HEXOSE METABOLISM

AJI SUTRISNOFOOD SCIENCE AND TECHUNIVERSITAS BRAWIJAYA

Common Hexoses

OCH2OH

HH

OHOH

H

H

OH

H

OH

OCH2OH

HOH

HOH

H

H

OH

H

OH

OCH2OH

HH

OHOH

H

OH

H

H

OH

O

OH

CH2OH

HH

OH H

CH2OH

OH

a-D-Glucose a-D-Galactose a-D-Mannose

a-D-Fructose

Sources of Sugars

• Glucose: lactose (dairy products) and

sucrose (table sugar)• Fructose: fruits and sucrose• Galactose: lactose• Mannose: polysaccharides and glycoproteins

Fructose Metabolism

Sucrose(Table Sugar)

O--D-Glucopyranosyl-(1—> 2)--D-Fructofuranoside

OO

CH2OH

HHO

H

HO OH

H

H

OH

H HOCH2

H

OH H

H

CH2OHO

All Tissues

Sucrose -D-glucose + -D-f ructosea-Glucosidase(I nvertase)

Glycolysis

Mutarotation-D-f ructose

Cleavage of Sucrose(-glucosidase or invertase)

OO

CH2OH

HHO

H

HO OH

H

H

OH

H HOCH2

H

OH H

H

CH2OHO

H2O

OCH2OH

HH

HO OH

H

H

OH

H

OH

OHO

HOCH2

H

OH H

H

CH2OHH

Glucose Fructose

Mutarotation of Fructose

HOCH2 OH

CH2OHH

OH

HO

H

OCH2OH

C

O

H OHCH2OH

CHO HCH OH

C HOCH2

H

CH2OH

OHH

OH

HO

H

O

D-Fructose-D-Fructose -D-Fructose

Muscle Metabolism of Fructose

(Anaerobic Glycolysis)Large Amounts of Hexokinase

OHO

HOCH2

H

OH H

CH2OH

OHH

ATP ADPO

HOPOCH2

H

OH H

CH2OH

OHHHexokinase

-D-Fructose

Glycolysis

Fructose-6-P

Liver Metabolism of Fructose I

(Little Hexokinase)

OHO

HOCH2

H

OH H

CH2OH

OHH

ATP ADPO

HOHOCH2

H

OH H

CH2OP

OHHFructokinase

-D-Fructose

(Committed Step)

Fructose-1-P

Liver Metabolism of Fructose II

CH2OPCCCCCH2OH

OHHOOHH

H OH

Glycolysis

CHOCHOHCH2OH

Glyceraldehyde

OHO

HOCH2

H

OH H

CH2OP

OHH

DHAP

CH2OPCCH2OH

O

Fructose-1-P

Fructose-1-P Aldolase

Mechanism of Aldolase(Formation of Schiff Base)

Mechanism of Aldolase(Aldol Cleavage Reaction)

HH

H2COPCCCCCH2OH

NHHOOHOHH

Enzyme CH2OPCC

NHEnzymeHHO

:CHOCHOHCH2OH

:B

+

Mechanism of Aldolase(Formation of Dihydroxyacetone-P)

CH2OPCC

NHHHO

Enzyme:

H2OCH2OPCCH2OH

O

H2N–Enzyme

Liver Metabolism of Fructose III

CHO

CHOH

CH2OH

ATPADP

CHO

CHOH

CH2OP

NAD+

CH2OH

CHOH

CH2OH

NAD+

CH2OH

C

CH2OP

O

CH2OH

CHOH

CH2OP

Glyceraldehyde

Glyceraldehyde Kinase

Glyceraldehyde-3-P

Glycolysis

AlcoholDehydrogenase

NADH + H+

Glycerol

GlycerolKinase

Glycerol-3-P

Dihydroxyacetone-P(DHAP)

NADH + H+

Glycerol-PDehydrogenase

Triose-PIsomerase

Complexity of Liver Metabolism

Breakdown of Many Metabolites

Fructose Intolerance

• Too Much Fructose– Fructose-1-P Aldolase is rate-limiting– Depletion of Pi– Reduction in [ATP]– Increase in glycolysis– Accumulation of lactate (acid) in

blood• Fructose-1-P Aldolase

Deficiency (Genetic Disease)

Galactose Metabolism

Lactose Metabolism(Dairy Products)

Glycolysis

O

O

CH2OH

HHO

HOH

H

H

OH

H

O

CH2OH

H

OH

H

H

OH

H

OH

O

CH2OH

HHO

HOH

H

H

OH

OH

H

Lactose

Glucose

-D-Galactose

-Galactosidase

Mutarotation of -D-Galactose

Glycolytic Enzymes are specific and do not recognize

galactose!

