Glycolysis Flashcards
Glycolysis occurs in
cytosol
Decreased function of glucokinase is assciated with
Maturity onset diabetes of the young
Fructose-6-phosphate can be converted into Fructose-2,6-bisphosphate by the enzyme
Phosphofructokinase 2
Fructose 2,6 bisphosphate induces glycolysis by upregulating the enzyme
PFK1
which converts fructose-6-phosphate to fructose 1,6 phosphate
PFK1 is inhibited by
Citrate
ATP
(Metabolites from ETC and Krebs)
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
On a fasting state, glucagon levels are high which decreases fructose 2,6 bisphosphate and will halt hepatic glycolysis and increase
Gluconeogenesis
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
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
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
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
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
If there is enough oxygen, pyruvate is converted into
Acetyl coa
If there is insufficient oxygen, pyruvate is converted into
Lactate
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
First step in glycolysis
Irreversible
Uses up energy
Glucose -> glucose 6 phosphate by Hexokinase and Glucokinase
Addition of phosphate
Step 2:
Rearrangement of covalent bonds
Glucose 6 phosphate -> Fructose 6 phosphate by phosphoglucose isomerase
3rd step:
Irreversible
Second energy consumption step
First committed step
Fructose 6 phosphate -> Fructose 1,6 bisphosphate by Phosphofructokinase 1
Step 4:
Splitting of 6 to 3 carbon sugars
Fructose 1,6 bisphosphate -> GDAP (glyceraldehyde-3 phosphate) + DHAP (dihydroacetone phosphate)
by Fructose bisphosphate aldolase
Step 5
Isomerization
DHAP -> GDAP by triosephosphate isomerase
2 GDAP
2 ATPs consumed
Step 6:
Energy generation
Inhibited by Arsenic
GDAP -> 1,3 bisphosphoglycerate
by Glyceraldehyde phosphate dehydrogenase
2 NADH
Step 7:
Reversible
Energy generating
1,3 bisphosphoglycerate -> 3 phosphoglycerate
By Phosphoglycerate kinase
Transfer of phosphate
+ ATP
Step 8:
3 phosphoglycerate -> 2 phosphoglycerate
By Phosphoglycerate mutase
Step 9:
Lyase
Inhibited by Flouride
Dependent on Mg or Mn
2 phosphoglycerate -> Phosphoenolpyruvate
By Enolase
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
5
Substrate level phosphorylation
1,3 bisphosphoglycerate -> 3 phosphoglycerate by phosphoglycerate kinase
yields how many ATPs
2
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)