METABOLISM OF CARBOHYDRATES 5

web

József Mandl

2017

Entry of glucogenic substrates

into gluconeogenesis

glucoseG-6P

F-6Pfructose-1,6bisP

glyceraldehide-3P + diOH-aceton-P

1,3-bisphospho-glycerate

3P-glycerate

2P-glycerate

PEPpyruvate

F1,6bP-ase

G6P-ase

PEPCKPCOAA

alanine,

lactateglucoplastic

aminoacids

glycerin

glucose-1Pglycogen

lactate

Cori cycle

glycerol

trigliceride

glycerol

glycerol-3-P

dihydroxiacetone-P

lipase

glycerol

kinase

glycerol-3-P

dehydrogenase

Fatty cids

H2O

adipocyte

hepatocyte

blood

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

Enzymic hydrolysis of α1→4 and α1→6 glycosidic linkages in intestinal

lumen

maltase

glucosegalactose

lactose sucrose

fructose

Glucose, fructose and galactose:

main monosacharides ingested

maltose

starch

glycogen

Lactose intolerance – deficiency of lactase

Decrease in lactase is normal during development, declines to

about 5-10% of the level at birth

Milk sugar

Fructose, galactose

baso-

lateral

membrane

apical

membr.

ATP

ADP

+Pi

K+

Na+ K+glucose or

galactose

GLUT2

Na+

Na+

glucose or

galactose

glucose or

galactose

SGT

fructose

GLUT5

fructose

fructose

GLUT5GLUT2

Intestinal absorption of fructose and galactose

intestinal

lumen

glucose

galactose

fructose

glucose

fructose

glucose-6-phosphate

glucose-6-phosphate

galactose-1-phosphate

fructose-1-phosphate

fructose-6-phosphate

ATP ADP

ATP ADP

ATP ADP

ATP ADP

ATP ADP

HEXOKINASE

FRUCTOKINASE

GALACTOKINASE

GLUCOKINASE

LIVER, KIDNEY, INTESTINE

OTHER TISSUES

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

NADPH

+ H+ NADP+

NADH

+ H+NAD+

aldose reductase sorbitol

dehydrogenase

Polyol pathway

glucose sorbitol

(glucitol)

fructose

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

fructose-1-phosphate

diOH-acetone-P

glyceraldehyde

glycerolglycerol-3-P

fructokinase

aldolase B

alcohol

DH

glycerol kinase

glycerol-3P

DH

ADP ATP

NAD+

NADH + H+

ATP

ADP

aldolase B

(fructose-1-P aldolase)

fructose-1-phosphate

dihydroxyacetone-P

glyceraldehyde

fructose-1,6-bisphosphate

dihydroxyacetone-P

glyceraldehyde-3P

aldolase A

(in glycolysis)

glucoseglucose-6P

fructose-6Pfructose-1,6bisP

glyceraldehyde-3P + diOH-acetone-P

1,3-bisphospho-glycerate

3P-glycerate

2P-glycerate

PEPpyruvatePK-L

PFK1

GK

fructose

fructose-1-P

glyceraldehyde

glicerolglycerol-3-P

FK

aldolase

B

alcohol

DH

glycerol kinase

glycerol-3P

DH

main point of

regulation

liver

F-1,6 -bisP

F-6-P

Essential

fructosuria

Congenital fructose

intolerance

fructose

fructose-1-phosphate

diOH-acetone-P + glyceraldehyde

FK

aldolase B

ATP

ADP

Essential fructosuria

XX

accumulates in

blood after

meals

metabolized in

other tissues

and secreted

into urine

Regulation of activity of glucokinase

R

Gk glucokinase

regulator protein binds to

Inactive Gk

Gk

F- 6 - P

inactive

Gk

RF- 6 - P binds to R complex

G-6-P does not bind to R

F - 1 - P

ActiveGk

F-1-P binds to R

R

Gk

Prevents binding to Gk

fructose

fructose-1-phosphate

diOH-acetone-P + glyceraldehyde

FK

aldolase B

ATP

ADP

sustained ATP

and Pi depletion

glycogen

phosphorylase ↓↓

glucokinase ↑↑

pyruvate kinase ↑↑

glucose synthesis

blocked,

glycolysis activated

severe abdominal distress,

nausea, vomiting, hypoglycemia

and hyperuricemia after

fructose consumption;

liver damage in the long run,

gout, renal failure.

Fructose intolerance

XX

Fructokinase is expressed

in liver, kidney and small intestine.

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).

Summary

Galactose – glucose interconversion

liver

galactose galactose-1P

UDP-glucose

UDP-galactose

glucose-1P

galactokinase

UDP-glucose:galactose-1P

uridyltransferase

4-epimerase

(NAD+)

ATP ADP

glucose-6P

phospho-

glucomutase

Genetic deficiency:

GalactosemiaVomitus, diarrhea after

Milk, hepatomegaly,

Cirrhosis,

mental retardation

Reversible

Essential for

biosynthesis

Accumulated in lens - cataract

Type Defective enzyme

Type 1 galactose-1-phosphate uridyltransferase „classic galactosemia”

Type 2 galactokinase

Type 3 UDP-galactose 4-epimerase

Galactosemia: inborn defect of galactose metabolism

Accumulation of intermediates

of galactose metabolism (e.g.

galactose-1P, galactitol) causes

damages in various tissues.

glucoseglucose-6P

fructose-6Pfructose-1,6bisP

glyceraldehyde-3P + diOH-acetone-P

1,3-bisphospho-glycerate

3P-glycerate

2P-glycerate

PEPpyruvatePK-L

PFK1

GK

G6Pase

glucose-1Pgalactosephospho-

glucomutase

glycogen

Galactose is equivalent with glucose

in the liver, kidney and small intestine.

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

Summary

UDP-glucose, or

UDP-galactose

Synthesis of lactose, glycoproteins

In mammary gland only

UDP-galactose + glucose lactose + UDPLactose synthase (galactosyl transferase), α-lactalbumin

present in most tissues modifier subunit in mamma

In several tissues glycoprotein synthesis

UDP-galactose + N-acetylglucosaminegalactosyl transferase

N-acetyllactosamine + UDPglycoproteins

glucose-1-phosphate

lactose

glucose glucose-6-phosphateglucose

Synthesis of lactose in lactating mammary gland

lactose

synthase

phospho-

glucomutase

hexokinase

GLUT1/3

UDP-glucose

pyrophosphorylase

blood cytosol

ATP ADP

UDP

UDP-glucose

PPi

UTP

UDP-galactose

4-epimerase