45
Metabolic Disorders Induced by Impaired Galactose
Metabolism
Lactose, a disaccharide consisting of galactose and its 4′-epimer glucose, is present
in human milk, cow’s milk, and in some infant formulas [11]. Metabolism of galactose is carried out in the Leloir pathway [12] which has three main enzymes galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and
UDP-galactose 4′-epimerase (GALE) [13]. A schematic representation of the Leloir
pathway of galactose metabolism has been shown in Fig. 2.2 [12]. Due to hydrolysis, ingested lactose is converted into glucose and galactose via lactase enzyme in
MDH
ATP, CO2
NADPH2
CO2
NADH2
NADPH2
NADH2+
AST
Glycolysis
Acetyl-CoA
Acetyl-CoA
MCoA
FAS, SCD
GA3PDH
Acyl-CoA
Fatty acid
GA3P
1,3BPGA
Citrate
Citrate
ATP.CoA-SH
Lyase
Isocitrate
Malate
Succinate
Glucose
ASP
Acc
DHAP
Gly3P
Transamination
Alanine
Pyruvate
OAA
G3PDH
G3PDH
UQ
2H
+
G
l y c o l y s i s
G ly c o ly s is
Lipogenesis
1 , 3 B P G
G
A 3 P D
H
G
A 3 P
Low energy
PDH activation &
FA oxidation Acyl-CoA
NADH2
NAD
+
1
Gluconeogenesis
FAD
+
Pyruvate
CO2,ATP
Acetyl-CoA
CoA-SH
OXPHOS
OAA
3
2
NADH2
5
4
OAA MDH
UQH2
FADH2
PEP
OAA
Malate
Malate
NADH2
Co2
AST
6
Citrate
OAA
Fumarate
Succinate
Glu
Glu
ASP
Isocitrate
H +
Ca
2+
αKG
αKG
HPO4
C
y
to
p
la
s
m
i
c
m e m b r a n e
Mit
oc
ho
n
d
r
ia
Cyt
op
la
s
m
Fig. 2.1 Presentation of metabolic pathways happening inside the cytoplasm and mitochondria
1-Glycerol phosphate shuttle, 2-NADH shuttle into IMM, 3-transhydrogenase cycle, 4-Citrate
cycle, 5-TCA cycle, 6-malate-aspartate shuttle. Adopted from ref. [9]. ACC acetyl coenzyme-A
carboxylase, ADP adenosine diphosphate, Asp aspartic acid, AST aspartate aminotransferase, ATP
adenosine triphosphate, 1,3-BPGA 1,3-biphosphoglyceric acid, CO 2 : carbon dioxide, DAP dihydroxyacetone phosphate, DHAP dihydroxyacetone phosphate, FAD flavin adenine dinucleotide,
FADH 2 : reduced flavin adenine dinucleotide, FA-oxi fatty acid oxidation, GA3P glyceraldehyde- 3phosphate, GA3PDH glyceraldehyde-3-phosphate dehydrogenase, G3PDH glycerol-3-phosphate
dehydrogenase, Glu: glutamic acid, IMM inner mitochondrial membrane, α-KG alphaketoglutarate, α-KGDH alpha-ketoglutarate dehydrogenase, MCo-A malonyl coenzyme-A, MDH
malate dehydrogenase, NAD+ nicotinamide adenine dinucleotide, NADP nicotinamide adenine
dinucleotide phosphate, NADPH nicotinamide adenine dinucleotide phosphate hydrogen, OAA
oxaloacetic acid, OXPHOS oxidative phosphorylase, PDH pyruvate dehydrogenase complex, PEP
phosphoenolpyruvate, SCD stearoyl coenzyme-A desaturase, UQ ubiquinone, UQH 2 ubiquinol
2 Impaired Carbohydrate Metabolism in Metabolic Disorders
Metabolic Disorders Induced by Impaired Galactose
Metabolism
Lactose, a disaccharide consisting of galactose and its 4′-epimer glucose, is present
in human milk, cow’s milk, and in some infant formulas [11]. Metabolism of galactose is carried out in the Leloir pathway [12] which has three main enzymes galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and
UDP-galactose 4′-epimerase (GALE) [13]. A schematic representation of the Leloir
pathway of galactose metabolism has been shown in Fig. 2.2 [12]. Due to hydrolysis, ingested lactose is converted into glucose and galactose via lactase enzyme in
MDH
ATP, CO2
NADPH2
CO2
NADH2
NADPH2
NADH2+
AST
Glycolysis
Acetyl-CoA
Acetyl-CoA
MCoA
FAS, SCD
GA3PDH
Acyl-CoA
Fatty acid
GA3P
1,3BPGA
Citrate
Citrate
ATP.CoA-SH
Lyase
Isocitrate
Malate
Succinate
Glucose
ASP
Acc
DHAP
Gly3P
Transamination
Alanine
Pyruvate
OAA
G3PDH
G3PDH
UQ
2H
+
G
l y c o l y s i s
G ly c o ly s is
Lipogenesis
1 , 3 B P G
G
A 3 P D
H
G
A 3 P
Low energy
PDH activation &
FA oxidation Acyl-CoA
NADH2
NAD
+
1
Gluconeogenesis
FAD
+
Pyruvate
CO2,ATP
Acetyl-CoA
CoA-SH
OXPHOS
OAA
3
2
NADH2
5
4
OAA MDH
UQH2
FADH2
PEP
OAA
Malate
Malate
NADH2
Co2
AST
6
Citrate
OAA
Fumarate
Succinate
Glu
Glu
ASP
Isocitrate
H +
Ca
2+
αKG
αKG
HPO4
C
y
to
p
la
s
m
i
c
m e m b r a n e
Mit
oc
ho
n
d
r
ia
Cyt
op
la
s
m
Fig. 2.1 Presentation of metabolic pathways happening inside the cytoplasm and mitochondria
1-Glycerol phosphate shuttle, 2-NADH shuttle into IMM, 3-transhydrogenase cycle, 4-Citrate
cycle, 5-TCA cycle, 6-malate-aspartate shuttle. Adopted from ref. [9]. ACC acetyl coenzyme-A
carboxylase, ADP adenosine diphosphate, Asp aspartic acid, AST aspartate aminotransferase, ATP
adenosine triphosphate, 1,3-BPGA 1,3-biphosphoglyceric acid, CO 2 : carbon dioxide, DAP dihydroxyacetone phosphate, DHAP dihydroxyacetone phosphate, FAD flavin adenine dinucleotide,
FADH 2 : reduced flavin adenine dinucleotide, FA-oxi fatty acid oxidation, GA3P glyceraldehyde- 3phosphate, GA3PDH glyceraldehyde-3-phosphate dehydrogenase, G3PDH glycerol-3-phosphate
dehydrogenase, Glu: glutamic acid, IMM inner mitochondrial membrane, α-KG alphaketoglutarate, α-KGDH alpha-ketoglutarate dehydrogenase, MCo-A malonyl coenzyme-A, MDH
malate dehydrogenase, NAD+ nicotinamide adenine dinucleotide, NADP nicotinamide adenine
dinucleotide phosphate, NADPH nicotinamide adenine dinucleotide phosphate hydrogen, OAA
oxaloacetic acid, OXPHOS oxidative phosphorylase, PDH pyruvate dehydrogenase complex, PEP
phosphoenolpyruvate, SCD stearoyl coenzyme-A desaturase, UQ ubiquinone, UQH 2 ubiquinol
2 Impaired Carbohydrate Metabolism in Metabolic Disorders