Lecture #25S-Carbohydrate metabolism-39...
Transcript of Lecture #25S-Carbohydrate metabolism-39...
Carbohydrate
Metabolism
Dietary carbohydrates (starch, glycogen,
sucrose, lactose
Oligosaccharides and disaccharides
Mouth salivary amylase
Stomach, non-enzymatic hydrolysis
Monosaccharides
Small intestine, pancreatic amylase
Monosaccharides in bloodstream
Small intestinal lining
Storage (glycogenesis)
Conversion to other carbohydrates
Utilization for energy (glycolysis)
Excretion
Undesired biochemical
processes
Summary of Carbohydrate
Utilization
Glycolysis
Glycolysis is a nine step biochemical pathway that oxidizes glucose into two molecules of pyruvic acid (pyruvate).
During this process, energy is released and some of it is captured
in the form of ATP.
The electrons removed from glucose are captured in the form of NADH.
O
CH2OH
OH
OH
HO OH
+ 2 NAD+ + 2 ADP + 2 Pi
2 + 2 ATP + 2 NADH + 2 H+ + 2 H2OC6H12O6
C3H3O3-
glucose
pyruvate
H3CC
CO
O
O
Glycolysis
The pyruvate formed may be
oxidized to carbon dioxide and water in the citric acid cycle
may be reduced to L-lactic acid
or
Lactate Dehydrogenase Reaction
C
C
CH3
O
O
O
C
C
CH3
O
OH
O
H
NADH,H+ NAD+
Glycolysis Proceeds in Two Stages
Stage 1 of Glycolysis:
Glucose and other hexoses are converted into glyceraldehyde-3-phosphate.
Stage 1 of Glycolysis:glucose
glucose-6-phosphate
fructose-6-phosphate
fructose-1,6-bisphosphate
glyceraldehyde -3-phosphate
dihydroxyacetone phosphate
ATP
ADP
ATP
ADPhexokinase
phosphohexose isomerase
phosphofructo kinase
aldolase
triosephosphate isomerase
6 C
6 C - P
6 C - P
P - 6 C - P
3 C - P 3 C - P
Stage 2 of Glycolysis:
2 molecules of glyceraldehyde-3-phosphate are oxidized and converted into two molecules of pyruvate.
The NADH generated during stage 2 may be used to reduce the pyruvate molecules to lactate molecules.
Stage 2 of Glycolysis:glyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvate
ATP
ADP
NAD+, Pi
NADH, H+
ADP
ATP
3 C - P
P - 3 C - P*
3 C - P
3 C - P
3 C - P
P - 3 C - P*
glyceraldehyde-3-phosphate dehydrogenase
phosphoglcerate kinase
phosphoglycerate mutase
enolase
pyruvate kinase
G3P
BPG
3PG
2PG
PYR
PEP
GLU
G6P
F6P
FBP
G3P DHAP
Stage 1 Stage 2
Energy consumed Energy produced
The Individual Chemical Transformations of
Glycolysis
Distinguish Between the Two Stages Count the Carbons
Identify High Energy Compounds Understand the Overall Transformation
Chemical Transformations of GlycolysisThe overall reaction of steps 1-10 is:
In cells where a high rate of ATP production is not needed, the pyruvate formed by glycolysis is not reduced to lactate, but instead is oxidized to
carbon dioxide and water in the mitochondria.
This allows the cell to capture a greater amount of energy from the original glucose molecule.
Note:In some microorganisms, such as yeast, pyruvate is first decarboxylated and the resulting acetaldehyde is reduced to ethanol, regenerating NAD+.
Glucose + 2 ADP + 2 Pi 2 lactate + 2 ATP
C
C
CH3
O
O
OH
C
CH3
O
CO2
H
HC
CH3
OH
NADH,H+ NAD+pyruvate
decarboxylase
alcohol dehydrogenase
6C 3C
The Pentose Phosphate Pathway
The pentose phosphate pathway utilizes glucose to produce pentoses (for DNA, RNA) and NADPH (for reductive biosynthesis).
This pathway includes additional enzymes that allow the interconversion of pentoses and hexoses.
This allows the cell four alternatives:
Produce both pentoses and NADPH.
Produce only NADPH when pentoses are not required.
Produce only pentoses when NADPH is not required.
Produce ATP (glycolysis) and NADPH when both are required.
Glucose-6-PO42- + 2 NADP+ ribose-5-PO42- + 2 NADPH + 2 H+ + CO2 5C6C
Name Derivation of Name Function
Glycolysis glyco-, glucose “sweet” glucose--->pyruvate
Pentose Phosphate Pathway
pentose-, five carbon sugar
glucose---> 5-carbon sugars
Gluconeogenesis neo-, “new” genesis-, “creation”
small molecules---> glucose
Glycogenesis glyco (gen)-glycogen genesis-, “creation” glucose--->glycogen
Glycogenolysis glyco (gen)-glycogen -lysis, “breakdown” glycogen--->glucose
Metabolic Pathways of Glucose
Gluconeogenesis
Gluconeogenesis is the biosynthesis of glucose from lactate and certain other small molecules.