Need Epimerization

OCH2OH

HHO

H OH

H

H

OH

H

OH

OCH2OH

HH

HO OH

H

H

OH

H

OH

GlucoseGalactose

Epimerization

Phosphorylation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OH

ATP ADPO

CH2OH

HOH

HOH

H

H

OH

H

OPO3=Galactokinase

Galactose Galactose-1-P

Activation of Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

OPO3=

O

CH2OH

HH

OHOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

O

CH2OH

HOH

HOH

H

H

OH

H

O P O

O

O–

P O

O–

O

Uridine

UMP

Galactose-1-P

Galactose-1-PUridylyl Transferase

UDP-Glucose

Glucose-1-P

UDP-Galactose

Glucose-6-P

Phosphoglucomutase

Glycolysis

Epimerization of UDP-Galactose

O

CH2OH

HOH

HOH

H

H

OH

H

O P UMP

O

O–

[NAD+]O

CH2OH

HH

OHOH

H

H

OH

H

O P UMP

O

O–

UDP-Galactose-4-Epimerase

UDP-GlucoseUDP-Galactose

Mechanism of Epimerization

O

C

CH2OH

H

OH

H

H

OH

H

O P UMP

O

O–

O

Why UDP-Galactose?

GlycoproteinsGlycolipids

(Require UDP-Galactose)

Formation of Glucose-1-P

O

CH2OH

HH

OHOH

H

H

OH

H

O P UMP

O

O–

PPi UTPO

CH2OH

HH

OHOH

H

H

OH

H

O P O–

O

O–

UDP-GlucosePyrophosphorylase

UDP-Glucose Glucose-1-P

Formation of Glucose-6-P

O

CH2OH

HH

OHOH

H

H

OH

H

O P O–

O

O–

O

CH2OPO32–

HH

OHOH

H

H

OH

H

OHPhosphoglucomutase

Glucose-6-PGlucose-1-P

Glucose-6-P ——> Glycolysis

Galactosemia(Mental Retardation and Death)

TreatmentGalactose-free diet

(reversal of all symptoms except mental retardation)

Cataracts

CCC

OHH

OH

HHOC HHOC OHHCH2OH

CH2OHCC

OHHHHO

C HHOC OHHCH2OH

NAD(P)H NAD(P)+

Galactose Galactitol

Mannose Metabolism

Phosphorylation of Mannose

OCH2OH

HH

OHOH

H

HO

H

H

OH

ATP ADPO

CH2OP

HH

OHOH

H

HO

H

H

OH

-D-Mannose

Hexokinase

Mannose-6-P

Isomerization of Mannose-6-P

OCH2OP

HH

OHOH

H

HO

H

H

OH

O

HO

POCH2

HH

OH H

CH2OH

OHPhosphomannoseIsomerase

Fructose-6-PMannose-6-P

THANK YOU

Mechanism of Isomerization

H C

CH O

O H

R

Aldose

C

CH O

O H

R

BH + C

CH O

O

R

BH

H

H C

H

O

C O

R

H

Ketose

B:B: +

Aldoses and Ketoses

CC

OH

COHHHHO

CC

OHH

CH2OHOHH

CH2OHCCCCCH2OH

OHHOOHHOHH

D-glucose D-f ructose

Mutarotation of Glucose

HH

HOO

HC

O

C

CH2OH

OH

OH H

OH

HO

OCH2OH

OH

OH

OR

OHHO

OCH 2OH

OH

OH

C

H

HO H

OH

CO

H OH

CH2OH

C

CH OH

CH ....

or

+

[+18.7°][+112.2°]

anomericcarbonatom

-D-glucose-D-glucose

Mutarotation of Fructose

HOCH2 OH

CH2OH

OH

HO

OCH2OH

CH OHCH2OH

CHO HCH OH

C OHOCH2 CH2OH

OH

OH

HO

O

D-Fructose -D-Fructose-D-Fructose