METABOLISM OF CARBOHYDRATES 5
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József Mandl 2017
Entry of glucogenic substrates into gluconeogenesis G6P-ase glycogen glucose-1P G-6P glucose
F1,6bP-ase fructose-1,6bisP F-6P
glyceraldehide-3P + diOH-aceton-P
glycerin 1,3-bisphospho-glycerate
3P-glycerate alanine, glucoplastic lactate aminoacids
2P-glycerate
PC PEPCK pyruvate OAA PEP lactate Cori cycle glycerol trigliceride
H2O lipase Fatty cids adipocyte glycerol blood
glycerol hepatocyte kinase glycerol-3-P
glycerol-3-P dehydrogenase dihydroxiacetone-P Digestion of carbohydrates
• Mouth salivary amylase α(1-4) glycosidic linkages are hydrolysed (starch, glycogen – to maltose, glucose, oligosaccharides) • Small intestine, duodenum pancreatic amylase β(1-4) linkages (cellulose) are not digested sucrase, maltase, lactase, isomaltase Glucose, fructose, galactose α-amylase
dextrinase
maltase
Enzymic hydrolysis of α1→4 and α1→6 glycosidic linkages in intestinal lumen Glucose, fructose and galactose: main monosacharides ingested starch glycogen
maltose lactose sucrose
galactose glucose fructose Milk sugar Lactose intolerance – deficiency of lactase Decrease in lactase is normal during development, declines to about 5-10% of the level at birth Fructose, galactose Intestinal absorption of fructose and galactose intestinal glucose or fructose lumen galactose Na+ SGT GLUT5 apical membr.
glucose or fructose galactose Na+ K+
ADP
ATP +Pi baso- lateral membrane GLUT2 GLUT2 GLUT5 fructose glucose or Na+ K+ galactose LIVER, KIDNEY, INTESTINE ATP GLUCOKINASE ADP glucose glucose-6-phosphate
ATP FRUCTOKINASE ADP fructose fructose-1-phosphate
ATP GALACTOKINASE ADP galactose galactose-1-phosphate
OTHER TISSUES ATP ADP glucose glucose-6-phosphate HEXOKINASE fructose fructose-6-phosphate ATP ADP Fructose consumption in U.S.
• 1900 15 g/day (4% of total calories) – fruits, vegetables • 1939 24 g/day • 1994 55 g/day (10%) • 2010 73 g/day (12%) – sweetener industry – juice intake Ethanol and fructose (sucrose) – „civilisation diet” – obesity epidemy, childhood obesity Polyol pathway
NADPH NADH + H+ NADP+ NAD+ + H+
aldose reductase sorbitol dehydrogenase glucose sorbitol fructose (glucitol) Hardly controlled NADH and acetyl-CoA production leads to enhanced triglyceride (fat) and cholesterol synthesis in the liver. Fructose consumption is now considered as a risk factor of obesity and the metabolic syndrome. fructose ATP fructokinase diOH-acetone-P ADP fructose-1-phosphate
NADH + H+ glyceraldehyde glycerol-3P DH alcohol NAD+ DH
glycerol-3-P glycerol glycerol kinase ADP ATP dihydroxyacetone-P fructose-1-phosphate
aldolase B (fructose-1-P aldolase)
glyceraldehyde dihydroxyacetone-P fructose-1,6-bisphosphate
aldolase A (in glycolysis)
glyceraldehyde-3P main point of regulation glucose-6P glucose GK
fructose-1,6bisP fructose-6P PFK1
glyceraldehyde-3P + diOH-acetone-P fructose
FK 1,3-bisphospho-glycerate fructose-1-P aldolase 3P-glycerate B glycerol-3P glyceraldehyde 2P-glycerate DH alcohol DH pyruvate PEP glycerol-3-P glicerol PK-L glycerol kinase liver
F-6-P
Essential fructosuria
Congenital fructose intolerance
F-1,6 -bisP Essential fructosuria
accumulates in metabolized in fructose blood after other tissues ATP meals and secreted into urine XXFK ADP fructose-1-phosphate
aldolase B
diOH-acetone-P + glyceraldehyde Regulation of activity of glucokinase
Gk glucokinase
R regulator protein binds to Gk Inactive Gk F- 6 - P F- 6 - P binds to R R Gk complex inactive G-6-P does not bind to R
F-1-P binds to R
R F - 1 - P Prevents binding to Gk Gk ActiveGk Fructose intolerance Fructokinase is expressed in liver, kidney and small intestine. fructose ATP sustained ATP FK and P depletion i glucose synthesis ADP glycogen blocked, fructose-1-phosphate phosphorylase ↓↓ glycolysis activated glucokinase ↑↑ pyruvate kinase ↑↑ XaldolaseX B severe abdominal distress, nausea, vomiting, hypoglycemia diOH-acetone-P + glyceraldehyde and hyperuricemia after fructose consumption; liver damage in the long run, gout, renal failure. Summary
Intestinal absorption and cellular uptake of fructose are passive facilitated diffusion mediated by GLUT2 and GLUT5.
