8 monsaccharide-gluconeogenesis
description
Transcript of 8 monsaccharide-gluconeogenesis
β-Galactose
GalactoseFound in milk sugar (lactose)
lactase
H
OHH
OH
Glycolysis
Glycolysis Lactose
In lactating M.G.
(Active Galactose)
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
Galactose metabolism:
1. Galactokinase
2. Galactose-1-phosphate uridyltransferase
3. UDP-galactose-4-epimerase
4. Pyrophosphorylase
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
Clinical Significance of Galactose Metabolism
Galactosemia
Galactokinase Deficiency
Galactosaemia
phosphate -1-Galactose
defecturidyl transferase-4-galactose-UDP
defectepimerase
Galactokinase defect
Classic Galactosemia
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
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
Fructose Metabolism
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
Fructose Fructose-1-
phosphate Fructose-1-
phosphate DHAP
Glyceraldehyde
B
Entry of fructose carbon atoms into the glycolytic pathway (Fructolysis) in hepatocytes
Conversion of Fructose into Glucose
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
Sorbitol Metabolism
Reduction of Glucose to Sorbitol
Aldose
Reductase
Metabolism of Sorbitol
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
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
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)
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
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
& Kidney
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
Steps of
Gluconeogenesis
1
a
b
2
3
In mitochondria
In cytoplasm
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
Substrates for
Gluconeogenesis
1
2
3
4
1
& RBCs
• Incorporation of Glycerol into Glycolysis in Liver
2
Glycerol kinase Glycerol phosphate
dehydrogenase
(10 % of Fat)
3
• Conversion of Propionyl CoA to Succinyl CoA
From Ruminants
-Oxidation
Odd chain fatty acids
3Conversion of Propionyl CoA to
Succinyl CoA
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
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
4
< TD>
4 Glucogenic Amino acids
Regulation of
Gluconeogenesis
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