Glycolysis Metabolism

$Glycolysis$: the process in which glucose is broken down to produce energy.

Glucose is converted to %%pyruvate%% under aerobic condition or converted to %%lactate%% under anaerobic condition.

$Site$: enzymes of glycolysis in the ==cytosol== of all cells

Two phases:

Phase I: Glucose to %%2 molecules of glyceraldehyde-3-phosphate%%

Phase II: 2 molecules of glyceraldehyde-3-phosphate converted into %%2 molecules of pyruvate (aerobic) or lactate (anaerobic)%%

Energy production aerobic and anaerobic

Aerobic condition

Glucose → 2 pyruvate + 8 ATP

Pyruvate transported into the ==mitochondria== and converted to %%two active acetate%% that are oxidized by citric acid cycle.

• two molecules of @@NADH@@ are produced by ^^glyceraldehyde-3-phosphate dehydrogenase^^
• 4 molecules of ATP formed by substrate level oxidative phosphorylation
    * Two by phosphoglycerate kinase
    * Two by pyruvate kinase
• Net gain of ATP = @@8 molecules of ATP@@

Anaerobic condition

Glucose → 2 lactate + 2 ATP

• in severe exercise and red blood cells ( absence of mitochondria)
• NADH not oxidized
• Net gain of ATP = @@2 molecules ATP@@
• NADH is not oxidized by the ETC
• glycolysis is the only pathway that can function independent on the ETC and occur under anaerobic conditions

Importance of Glycolysis in Red Blood Cells

Energy production: only pathway that supplies red blood cells with ATP

Reduction of methemoglobin: glycolysis provides @@NADH for reduction of met-Hb@@ in red blood cells by the NADH-Cytb5 methemoglobin reductase system

Bisphosphoglycerate shunt (BPG shunt): in red blood cells 1,3-bisphosphogycerate is converted to 2,3-bisphosphogycerate (2,3BPG), which units with hemoglobin at @@low oxygen tension and helps release of oxygen to tissues@@. No net production of ATP

Hemolytic anemia due to deficiency of glycolysis enzymes: inherited deficiency of glycolytic enzymes %%produces hemolytic anemia%% because red blood cells are dependent on glycolysis for production of ATP. 95% of patients have deficiency of ==pyruvate kinase==, and 4% have deficiency of ==phosphohexose isomerase.==

Reversal of glycolysis (gluconeogenesis)

• during @@fasting@@ and @@low dietary carbohydrates@@$,$ for synthesis of glucose from non-carbohydrate compounds ($gluconeogenesis$)
• Rate of glycolytic pathway regulated by activity of ^^3 irreversible enzymes (key enzymes^^): @@increases@@ during @@carbohydrate feeding@@ and %%decreases%% during %%fasting or carbohydrate deprivation%%

1. Glucokinase reversed by glucose-6-phosphatase (present in the liver, kidney only)
2. Phosphofructokinase-1 (PFK-1) reversed by fructose-1,6-bisphosphatase (present in the liver, kidney only)
3. Pyruvate kinase (PK) reversed by dicarboxylic acid shuttle

Hexokinases and glucokinase:

• First step in metabolism of glucose and other sugars, after entering a cell, is @@phosphorylation@@.
• Phosphorylation prevents the leakage of sugar molecules from the cell, since phosphorylation sugars do not move across cell membranes.
• Also, phosphorylation of sugars facilities the binding of these substrates to the active sites of enzymes.
• Several hexokinases are found in the body.
• An isozyme is termed glucokinase (Hexokinase D)

Phosphofructokinase-1 (PFK-1):

• Inhibited by: glucagon, ATP, and citrate
• Activated by: insulin, AMP, fructose-6-phosphate and fructose-2,6-bisphosphate

Pyruvate kinase (PK)

• Inhibited by: glucagon and ATP
• Activated by: fructose-1,6-bisphosphate and insulin

Regulation by the Energy State of the cell

• high level of AMP activates PFK-1 (activation of glycolysis)
• high level of ATP inhibits PFK-1 and pyruvate kinase (inhibition of glycolysis)
• fatty acid oxidation decreases the rate of glycolysis
    * FA produces ATP, active acetate (which forms citrate)

Hormonal Regulation

1. Glucagon: secreted during carbohydrate deficiency or in response to low blood glucose level ($hypoglycemia$). It affects liver cells mainly as follows:
      * acts as a ==repressor== of glycolytic key enzymes
      * binds to specific cell membrane receptors and activates guanylate binding proteins. The activated G proteins produce a__ctivation of adenylyl cyclase__ and production of @@cAMP@@, which activates @@protein kinase A@@. The latter produces ==inactivation== of glycolytic enzymes.
2. Insulin: secreted after feeding of carbohydrates or in response to high blood glucose level ($hyperglycemia$). Insulin generally stimulates all the pathways of glucose utilization. Insulin binds to specific cell membrane receptors and produces certain signal cascade resulting in the following:
      * acts as an ==inducer== for the synthesis of glycolytic key enzymes
      * produces activation of @@phosphodiesterase@@ (decreases cAMP which inhibits protein kinase A)
      * produces activation of the protein phosphatase

Metabolism of Pyruvate and Oxaloacetate

Metabolism of Pyruvate

Metabolism of Oxaloacetate

Conversion of Pyruvate to Oxaloacetate

• by ==mitochondrial== enzyme %%pyruvate carboxylase%%
• important step during gluconeogenesis

Inducers of Pyruvate Carboxylase

• glucagon
• epinephrine
• glucocorticords

Repressors of Pyruvate Carboxylase

• insulin

Conversion of Pyruvate to Active Acetate

• aerobic condition
• pyruvate transported from cytosol to ==mitochondria==
• converted to active acetate by %%pyruvate dehydrogenase complex%% (requires 5 coenzymes):
    * TPP
    * lipoate
    * FAD
    * NAD+
    * COA-SH
• 2 pyruvate → 2 active acetate + 2 NADH,H+
• 6 ATP formed by oxidation of 2 NADH
• Deficiency of %%PDH%% or %%thiamine%% produces accumulation for pyruvate that is converted to lactate, so it leads to $lactic acidosis$

Activators of PDH

• Pyruvate, NADH+, COA, ADP allosteric activators to PDH
• Insulin increases activity of PDH
• Ca ions

Inhibitors of PDH

• NADH, acetyl-CoA, ATP
• Fatty acid oxidation

Summary for Complete Oxidation of Glucose

Complete aerobic oxidation of one molecule of glucose in glycolysis, citric acid cycle and ETC produces: $<strong>6 molecules of CO2 + 38 molecules of ATP</strong>$