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GLYCOLYSIS
MS C
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•

Glycolysis is the major pathway for glucose metabolism occurring in the
cytosol of all cells
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•

During the sequential reactions of glycolysis, some of the free energy released
from glucose and other intermediates is conserved in the form of ATP and
NADH
...


• Erythrocytes are completely reliant on glucose as their metabolic fuel and
metabolize it by anaerobic glycolysis
...

• Cardiac muscle, which is adapted for aerobic performance, has relatively
low glycolytic activity and poor survival under conditions of ischemia
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• The lactate is used for gluconeogenesis in the liver
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OVERVIEW OF
GLYCOLYSIS

Glycolysis Has Two Phases
• The breakdown of the six-carbon glucose into two molecules of the threecarbon pyruvate occurs in ten steps, the first five of which constitute the
preparatory phase
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• The energy gain comes in the payoff phase of glycolysis
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• Energy is also conserved in this phase in the formation of two molecules
of NADH per molecule of glucose
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Phosphorylation of Glucose: Glucose is activated by its phosphorylation
at C-6 to yield glucose 6-phosphate, with ATP as the phosphoryl donor
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• Hexokinase requires Mg2+ for its activity, because the true substrate of the
enzyme is not ATP4- but the MgATP2- complex
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Conversion of Glucose 6-Phosphate to Fructose 6-Phosphate: The
enzyme phosphohexose isomerase (phosphoglucose isomerase)
catalyzes the reversible isomerization of glucose 6-phosphate to fructose
6-phosphate
...

• The phosphorylation that occurs in the step 3 requires that the group at C1 first be converted from a carbonyl to an alcohol, and in the subsequent
reaction (step 4 ) cleavage of the bond between C-3 and C-4 requires a
carbonyl group at C-2
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Phosphorylation of Fructose 6-Phosphate to Fructose 1,6- Bisphosphate:
Phosphofructokinase-1 (PFK-1) catalyzes the transfer of a phosphoryl
group from ATP to fructose 6-phosphate to yield fructose 1,6bisphosphate:

• The PFK-1 reaction is essentially irreversible under cellular conditions
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Cleavage of Fructose 1,6-Bisphosphate: The enzyme fructose 1,6bisphosphate aldolase, often called simply aldolase, catalyzes a
reversible aldol condensation
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Interconversion of the Triose Phosphates: Only glyceraldehyde 3phosphate, can be directly degraded in the subsequent steps of
glycolysis
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• This reaction completes the preparatory phase of glycolysis
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6
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7
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Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate: The enzyme
phosphoglycerate mutase catalyzes a reversible shift of the phosphoryl
group between C-2 and C-3 of glycerate; Mg2+ is essential for this
reaction:

• The reaction occurs in two steps
...

• The phosphoryl group at C-3 of 2,3-BPG is then transferred to the same
His residue, producing 2- phosphoglycerate and regenerating the
phosphorylated enzyme
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Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate: In this
reaction, enolase promotes reversible removal of a molecule of water
from 2-phosphoglycerate to yield phosphoenolpyruvate (PEP):

• Although 2-phosphoglycerate and phosphoenolpyruvate contain nearly
the same total amount of energy, the loss of the water molecule from 2phosphoglycerate causes a redistribution of energy within the molecule,
greatly increasing the standard free energy of hydrolysis of the phosphoryl
group
...
Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP:
The last step is the transfer of the phosphoryl group from
phosphoenolpyruvate to ADP, catalyzed by pyruvate kinase, which
requires K and either Mg2+ or Mn2+ :

• The pyruvate kinase reaction is essentially irreversible under intracellular
conditions and is an important site of regulation
...

• These enzymes function as “valves”, regulating the flow of carbon through
glycolysis
...

• Enzymes that catalyze these exergonic, rate-limiting steps are commonly
the targets of metabolic regulation
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•

The activity of PFK-1 is increased whenever the cell’s ATP supply is depleted or
when the ATP breakdown products, ADP and AMP (particularly the latter), are
in excess
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ATP binds to an allosteric site and lowers
affinity for fructose 6-phosphate
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•

Pyruvate kinase is activated by fructose 1,6-bisphosphate, to enable it to keep
pace with the oncoming high flux of intermediates
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•

Allosterically inhibited by alanine, to signal that the building blocks are
abundant
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The phosphorylated glycolytic intermediates cannot leave the cell
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The plasma membrane is impermeable to charged
molecules
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Energy used in the formation of the phosphate ester is conserved
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3
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Fates of Pyruvate
• The pyruvate formed by glycolysis is further metabolized via one of three
catabolic routes
...
Pyruvate is oxidized, with loss of its carboxyl group
as CO2, to yield acetyl CoA; the acetyl group is then oxidized completely to
CO2 by the citric acid cycle
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• Under anaerobic conditions or hypoxia, NADH cannot be reoxidized to
NAD+, but NAD+ is required as an electron acceptor for the further
oxidation of pyruvate
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• Lactate produced in muscle during a short burst of physical activity is
converted back to glucose in the liver
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Feeder Pathways for Glycolysis
• Many carbohydrates besides glucose meet their catabolic fate in glycolysis,
after being transformed into one of the glycolytic intermediates
...

• Glycogen and starch enter glycolysis in a two-step process
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Phosphoglucomutase then converts the glucose 1phosphate to glucose 6-phosphate, which can enter glycolysis
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• A variety of D-hexoses, including fructose, galactose, and mannose, can be
funneled into glycolysis
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• Conversion of galactose 1-phosphate to glucose 1-phosphate involves two
nucleotide derivatives: UDP-galactose and UDP-glucose

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