Glycolysis Flashcards by Denisse Tiangco

Glycolysis occurs in

cytosol

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Decreased function of glucokinase is assciated with

Maturity onset diabetes of the young

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Fructose-6-phosphate can be converted into Fructose-2,6-bisphosphate by the enzyme

Phosphofructokinase 2

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Fructose 2,6 bisphosphate induces glycolysis by upregulating the enzyme

PFK1

which converts fructose-6-phosphate to fructose 1,6 phosphate

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PFK1 is inhibited by

Citrate
ATP

(Metabolites from ETC and Krebs)

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In the well fed state, insulin is high which increases fructose 2, 6 phosphate utilized by both muscle and liver leading to increased hepatic

Glycolysis

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On a fasting state, glucagon levels are high which decreases fructose 2,6 bisphosphate and will halt hepatic glycolysis and increase

Gluconeogenesis

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Fructose 1,6 bisphosphatase converts fructose 1,6 phosphate to fructose 6 phosphate which allows liver to produce glucose and is inhibited by decreased

If fructose 2,6 bisphosphates is decreased, skeletal muscles are starved glucagon levels are high, hepatic gluconeogenesis is

fructose 2,6 bisphosphate

increased

allows liver to break down AA and other products to create glucose

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A drug decreases hepatic concentration of fructose 2,6 bisphosphate.

How will this drug likely alter the activity of aspartate transaminase (converts asparate -> oxaloacetate)

Decreased fructose 2,6 bisphosphate results in gluconeogenesis

If gluconeogenesis is increased, there is increased catabolism of amino acid and glycerol

Asparate transaminase breaks down aspartate to oxaloacetate which increases during gluconeogenesis to make glucose

Increased activity of aspartate transaminase

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Decrease in fructose 2,6 bisphosphate upregulated production of fructose 1,6 bisphosphatase resulting in increased production of fructose 6 phosphate for glucose and increased

Gluconeogenesis

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In RBCs, 1,3 bisphosphoglycerate from GDP can be converted to

via the enzyme

2,3 bisphosphoglycerate
2,3 BPG

BPG mutase

with loss of ATP

this regulates oxygen delivery to tissue, binds to hemoglobin and decreases hemoglobin affinity to tissue

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Deficiency of pyruvate kinase (Phosphoenolpyruvate -> Pyruvate) leads to decreased ability of RBCs to pump cations against concentration gradient and are unable to maintain homeostasis

Decreased ATP resulting in hemolysis

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If there is enough oxygen, pyruvate is converted into

Acetyl coa

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If there is insufficient oxygen, pyruvate is converted into

Lactate

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9 year old/male
History of anemia due to enzyme deficiency
Splenomegaly
Conjunctival pallor
Elevated reticulocyte count
Hemolytic anemia

Pyruvate kinase converts PEP to pyruvate

If pyruvate kinase is deficient, it is unable to pump cations out of cell due to dec ATP leading to decreased homeostasis and HEMOLYSIS

Pyruvate kinase deficiency

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First step in glycolysis

Irreversible

Uses up energy

Glucose -> glucose 6 phosphate by Hexokinase and Glucokinase

Addition of phosphate

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Step 2:

Rearrangement of covalent bonds

Glucose 6 phosphate -> Fructose 6 phosphate by phosphoglucose isomerase

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3rd step:

Irreversible

Second energy consumption step

First committed step

Fructose 6 phosphate -> Fructose 1,6 bisphosphate by Phosphofructokinase 1

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Step 4:

Splitting of 6 to 3 carbon sugars

Fructose 1,6 bisphosphate -> GDAP (glyceraldehyde-3 phosphate) + DHAP (dihydroacetone phosphate)

by Fructose bisphosphate aldolase

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Step 5

Isomerization

DHAP -> GDAP by triosephosphate isomerase

2 GDAP
2 ATPs consumed

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Step 6:

Energy generation

Inhibited by Arsenic

GDAP -> 1,3 bisphosphoglycerate

by Glyceraldehyde phosphate dehydrogenase

2 NADH

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Step 7:

