6 monsaccharide-gluconeogenesis

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β-Galactose

Transcript of 6 monsaccharide-gluconeogenesis

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β-Galactose

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GalactoseFound in milk sugar (lactose)

lactase

H

OHH

OH

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Glycolysis

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Glycolysis Lactose

In lactating M.G.

(Active Galactose)

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Pathways for utilizing galactose into

G –6–P, lactose, glycogen, GAGs,

glycolipids, and in glycolysis

(Active Galactose)

Lactose synthase

LactoseIn lactating

Mammary Gland

Glycogen

+ Glucose

1

2

Glycolipids

Into Glycolysis

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Galactose metabolism:

1. Galactokinase

2. Galactose-1-phosphate uridyltransferase

3. UDP-galactose-4-epimerase

4. Pyrophosphorylase

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Disorders of Galactose Metabolism

• Galactosemia is a group of disorders, which can be defined as a

congenital disease due to deficiency of an enzyme in galactose

metabolism, leading to accumulation of galactose in blood and

its reduction into the sugar alcohol “galactitol” by:

• NADPH-dependent galactose reductase that is present in neural

tissue and in the lens of the eye

• A high concentration of galactitol (hygroscopic) in the lens

causes osmotic swelling, with the formation of cataract

• The principal treatment of these disorders is to eliminate lactose

from the diet

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Clinical Symptoms of Galactosemia

1. A failure of neonates to thrive (to develop well

and to be healthy)

2. Vomiting and diarrhea occur following

ingestion of milk, hence individuals are termed

lactose intolerant

3. Impaired liver function

4. Elevated blood galactose (Hypergalactosemia)

5. Metabolic acidosis

6. Urinary galactitol excretion and

hyperaminoaciduria

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Clinical Symptoms of Galactosemia

7. If Galactosemia is not treated, it will produce:

• cataract (Lens obeique) المياه البيضاء ,

• blindness and

• fatal liver damage (Cirrhosis)

• Glucoma (increased intraocular pressure,

(المياه الزرقاء

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Fructose Metabolism

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Fructose Metabolism

• People eating diets containing large amounts of sucrose,

can utilize fructose as a major source of energy

• The pathway for utilization of fructose differs in muscle

and liver

• Muscle which contains only hexokinase can phosphorylate

fructose into F-6-P which is a direct glycolytic

intermediate

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Fructose Fructose-1-

phosphate Fructose-1-

phosphate DHAP

Glyceraldehyde

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B

Entry of fructose carbon atoms into the glycolytic pathway (Fructolysis) in hepatocytes

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Conversion of Fructose into Glucose

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Glucose Sorbitol FructoseAldose reductase

NADPH NADP+

Sorbitol DH

NAD+ NADH

Synthesis of Fructose in Seminal Vesicles

Estimation of seminal fructose is used as a Male

Fertility Test

Deficiency of aldolase B (Hereditary Fructose

Intolerance) leads to:

1. Accumulation of Fructose & F–1–P

2. F–1–P inhibits glycogen phosphorylase enzyme

leading to hypoglycemia especially after

ingestion of fructose

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Sorbitol Metabolism

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Reduction of Glucose to Sorbitol

Aldose

Reductase

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Metabolism of Sorbitol

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Glucose Sorbitol FructoseAldose reductase

NADPH NADP+

Sorbitol DH

NAD+ NADH

Metabolism of Sorbitol

Aldose reductase (NADPH-linked) reduces

glucose into Sorbitol

Sorbitol dehydrogenase converts Sorbitol into

fructose

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Metabolism of Sorbitol

Aldose reductase is found in significant amounts in:

1. Liver

2. Seminal vesicle

3. Epithelium of the eye lens

4. Schwann cells of peripheral nerves

5. Papillae of the kidney

While Sorbitol dehydrogenase is present only in:

1. liver

2. Seminal vesicle

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In Diabetes Mellitus:

Glucose enters tissues listed above freely (requires no

insulin)