Gluconeogenesis occurs in the liver and kidney.
Gluconeogenesis reverses many of the reactions in glycolysis; however, three irreversible reactions
must be bypassed using different reactions and enzymes.
glucose
glucose-6-phosphate
fructose-6-phosphate
fructose-1,6-bisphosphate
glyceraldehyde-3-phosphate
ATP
ADP
ATP
ADP
glyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvate
ADP
ATP
ATP
ADP
NAD+, Pi
NADH, H+
Glycolysis
Glycolytic Reaction Step ΔG(kJ/mol)1 glucose + ATP → glucose-6-phosphate + ADP -332 glucose-6-phosphate ⇄ fructose-6-phosphate 0 to 2.53 fructose-6-phosphate + ATP → fructose-1,6-bisphosphate + ADP -224 fructose-1,6-bisphosphate ⇄ DHP + G3P 0 to -6
dihydroxyacetone phosphate ⇄ glyceraldehyde-3-phosphate 0 to 45 glyceraldehyde-3-phosphate ⇄ 1,3-bisphosphoglycerate -2 to 26 1,3-bisphosphoglycerate + ADP ⇄ 3-phosphoglycerate + ATP 0 to 27 3-phosphoglycerate ⇄ 2-phosphoglycerate 0 to 0.88 2-phosphoglycerate ⇄ phosphoenolpyruvate 0 to 3.39 phosphoenolpyruvate + ADP → pyruvate + ATP -17
Free Energy Changes for Glycolysis Reactions Steps*
*calculated from the actual physiological concentrations in erythrocytes
glucose
glucose-6-phosphate
fructose-6-phosphate
fructose-1,6-bisphosphate
glyceraldehyde-3-phosphate
ATP
ADP
ATP
ADP
glyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvate
ADP
ATP
ATP
ADP
NAD+, Pi
NADH, H+
Glycolysis
Gluconeogenesis
glyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvateglyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvate
ADP
ATP
ATP
ADP
NAD+, Pi
NADH, H+
Glycolysis
NAD+, Pi
NADH, H+
ATP
ADP
cytosolmitochondria
pyruvate
oxaloacetate
phosphoenolpyruvate
oxaloacetate
malate
malate
Gluconeogenesis
GDP, HCO3-
GTP
ATP, HCO3-
ADP
NADH, H+
NAD+
NADH, H+
NAD+
glyceraldehyde-3-phosphate
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
phosphoenolpyruvate
pyruvate
ATP
ADP
NAD+, Pi
NADH, H+
pyruvate
oxaloacetate
phosphoenolpyruvate
oxaloacetate
malate
malate
GDP, HCO3-
GTP
ATP, HCO3-
ADP
NADH, H+
NAD+
NADH, H+
NAD+
pyruvate carboxylase (requires biotin)
phosphoenolpyruvate carboxykinase
ATP
GDP
ADP
mitochondria
cytosol
only occurs when there is an
abundance of ATP
Glycolysisglucose
glucose-6-phosphate
fructose-6-phosphate
fructose-1,6-bisphosphate
glyceraldehyde-3-phosphate
ATP
ADP
ATP
ADP
Gluconeogenesisglyceraldehyde
-3-phosphatedihydroxyacetone
-3-phosphate
fructose-1,6-bisphosphate
fructose-6-phosphate
glucose-6-phosphate
glucose
H2O
Pi
glucose- 6-phosphatase
H2O
Pi
fructose-1,6- bisphosphatase
Dietary carbohydrates (starch, glycogen,
sucrose, lactose
Oligosaccharides and disaccharides
Mouth salivary amylase
Stomach, non-enzymatic hydrolysis
Monosaccharides
Small intestine, pancreatic amylase
Monosaccharides in bloodstream
Small intestinal lining
Storage (glycogenesis)
Conversion to other carbohydrates
Utilization for energy (glycolysis)
Excretion
Undesired biochemical
processes
Summary of Carbohydrate
Utilization
Glycogenesis and
Glycogenolysis
Glucose-1-phosphate
(Glucose)n glycogen
UTP
Glucose-UDP
2 Pi
UDP (Glucose)n-1
glycogenesis
Glucose
Glucose-6-phosphate glycolysis
gluconeogenesis
HPO32-
(Glucose)n-1
glycogenolysis
GlycogenesisWhen the concentration of ATP is high, glycogen is synthesized and stored in liver and muscle cells as
glycogen granules.