Reversible

Energy generating

1,3 bisphosphoglycerate -> 3 phosphoglycerate

By Phosphoglycerate kinase

Transfer of phosphate
+ ATP

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Step 8:

3 phosphoglycerate -> 2 phosphoglycerate

By Phosphoglycerate mutase

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Step 9:

Lyase

Inhibited by Flouride

Dependent on Mg or Mn

2 phosphoglycerate -> Phosphoenolpyruvate

By Enolase

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Step 10 Irreversible Generation of ATP

Phosphoenolpyruvate -> Pyruvate By Pyruvate kinase

End product of Glycolysis from 1 glucose molecule

2 NADH 4 ATP 2 Pyruvate

Glucose and maltose enters glycolysis by

Step 1 Glucose -> Glucose 6 phosphate

Starch, Galactose-1 phosphate, Galactose and Lactose enter glycolysis by

Second step: Glucose 6 -> Fructose 6 phosphate

Fructose, sucrose and mannose enters glycolysis at

Step 3: Fructose 6 phosphate -> Fructose 1,6 bisphosphate

Glycerol and Glycerol 3 phosphate enters glycolysis via

Step 5: DHAP -> GHAP by triose phosphate isomerase

Major pathway for glucose metabolism Functions aerobically and anaerobically Glucose -> pyruvate

Glycolysis

Preliminary oxidation of glucose prior to complete oxidation in the Citric Acid Cycle Generates ATP through substrate level phosphorylation and NADH through oxidative phosphorylation

Glycolysis

ATP generation in glycolysis type of phosphorylation

Substrate level phosphorylation

NADH generation in glycolysis type of phosphorylation

Oxidative phosphorylation

Oxidation of glucose beyond pyruvate

Pyruvate dehydrogenase complex Citric acid cycle Respiratory chain

Functions for the production of other substances like amino acids and fatty acids Exercising muscle, cardiac muscle: ischemia, hemolytic anemia, cancer, lactic acidosis

Glycolysis

Occurs in cells with mitochondria With adequate supply of oxygen Product:

Aerobic glycolysis 2 NADPH from pyruvate

Tissues without mitochondria Without oxygen Product

Anaerobic glycolysis Lactate NADH is reconverted to NAD+

First committed step in glycolytic pathway

Fructose 6 -> Fructose 1,6 bisphosphate by PFK1

Tissues that depend on glycolysis as their major mechanism for ATP

RBC, cornea, lens, regions of retina (lack mitochondria) Kidney medulla, testis, leukocytes, white muscle fibers = few mitochondria almost totally dependent on glycolysis

Absolute need for glucose via glycolysis How many grams of glucose consumed per day

Brain 120 g

Regulatory enzymes of glycolysis

Hexokinase (low km, low vmax all cells)/Glucokinase PFK1 Pyruvate kinase

PFK 1 is stimulated by

ADP AMP dec ATP/AMP ratio Fructose 2,6 bisphosphate

PFK1 is inhibited by

``` ATP citrate H ions cAMP inc ATP/AMP ratio ```

Pyruvate kinase is stimulated by

Fructose 1 6 bisphosphate

Pyruvate kinase is inhibited by

ATP Alanine Acetyl coa Fatty acids

Glucose 6 is broken down into 2 phosphoglyceraldehyde (GDAP and DHAP) Requires two ATPs

Energy investment phase

``` Phosphorylation of glucose Isomerization of glucose Phosphorylation of fructose-6-phosphate Cleavage of fructose 1,6 bisphosphate Isomerization of DHAP ```

Energy investment phase

Used by most tissues Low Km Low Vm Inhibition by Glucose-6-phosphate

Hexokinase

Used in liver and B cells High Km High Vm Not inhibited by Glucose-6-phosphate

Glucokinase

Rate limiting step of Glycolysis Irreversible reaction Inhibited by high levels of ATP and citrate Stimulated by high levels of AMP, fructose 2,6 bisphosphate (most potent) produced by phosphofructokinase 2

