بسم الله الرحمن الرحيم

• Carbohydrate Metabolism

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• prof.dr azza elkattawy

�Gluconeogenesis�

Three reactions catalyzed by hexokinase,glucokinase,

phosphofructokinase, and pyruvate kinase prevent simple reversal of glycolysis for glucose synthesis

Mitochondrial pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate

A second enzyme, phosphoenolpyruvate

carboxykinase, catalyzes the decarboxylation

and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP (or ITP)

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prof.dr.Azza M.Elkattawy

The conversion of fructose 1,6-bisphosphate kinase to fructose 6-phosphate, to achieve a reversal of glycolysis, is catalyzed by fructose-1,6-bisphosphatase.

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The conversion of glucose 6-phosphate to glucose is catalyzed by glucose-6-phosphatase. It is present in liver and kidney but absent from muscle and adipose tissue

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prof.dr.Azza M.Elkattawy

Pyruvic carboxylase enzyme

It is mitochondrial enzyme depend on presence of acetyl CoA it is allosteric activation

Level of ATP will directed oxaloacetic to gluconeogenesis or citric acid cycle

glucose

Oxaloacetate

Citric acid

High ATP

Gluconeogenesis

Low ATP

Acetyl coA

CONTROL OF GLUCONEOGENESIS

A- Non hormonal regulation

• Substrate concentration are an important factor in the regulation of the gluconeogenic pathway; this is true for pyruvate and alanine as well as for lactate.

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• Allosteric regulation:

1-For pyruvate carboxylase, acetyl CoA is a dose-dependent positive regulator.

2-Pyruvate kinase is inhibited by ATP, alanine, free fatty acids, and acetyl CoA; the inhibition directs the reactions towards gluconeogenesis.

B- Hormonal regulation

Slow effects

• Glucagon, epinephrine, and glucocorticoids can all cause increased synthesis of the bypass enzymes of gluconeogenesis (i.e., PEPCK, Fl,6DPase, and G6Pase).
• Insulin suppresses the synthesis of these enzymes and at the same time induces increased synthesis of the three allosteric enzymes of glycolysis (i.e., hexokinase, phosphofructokinase,and pyruvate kinase).

�Rapid effects �

• glucagon is stimulated by low blood glucose levels Thus glucagon increases gluconeogenesis probably involves the inactivation of pyruvate kinase by a cyclic adenosine monophosphate-dependent (cAMP-dependent) phosphorylation of the enzyme, and the inhibition of phosphofructokinase by changing levels of intermediates, particularly F2,6DP.

• A high blood glucose level stimulates insulin secretion, which reduces gluconeogenesis by lowering cAMP levels in the liver.
• The major short-term hormonal control of the gluconeogenic pathway is thus the ratio of glucagon to insulin.
• Glucocorticoids have a rapid effect on the pathway by causing peripheral protein break-down, which provides additional amino acid substrates for gluconeogenesis

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Interconversion of hexoses

galactose

glycogen

fructose

mannose

ATP

ATP

ATP

ADP

ADP

ADP

Galactokinase

hexokinase

hexokinase

phosphorylase

Galactose-1-p

Glucose-1-p

fructose-1-p

mannose-1-p

Phospho mannose

isomerse

Galactose1p uridyl

transferase

UDPglucose

UDPgalactose

NAD+

UDPgalactose

4epimerase

Glucose-6-p

glucose

mutase

isomerase

Galactose

• Galactose is phosphorylated by galactokinase to form galactose -l-phosphate.
• Hexose l-phosphate uridyl transferase catalyzes the transfer of UDP from UDP-glucose to galactose l-phosphate to form UDP-galactose and glucose -l-phosphate (G-1-P).

An epimerase converts UDP-galactose to UDP-glucose

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Galactosemia

• Galactokinase deficiency: leads to accumulation of galactose in blood and tissues. In the lens of the eye, galactose is reduced by aldose reductase to dulcitol (galacitol), The osmotic effect of the sugar alcohol contributes to the development of cataracts.
• Galactose 1-phosphate uridyl transferase deficiency:

(1) leads to the accumulation of both galactose and galactose l-phosphate in tissues.

(2) Cataracts also arise, as in galactokinase deficiency.

(3) It is believed that the mental retardation and liver cirrhosis are related to increased cellular levels of galactose l-phosphate in neural tissues and liver cells.

Fructose metabolism

Special pathway of fructose metabolism:

• 1- fructose metabolism in spermatozoa
• fructose is the major energy to sperm and formed from glucose in seminal vesicle.
• D-glucose → D-sorbitol → D-fructose

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1. Deficiency of fructokinase leads to fructosemia and fructosuria.

b. Hepatic glycogen phosphorylase. The lack of this enzyme is in part responsible for the postprandial hypoglycemia and glucagon unresponsiveness.

c. Fructose 1.6-diphosphate aldolase. Without this enzyme, gluconeogenesis is blocked ,contributing to the postprandial hypoglycemia.

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prof.dr.Azza M.Elkattawy