucose molecules are linked together via _ bonds in glycogen with branch points formed via _ bonds

a-1,4 glycosidic bonds

a-1,6 glycosidic bonds

55

Glycogen stored in _ which contain not only glycogen but also _

Granules

Enzymes needed for glycogen metabolism

56

Trapping and activation of glucose in glycogenesis in 3 steps

Occurs in liver and muscle

  • Glucose --> G6P
    • HK/GK
  • G6P --> G1P
    • Phosphoglucomutase
  • G1P --> UDP Glucose (Active Form)
    • UDP Glucose pyrophosphorylase

57

Elongation of glycogen primer utilizes this rate limiting enzyme

Glycogen synthase catalyzes transfer of glucose from UDP-glucose to non-reducing end of glycogen

58

Branching of glycogen chains occurs via this enzyme

Why is branching important?

Glucosyl (4:6) transferase

Increases solubility of glycogen and increases number of non-reducing terminal ends

59

Glycogenolysis starts with chain shortening phase to release G1P via this rate limiting enzyme

What cofactor is used?

Process continues until enzyme gets within _ residues of a-1,6 linkage

Glycogen phosphorylase

Pyridoxal phosphate (Vit B6)

4 residues

60

This enzyme transfers block of 3 of 4 remaining glucose to non reducing end. 

Debranching enzyme

61

In the liver, G1P is converted to G6P and then to glucose by this enzyme that is not present in muscles

Phosphatase

62

GP and GS are regulated by phosphorylation. 

GS is active when _ 

GP is active when _

GS: active dephosphorylated/inactive phosphorylated

GP: active phosphorylated/inactive dephosphorylated

63

Reciprocal regulation of glycogenesis and glycogenolysis

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64

Insulin regulation mechanism has 4 key proteins involved and what is the net result?

  • GLUT4, Protein Kinase B, Protein Phosphatase 1, Glycogen Synthase Kinase 3
  • Net Result Glycogen Synthesis

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65

Regulation of Glycogenolysis has 5 key enzymes and second messengers

  • G protein, Adenylate cyclase (AC) and cAMP, PKA, PP1, Phosphorylase Kinase
  • Net result is glycogen breakdown

66

GSD 0

GSD II/Pompe Disease

GSD III/Cori Disease

GSD IV/Anderson Disease

GSD V/McArdle Disease

GSD VI/Hers Disease

 

  • Deficiency in GS
    • Chain elongation
  • Deficiency in acid maltase (a-glucosidase)
    • Lysosomal glycogenolysis
  • Deficiency in a-1,6 glucosidase (Debranching Enzyme)
    • Glycogen molecules with large number of short branches
  • Deficiency in glucosyl (4:6) transferase (Branching Enzyme)
    • Long chain glycogen with fewer branches
  • Deficiency in muscle glycogen phosphorylase
    • Cannot supply muscles with glucose
  • Deficiency in Liver glycogen phosphorylase
    • Glycogen accumulates in liver, hypoglycemia