In hyperglycemia large amounts of glucose enter these

tissues & converted into sorbitol which is dead metabolite

in the retina, kidney & peripheral nerves, due to absence

of Sorbitol DH

Sorbitol will accumulates in these cells, causing many

physiologic & pathologic manifestation including:

1. Cataract

2. Retinopathy of eye lens

3. Peripheral neuropathy of peripheral nerves

4. Nephropathy of kidney

5. Vascular problems (Atherosclerosis)

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Gluconeogenesis• Definition: It is the formation of glucose from non-

carbohydrate sources

• Site: Only in Liver & Kidney

• It occurs partly in cytoplasm & partly in mitochondria

• Importance of Gluconeogenesis:

1. It is the chief source of blood glucose after the first 18

hours-fasting

2. It removes blood lactate produced by RBCs & muscles

and blood glycerol produced by adipose tissue or

absorbed by intestine

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Enzymes of Gluconeogenesis

1. Pyruvate Carboxylase:

• Converts pyruvate to oxaloacetate

2. Phosphoenolpyruvate Carboxykinase (PEP

Carboxykinase):

• Converts oxaloacetate to PEP

3. Fructose–1,6–diphosphatase:

• To reverse F–1,6–diP into F–6–P

4. Glucose–6–phosphatase:

• To reverse Glucose–6–P into Glucose

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& Kidney

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In Mitochondria

In Cytoplasm

In Mitochondria

In Cytoplasm

• Phosphoenol pyruvate carboxykinase enzyme is

present in the cytoplasm

• Oxaloacetate cannot diffuse through the

mitochondrial membrane to the cytosol

• This problem can be solved by the dicarboxylic acid

shuttle

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Steps of

Gluconeogenesis

1

a

b

2

3

In mitochondria

In cytoplasm

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Sources of Gluconeogenesis

1.Blood Lactate:

• From RBCs and exercising muscles

2.Glycerol:• From adipose or absorbed from intestine

3.Odd chain fatty acids:• From ruminants

4.Glucogenic Amino acids

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Substrates for

Gluconeogenesis

1

2

3

4

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1

& RBCs

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• Incorporation of Glycerol into Glycolysis in Liver

2

Glycerol kinase Glycerol phosphate

dehydrogenase

(10 % of Fat)

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3

• Conversion of Propionyl CoA to Succinyl CoA

From Ruminants

-Oxidation

Odd chain fatty acids

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3Conversion of Propionyl CoA to

Succinyl CoA

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Glucogenic Amino acids

• Proteins are the most important sources of glucose

during fasting after the liver glycogen is depleted

• 58% of proteins are convertible to glucose. This is

proved by the D/N ratio

• D/N ratio is the ratio between the amount of Dextrose

(D) or glucose and Nitrogen (N) in urine. it is zero in

normal animals due to absence of glucose in urine

4

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Glucogenic Amino acids

• An animal starved for 2 – 3 days,

pancreatectomized and given phlorizin

• The D/N ratio of this animal is 3.65/1, i.e., proteins

which contain one gram nitrogen give 3.65 grams

of glucose

• Since 100 grams of proteins contain 16 grams of

nitrogen, therefore, 100 grams of proteins can give

16 X 3.65 = 58.4 grams glucose

4

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4

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4 Glucogenic Amino acids

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Regulation of

Gluconeogenesis

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Regulation of Gluconeogenesis

1. After carbohydrate diet, Insulin inhibits the synthesis

of enzymes of gluconeogenesis

2. During starvation, glucocorticoids, growth hormone,

glucagon and adrenaline stimulate the synthesis of

enzymes of gluconeogenesis

3. Acetyl CoA is an allosteric activator of pyruvate

carboxylase, so oxaloacetate accumulate

4. Citrate & ATP stimulate fructose–1,6–diphosphatase

5. Fructose diphosphate & AMP inhibit fructose–1,6–

diphosphatase