Regulation of glycolysis and gluconeogenesis

1. Regulation of glycolysis and
gluconeogenesis
Amal George
SBS MGU

2. GLYCOLYSIS
sequence of
reactions that
converts one
molecule of
glucose to two
molecules of
pyruvate with the
formation of two
ATP molecules

3. GLUCONEOGENESIS
Gluconeogenesis
(abbreviated GNG) is a
metabolic pathway that
results in the generation
of glucose from non-
carbohydrate carbon
substrates such as
lactate, glycerol, and
glucogenic amino acids.
This process is
frequently referred to
as endogenous glucose
production (EGP).

4. POSSIBLE FATES OF
GLUCOSE
Tends to exist in ring form, very stable, doesn’t generally
glycosylate proteins

5. All of the All the intermediates in glycolysis have either 3 or 6 carbon
atoms
reactions fall into one of 5 categories
• phosphoryl transfer
• phosphoryl shift
• isomerization
• dehydration
• aldol cleavage
GLYCOLYSIS
glucose is trapped and destabilized
six carbon molecule is split into two three
carbon molecules
ATP is generated

6. GLYCOLYSIS

8. PHOSPHOFRUCTOKINASE
Phosphofructokinase (PFK) is the
enzyme that controls the third step
of glycolysis, the conversion of
fructose-6-phosphate (F6P) into
fructose-1,6-biphosphate (F1,6BP).
... PFK is inhibited by high levels of
ATP, low pH levels and high levels of
citrate, a byproduct of cell
metabolism
Citrate, the first product of the citric acid cycle, can also inhibit PFK. If citrate
builds up, this is a sign that glycolysis can slow down, because the citric acid
cycle is backed up and doesn't need more fuel.
ENZYMATIC REGULATION OF GLYCOLYSIS
Most important control point in mammalian glycolytic pathway
Allosteric enzyme
activated by AMP and fructose 2,6 bisphosphate
inhibited by high levels of ATP, citrate, fatty acids

9. HEXOKINASE
Regulated only by excess glucose-6-phosphate. If G6P
accumulates in the cell, there is feedback inhibition of
hexokinase till the G6P is consumed. The phosphofructokinase
step is rate-limiting step of glycolysis. High AMP/ADP levels are
activators of this enzyme, while high ATP levels are inhibitory
(energy charge).
Hexokinase is inhibited by its product glucose-6-PO4
glucose remains in blood
Glucokinase, an isozyme of hexokinase is not inhibited by
glucose-6-PO4
found in liver
has lower affinity for glucose

10. PYRUVATE KINASE
Pyruvate kinase activity is most broadly regulated by allosteric
effectors, covalent modifiers and hormonal control. However,
the most significant pyruvate kinase regulator is fructose-1,6-
bisphosphate (FBP), which serves as an allosteric effector for
the enzyme
Pyruvate kinase exists as isozymes
L form – predominates in liver
M form – mostly in muscle and brain
PK is an allosteric enzyme
activated by fructose 1,6 bisphosphate
inhibited by ATP, alanine
L form of PK influenced by covalent modification
inhibited by phosphorylation

12. GLUCONEOGENESIS

13. REGULATION OF GLUCONEOGENESIS
These enzymes are typically
regulated by similar molecules,
but with opposite results. For
example, acetyl CoA and citrate
activate gluconeogenesis
enzymes (pyruvate carboxylase
and fructose-1,6-
bisphosphatase, respectively),
while at the same time
inhibiting the glycolytic enzyme
pyruvate kinase.

14. Reciprocal Regulation of Gluconeogenesis and Glycolysis
fructose 2,6-bisphosphate
stimulates PFK and inhibits fructose
1,6-bisphosphase
controlled by insulin and
glucagon and reflects the
nutritional status of the cell
influence gene expression
change transcription rate
influence degradation of m-RNA
insulin PFK, PK
glucagon PEPCK, fructose
1,6-bisphosphatase

15. Allosteric regulation limits fructose-6-
phosphate phosphorylation cycling.
Phosphofructokinase is inhibited by
ATP. This makes sense, since ATP
formation is the main purpose of
glycolysis, in conjunction with the TCA
cycle and the respiratory chain. ...
Fructose-1,6-bisphosphatase is
stimulated by ATP and inhibited by
AMP
Enzymatic regulation of gluconeogenesis
Hexokinase/glucokinase, phosphofructokinase, and
pyruvate kinase enzymes of glycolysis are replaced
with glucose-6-phosphatase, fructose-1,6-
bisphosphatase, and PEP carboxykinase/pyruvate
carboxylase. These enzymes are typically regulated
by similar molecules, but with opposite results
Pyruvate Carboxylase, which converts pyruvate to
oxaloacetate, is allosterically activated by acetyl coenzyme A

17. Since fructose-2,6-
bisphosphate activates
phosphofructokinase and at
the same time inhibits
fructose-1,6-
bisphosphatase, the upshot
of glucagon and
epinephrine action is to
promote gluconeogenesis
and inhibit glycolysis.
Insulin has the opposite
effect.
Hormonal regulation of gluconeogenesis