Fructose is catabolized in two pathways: - major pathway in liver, kidney and small intestine, - minor pathway in all other tissues.
Fructose is a lipogenic sugar: enhances lipid synthesis and storage while does not increase blood sugar (glucose) level.
Fructose is also synthesized (from glucose) in certain cells (e.g. epithelial cells of lens and seminal vesicle).
Inborn defects of fructose metabolism: - essential fructosuria (mild), - fructose intolerance (severe). Galactose – glucose interconversion
liver ATP ADP
galactokinase
galactose galactose-1P
UDP-glucose
UDP-glucose:galactose-1P uridyltransferase
glucose-1P phospho- 4-epimerase glucomutase (NAD+)
UDP-galactose glucose-6P Genetic deficiency: Galactosemia Vomitus, diarrhea after Milk, hepatomegaly, Cirrhosis, mental retardation
Reversible Essential for biosynthesis Accumulated in lens - cataract Galactosemia: inborn defect of galactose metabolism
Type Defective enzyme
Type 1 galactose-1-phosphate uridyltransferase „classic galactosemia” Type 2 galactokinase Type 3 UDP-galactose 4-epimerase
Accumulation of intermediates of galactose metabolism (e.g. galactose-1P, galactitol) causes damages in various tissues. glycogen
galactose glucose-1P glucose-6P glucose phospho- GK glucomutase G6Pase fructose-1,6bisP fructose-6P PFK1
glyceraldehyde-3P + diOH-acetone-P
1,3-bisphospho-glycerate
3P-glycerate
2P-glycerate Galactose is equivalent with glucose pyruvate PEP in the liver, kidney and small intestine. PK-L Summary
Intestinal absorption of galactose is a secondary active transport. Its cellular uptake is passive facilitated diffusion mediated by GLUT transporters.
Galactose is catabolized mostly in the liver.
Galactose is equivalent with glucose. It can be readily converted to blood sugar (glucose).
Galactose is not essential because the cells possess 4-epimerase (e.g. lactating mammary gland can synthesize lactose from glucose).
Inborn defects of galactose metabolism: - 3 types of galactosemia UDP-glucose, or UDP-galactose
Synthesis of lactose, glycoproteins
In mammary gland only UDP-galactose + glucose lactose + UDP Lactose synthase (galactosyl transferase), α-lactalbumin present in most tissues modifier subunit in mamma In several tissues glycoprotein synthesis UDP-galactose + N-acetylglucosamine galactosyl transferase N-acetyllactosamine + UDP glycoproteins Synthesis of lactose in lactating mammary gland UDP-galactose
lactose 4-epimerase UDP UDP-glucose
PPi lactose UDP-glucose synthase pyrophosphorylase UTP glucose-1-phosphate phospho- glucomutase hexokinase glucose glucose glucose-6-phosphate GLUT1/3 ATP ADP
blood cytosol