Glycolysis And PPP Flashcards

1
Q

What is the fate of absorbed glucose?

A

GLUT (facilitated diffusion)
– GLUT 2 – liver
– GLUT 1 and 3 – neurons and brain – GLUT 1 - erythrocytes
– GLUT 4 - adipose tissue and muscle (Insulin- responsive)

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2
Q

How is glucose 6 phosphate formed?

A

• Glucokinase: liver and pancreatic -cells of pancreas (high Km)
– More active when blood glucose is elevated; ‘Glucose sensor’ • Othertissues–hexokinase(lowKm)

• Glucokinase mutations: Hyperglycemia and MODY-2
– -cells of pancreas cannot respond to high blood glucose levels!!!

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3
Q

What are the fates of glucose 6 phosphate in the liver?

A

Glycolysis

Glycogenesis

Ribulose 5-P NADPH (PPP)

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4
Q

Give an overview of the pentose phosphate pathway

A

CYTOSOL
• Glucose 6-phosphate dehydrogenase (key enzyme)
– Does NOT form ATP (energy) • Forms NADPH
– Fatty acid biosynthesis, cholesterol biosynthesis and steroid hormone synthesis in liver, adipocytes and endocrine glands

  • Malic enzyme also forms NADPH in these tissues
  • Forms Ribose phosphate – purine and pyrimidine synthesis

• Transketolase requires TPP (vitamin B1)
– Thiamine deficiency: Low transketolase activity

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5
Q

What are the functions of glycolysis ?

A

Generate ATP (energy) in presence or absence of O2 (aerobic and anaerobic) and in presence or absence of mitochondria
• Generates ATP (energy)
• Glycolytic enzymes are present in cytosol

– In brain (fed and fasted state), liver (fed state)
– Tissues that lack mitochondria or hypoxic (Only pathway for energy generation)
– Actively contracting skeletal muscle (Glucose obtained from glycogen or plasma glucose)

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6
Q

Give an overview of the glycolysis phases

A

Stage 1: energy investment phase( glucose to fructose 1,6-bisphosphate)

Stage 2: cleavage of 6C sugar into 3C intermediates (fructose 1,6 biphosphate splits to glyceraldehyde 3 phosphate and dihydroxyacetoje phosphate

Stage 3 energy generation phase

Each glyceraldehyde 3 phosphate and DHA phosphate is used to form pyruvate

2 ATP formed and NADH formed

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7
Q

How does Acetyl CoA enters the mitochondria?

A

Via shuttle systems

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8
Q

Describe the ATP formed substrate level phosphorylation

A

• Directly form ATP from ADP
• DO NOT require Electron Transportchainor
mitochondria or Oxygen

  • ONLY reactions that form ATP in cells that lack mitochondria and in hypoxic conditions
  • High energy compounds – 1,3-Bisphosphoglycerate – Phosphoenolpyruvate
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9
Q

What are the fates of Pyruvate ?

A

Aerobic- forms Acetyl CoA (Pyruvate dehydrogenase complex-requires TPP and is a mitochondrial enzyme)—> enters TCA cycle

Anaerobic- Anaerobjc-lactate (lactate dehydrogenase and is a cytosolic enzyme)—> goes to liver via Cori cycle

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10
Q

What situations call for anaerobic use of Pyruvate?

A

Absence of mitochondria (red blood cells, lens, cornea, leukocytes)

Poorly vascularized tissues or hypoxia (contracting skeletal muscle, cardiac muscle hypoxia)

Pyruvate dehydrogenase deficiency or thiamine deficiency

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11
Q

Explain the anaerobic fate of Pyruvate

A

• NADHformedbyglyceraldehyde3-phosphate dehydrogenase is reoxidized to form NAD+
– Allows glycolysis to proceed in absence of mitochondria

• LDH is cytosolic enzyme

• Direction of reaction: NADH/NAD+ ratio
– Higher NADH, increases lactate

  • Identify states of high NADH/NAD+ ratio
  • Contrast between muscle (fast-twitch) and liver
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12
Q

