Aulani "Biokimia" Presentation4 Aulanni’am Biochemistry Laboratory Chemistry Departement Brawijaya...

Aulani "Biokimia" Presentation4

Aulanni’amBiochemistry LaboratoryChemistry Departement

Brawijaya University

Carbohydrate MetabolismCont….


Gluconeogenesis

Some tissues, such as

brain, RBCs, kidney medulla, testes, embrionic tissues and exercising muscle require a continuing supply of glucose as a metabolic energy.

The human brain requires over 120 gm of glucose per day. Mammalian cells make glucose from simpler precursors. Liver glycogen can meet these needs only for 10 to 18 hours without dietary carbohydrate.


Glycolysis and Gluconeogenesis in the liver


Gluconeogenesis


Pyruvate precursors

The direct Glc reserves are sufficient to meet Glc needs for about a day!

Gluconeogenic pathway makes Glc from pyruvate precursors.

Triacyl glycerol-------> Glycerol + Fatty acids Glycerol is a precursor of glc, glycerol enters

glycolytic pathway as dihydroxyacetone phosphate.


Gluconeogenesis is NOT a reversal of glycolysis

Several reactions MUST differ because of the irreversible steps.

•HK (hexokinase)•PFK (phosphofructokinase)•PK (pyruvate kinase)


The stoichiometry of gluconeogenesis is:

2pruvate + 4ATP + 2GTP + 2NADH + 6H2O-------->Glc +4ADP + 2GDP + 6Pi + 2NAD+ + 2H+

In contrast, the stoichiometry of reversal of glycolysis is:

2 pyruvate + 2ATP + 2NADH + 2H2O------->

Glc + 2ADP + 2Pi + 2NAD+

•The difference is 4ATP, this is needed to turn energetically

unfavorable process to a favorable one!


Gluconeogenesis and glycolysis are reciprocally regulated

Both glycolysis and gluconeogenesis are highly exorgonic under cellular conditions so there is no thermodynamic barrier.

But, amounts and activities of the distinctive enzymes of each pathway are controlled so that both pathways are not highly active at the same time.


Substrate cycles

F-6-P -------> F 1,6BisP <--------- A pair of reactions such as the above one is called

“substrate cycle” There is also some cycling in irreversible reactions. “Imperfection” in metabolism? They are sometimes referred as “futile cycles”

•Futile cycles amplify metabolic signals!•The other potential biological role of

substrate cycles is the generation of heat produced by the hydrolysis of ATP.


Lactate and alanine formed by contracting muscle are used by other organs Lactate is a dead end in metabolism. Lactate should be converted to pyruvate. The plasma membranes of most cells are highly

permeable to lactate and pyruvate, therefore they easily diffuse to go to liver!

Excess lactate enters the liver and is converted pyruvate first then glucose.

• Thus, the liver restores the level of glucose necessary for active muscle cells, which derive ATP from the glycolytic conversion of glucose into lactate. Contracting skeletal muscle supplies lactate to the liver, which uses it to make glucose.

• These reactions constitute CORI CYCLE.


LDH enzyme

Lactate-------> Pyruvate by LDH (lactate dehydrogenase).

The interconversion of pyruvate and lactate are done by different subunits of LDH. LDH is a tetramer.


The Cori Cycle


Cooperation between glycolysis and gluconeogenesis


Two alternative fates of pyruvate


2nd control point


Hormonal Control

The special role of liver to maintain constant blood glucose level requires additional control mechanisms.

When blood glucose decreases, glycogen increases and glucose is released.

This hormonal regulation in liver is mediated by fructose-2,6-bisphosphate, which is a allosteric effector for PFK-1, and F-1,6-bisphosphate


Role of F2,6BP in regulation of Glycolysis and Gluconeogenesis


What is F-2,6-BP? It is structurally related to F-1,6-BP. It is not an intermediate. It is a “regulator” F-2,6-BP activates PFK-1 and glycolysis. FBPase and PFK-2 are part of the same enzyme! An increase in glucagon (during starvation) leads to

a decrease in F-2,6-BP overall which goes to a decrease in glycolysis, an increase in glucone ogenesis

A decrease in glucagon (after carbohydrate rich diet) leads to an increase in F-2,6-BP and an increase in glycolysis.

Therefore, F-2,6-BP acts as an intracellular signal indicating “glucose abundant”.

Aulani "Biokimia" Presentation4 Aulanni’am Biochemistry Laboratory Chemistry Departement Brawijaya...

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