Fructose 6 -> Fructose 1,6 bisphosphate by PFK1

Well fed state Glucagon Insulin Substrate Reaction

Dec glucagon Inc insulin Inc Fructose 2,6 bisphosphate Inc glycolysis

Starvation Glucagon Insulin Substrate Reaction

Inc glucagon Dec insulin Dec fructose 2,6 bisphosphate Dec glycolysis

Competes with inorganic phosphate as substrate for Glyceraldehyde 3 Phosphate Dehydrogenase Complex that hydrolyzes to form 3-phosphoglycerate Bypassing synthesis and dephosphrylation of 1,3 BPG leads to

Arsenic Cell deprivation of energy

Respiratory chain of NADH2 Inhibited by arsenic

Glyceraldehyde 3 phosphate -> 1,3 bisphosphoglycerate by glyceraldehyde-3 phosphate dehydrogenase

Dependent on presence of Mg or Mn Redistributes the energy within 2-phosphoglycerate molecule Catalyzes conversion of 2-phosphoglycerate molecule to Phosphoenolpyruvate PEP

Enolase

Enolase which catalyzes conversion of 2 phosphoglycerate -> phosphoenolpyruvate is inhibited by

Flouride

Inhibits enzymes which require Lipoic acid as coenzyme like pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase and glyceraldehyde 3 phosphate dehydrogenase

Arsenic

85% of patients with genetic defects of glycolytic enzyme 2nd most common cause of enzymatic related hemolytic anemia Restricted to erythrocytes produces mild to severe hemolytic anemia Severity depends on the degree of enzyme deficiency and on the extent to which individual compensates by synthesizing 2,3 BPG Mutant enzyme with abnormal properties

Pyruvate kinase deficiency

Phosphofructokinase deficiency

Tarui’s disease Type VII Like McArdle but has hemolysis

Feed forward regulation in liver

Pyruvate kinase activated by Fructose 1,6 bisphosphonate Linking 2 kinase activities Inc phosphofructokinase activity -> Inc Fructose 1,6 bisphosphate -> activated pyruvate kinase

Covalent modulation of pyruvate kinase

Phosphorylation by cAMP dependent protein kinase leads to INactivation of protein kinase in liver Low blood glucose levels -> glucagon secretion -> inc intracellular level of cAMP -> phosphorylation and inactivation of Pyruvate kinase -> PEP unable to continue glycolysis enters gluconeogenesis Dephosphorylation of pyruvate kinase by phosphoprotein phosphatase -> enzyme reactivation

Hormonal regulation of Glycolysis Increase in Insulin leads to activation of And dec in glucagon

Glucokinase Phosphofructokinase Pyruvate kinase

inc NADH production exceeds oxidative capacity of the respiratory chain inc NADH/NAD+ ratio favors

Reduction of pyruvate to lactate anaerobic glycolysis

Intense exercise: lactate accumulation in pH and drop in intracellular pH leading to Lactate can diffuse into blood stream -> gluconeogenesis (liver)

Muscle cramps

Depends on the relative intracellular concentrations of pyruvate and lactate NADH/NAD ratio Heart and liver lower NADH/NAD ratio than exercising muscles and can oxidize lactate to pyruvate In the liver, pyruvate is converted to In the heart, lactate is exclusively oxidized to

Glucose or oxidized in the TCA CO2 and H2O via citric acid cycle

Occur with collapse of the circulatory system Failure to bring adequate amounts of oxygen to tissues -> impaired oxidative phosphorylation -> dec ATP synthesis Solution: use of anaerobic system Oxygen debt: excess oxygen required to recover from a period when the availability of oxygen has been inadequate

Lactic acidosis

Respiratory chain of NADH GDAP -> 1,3 bisphosphoglycerate by G3P dehydrogenase yields how many ATPs

Substrate level phosphorylation 1,3 bisphosphoglycerate -> 3 phosphoglycerate by phosphoglycerate kinase yields how many ATPs

Substrate level phosphorylation Phosphoenolpyruvate -> pyruvate by pyruvate kinase yields

2 ATPs

Anaerobic glycolysis occurs because

there is no net formation of NADH (oxygen is required to reoxidize NADH formed during oxidation of GDAP)