Describe the energetics of aerobic glycolysis

A
  • Overall reaction: Glucose→2 Pyruvate
  • 2 NADH+ H+ (glyceraldehyde 3-phosphate dehydrogenase) = 2x3 = 6ATP
  • (1 NADH=2.5 ATP and 1 FADH2=1.5 ATP; Approximate 1 NADH = 3 ATP and 1 FADH2 = 2 ATP)
  • NADH in cytosol by glycolysis transported into mitochondria by shuttle systems (malate-aspartate or glycerol-phosphate shuttle) – Refer Shuttles and OxPhos
  • 4 ATP (substrate level phosphorylation) (2ATP from a glyceraldehyde 3-phosphate)
  • -2ATP used
  • Total = 8 ATP
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13
Q

Describe the energetics of glycolysis under anaerobic conditions

A
  • OverallreactionGlucose→2 Lactate
  • 2 NADH+ H+ (glyceraldehyde 3- phosphate dehydrogenase) used in lactate dehydrogenase
  • 4ATP(substratelevel phosphorylation) (2ATP from a glyceraldehyde 3-phosphate)
  • -2ATPused
  • Total = 2 ATP
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14
Q

Describe lactate formation during anaerobic exercise in muscle

A

• Lactate threshold and endurance training:

Weight loss advice

– 60-70% of maximum heart rate: Fat oxidation by
muscle

– 80-85% of MHR: Anaerobic oxidation forms
lactate

• Anaerobic (strenuous) activity, blood lactate
levels increase
– Lactate in muscle → pH drops and cramps

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15
Q

What are the major comparisons of aerobic exercise?

A

• Oxygen present

• Glycogenolysis is active and may last
hours

• Glycolysis is active

• Kreb’s cycle and electron transport
chain are both active, producing ample ATP; Oxygen is the final electron acceptor.

  • Fatty acid oxidation
  • ATP production is maximal
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16
Q

What are the features of anaerobic/strenuous/ischemic exercise?

A

• Oxygen absent

• Glycogenolysis is active, but of
short duration

  • Glycolysis is active
  • Pyruvate is reduced to lactate
  • ATP production is rapid but minimal
17
Q

What are the defects in muscle glycolysis?

A
  • Muscle cramps (due to low ATP) during high-intensity anaerobic exercise; hemolysis if associated RBC glycolytic defect
  • Myoglobin uria and high serum CK-MM levels following high intensity exercise
  • NO increase in blood lactate levels with high intensity exercise (Ischemic forearm test)
  • Aerobic exercise tolerated (Oxidation of fatty acids not affected)
  • PFK-1 deficiency (Tarui disease; Glycogen storage disease Type VII)
18
Q

What is the cori cycle?

A

A fate of lactate

Glucose (liver) and lactate (Skeletal muscle; RBC)
Lactate from skeletal muscle and RBC, transported to liver for
gluconeogenesis

19
Q

Whaat is the effect of arsenic poisoning?

A
  • Glyceraldehyde 3-phosphate dehydrogenase

* PDH complex and -ketoglutarate dehydrogenase complex (mitochondrial enzymes)

20
Q

What are the other fates of pyruvate?

A

Forms alanine(important substrate for gluconeogenesis; link to amino acid metabolism)

Forms acetyl coa (for aerobic oxidation, by Pyruvate dehydrigenase complex)

Forms lactate(via lactate dehydrogenase)

Forms oxaaloacetate(via pyruvate carboxylase)

21
Q

What is lactic acidosis?

A

• High anion gap metabolic acidosis
– pH=low; HCO3–decreased; PCO2 decreased (compensation)
– High anion gap; Elevated lactate levels (unmeasured anion)

22
Q

Whhat are the conditions of lactic acidosis?

A

• Conditions of Lactic acidosis
– Increased NADH/NAD+ ratio: Binge alcohol consumption
– Pyruvate dehydrogenase deficiency (Leigh disease)

– Thiamine deficiency (pyruvate dehydrogenase complex)

– Gluconeogenesis defect – von Gierke disease – Defect in Cori cycle

– Decreased blood supply (circulatory shock): hypoxia and anaerobic metabolism
– Pulmonary embolism (poor oxygenation)

23
Q

What is the significance of glycolysis ?

A
  • Aerobic Tissues (brain, skeletal muscle) Glucose→ pyruvate→ acetyl CoA → TCA cycle
  • Adipose tissue: Dihydroxyacetone phosphate (forms glycerol 3-P) used for triacylglycerol formation (Link to lipid metabolism)

• Tissues of eye: cornea, lens (no mitochondria)
• Tumor cells
• Wound and healing injured tissue
• Red blood cells, anaerobic glycolysis
– Only source of energy (ATP)
– Forms 2,3 bisphosphoglycerate (2,3 BPG)

24
Q

Whwt is clmmon in gkycolysus and gluconeogenesis?

A
  • Reversible reactions of gluconeogenesis are same as glycolysis (but in reverse direction)
  • Four irreversible reactions in gluconeogenesis to bypass the three irreversible reactions of glycolysis
25
Q

How is glycolysis regulated in liver?

A
  • Liver glycolysis and gluconeogenesis are reciprocally regulated • Glycolysis active when high blood glucose levels/ insulin
  • Gluconeogenesis: Low blood glucose levels/ glucagon
  • Irreversible/ regulated reactions:
  • Glukokinase
  • Phosphofructokinase-1(PFK-1)
  • Pyruvare kinase
26
Q

What is the significance of glucokinase?

A

• Glucokinase (liver) high Km; high Vmax
– More active as blood glucose level elevated (after a meal)
• No product inhibition

  • ‘Glucose sensor’ in liver and beta-cells of pancreas
  • Enzyme sequestered in nucleus when plasma glucose level is low
  • GlucokinaseMutations:HyperglycemiaandMODY-2
27
Q

What is the significance of PFK-1?

A
  • Allosteric enzyme and committed enzyme
  • Muscle: ATP(inhibits) & AMP(stimulates)
  • Liver:Fructose2,6-bisphosphate(stimulates) and citrate(inhibits)
28
Q

Explain PFK-2/FBPase-2?

A

• PFK-2 forms Fructose 2,6-bisphosphate
– Allosteric regulator of glycolysis and gluconeogenesis
• Fructose 1,6-bisphosphate: intermediate of glycolysis and gluconeogenesis

  • Fructose 2,6-bisphosphate degraded by Fructose bisphosphatase-2 (FBPase-2)
  • PFK-2/ FBPase-2 :‘Bifunctional enzyme’
  • Phosphorylation by glucagon
  • Dephosphorylation by insulin
29
Q

Explain the regulation of bifunctuonal enzyme

A

Insulin (high blood glucose level) – Dephosphorylation
– Active PFK-2
– Increases [Fructose 2,6-bisphosphate] – Allosterically activates PFK-1 (glycolysis)

Glucagon (low blood glucose level) – Phosphorylation
– FBPase-2 active
– Decreases [Fructose 2,6-bisphosphate]
– Activates Fructose 1,6-bisphosphatase (gluconeogenesis)

30
Q

Explain pyruvate kinase regulation

A

• Feed forward activator: Fructose1,6
bisphosphate
• Phosphorylation(glucagon) decreases activity
• Low blood glucose: Liver glycolysis less active, and gluconeogenesis active.
• Alanine (substrate for gluconeogenesis) inhibits pyruvate kinase

31
Q

How is glycolysis regulated?

A

• High carbohydrate diet and insulin: induce glycolytic enzymes (Increased synthesis increases concentration of enzymes)
– Low levels of insulin (diabetes mellitus) represses glycolytic enzymes

• Glucagon and fasting repress glycolytic enzymes