The addition of a molecule of glucose to a growing α 1→4 glycogen strand involves these reactions:
1) Glucose-6-phosphate → Glucose-1-phosphate
2) Glucose-1-phosphate + UTP → UDP-glucose + PP,
PPi + H2O → 2 Pi
3) UDP-glucose + (glucose)n-1 → UDP + (glucose)n
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
HO O
HO
O
OCH2
OHOH
PO
O
P
O
O O
ON
NH
O
O
O
CH2
OH
OH
HO O
HO
OCH2
OHOH
PO
O
P
O
O O
ON
NH
O
OUDP-Glucose
non-reducing end of glycogen
elongated glycogenUDP
Glycogen Synthase Reaction
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
HO O
HO
Glycogenesis
When a growing α 1→4 glycogen strand reaches a certain length, a branching enzyme breaks the α 1→4 chain and
remakes an α 1→6 linkage. this results in branches, each of which can be extended by further α 1→4 linkages
glycogenin
glycogenin
OCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HOOCH
2
OH O
HO
OCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HO
OCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HO
OCH
2
OH
OH
O
HO
HO
OCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HOOCH
2
OH
OH
O
HO
OH
autocatalysis
O
CH2
OH
OH
O
HO
HO
O
CH2
OH
OH
O
HOO
CH2
OH
OH
O
HOO
CH2
OH
OH
O
HO
glycogenin
glycogen synthase
glycogenin
OCH2
OH
OH
O
HO
HO
OCH2
OH
OH
O
HOOCH2
OH
OH
O
HOOCH2
OH
OH
O
HO
OCH2
OH
OH
O
HOOCH2
OH
OH
O
HOOCH2
OH
OHHOO
HO
OCH2
OH
OH
O
HOOCH2
OH
OH
O
HOOCH
OH
OH
O
H
OCH2
OH
OH
O
HOOCH2
OH
OH
O
HOOCH2
OH
OH
O
HO
glycogen branching enzyme
Further elongation and branching
Glycogenesis
Glycogen synthesis is stimulated by insulin through a covalent modification of the glycogen synthase kinase
enzyme.
Glycogen synthesis is inhibited by glucagon and epinephrine through a covalent modification of the
glycogen synthase phosphatase enzyme.
Glycogenolysis
When the blood glucose concentration drops below about 5 mM, glycogen in the liver is degraded to free glucose
which is released into the bloodstream.
Glycogenolysis proceeds by a different route from glycogen biosynthesis.
Glucose, as glucose-1-phosphate, is released from glycogen by the active form of the enzyme: glycogen phosphorylase.
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
HO O
HO
non-reducing end of glycogen
shortened glycogen
Glycogen Phosphorylase
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
O
HO
O
CH2
OH
OH
HO O
HO
Glycogenolysis
HOPO
OO
O
CH2
OH
OH
HO O
HO
PO
OO
Called a “phosphorolysis” reaction
Glycogenolysis
When a shrinking α 1→4 glycogen strand approaches a branching point, a debranching enzyme transfers a
portion of the α 1→6 branching chain and remakes an α 1→4 linkage. A second enzyme (an α 1→6 glucosidase)
removes the remaining glucose residue from the branching point, and degradation continues by the
phosphorylase.
glycogenin
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
glycogenin
OCH2
OH
OHO
HO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
phosphorylase
transferase
glucosidase
phosphorylase
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
HO
HO
glycogenin
O
CH2
OH
OH
HO O
HO
PO
OO
HOPO
OO
O
CH2
OH
OH
HO O
HO
PO
OO
glycogenin
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO
HO
OCH2
OH
OHO
HOO
CH2
OH
OHO
HOO
CH2
OH
OHO
HO HO
HOPO
OO
O
CH2
OH
OH
HO O
HO
PO
OO Further chain cleavage
HOPO
OO
Glycogenolysis
Glycogenolysis is stimulated by glucagon and epinephrine through covalent modification of a
phosphorylase kinase enzyme.
Insulin
Hormonal Regulation of Blood Glucose
Glucagon, epinephrine
ACTIVE Phosphorylase
kinase
INACTIVE Glycogen Synthase
kinase
ACTIVE Glycogen Synthase
phosphorylase
ACTIVE Glycogen Synthase a
Storageof
glucose
ACTIVE Glycogen Phosphorylase a
Releaseof
glucose
P
Active phosphorylase
kinase
Inactive phosphorylase
kinase
Active phosphorylase
Inactive phosphorylase
(Glucose)n (Glucose)n-1 + Glucose-1-PO42-
Glucose-6-PO42-
Glucose
Liver and Muscle
Liver
Glycolysis
Bloodstream
Glucagon, epinephrine
Active adenyl cyclase
Inactive adenyl cyclase
Active G-protein
Inactive G-protein
cAMPATP
Active protein kinase
Inactive protein kinase
Active phosporylase
kinase
Inactive phosphorylase
kinase
Active phosphorylase
Inactive phosphorylase
Primary messenger (glucagon, epinephrine)
binds to cell surface.
*
(Glucose)n (Glucose)n-1
+ Glucose-1-PO42-
Secondary messenger
1x
40x
10x
100x
1000x
10,000x
Glucagon, epinephrine
Amplification Mechanisms
The glycogen cascade is one example of a general biochemical scheme for the use of relatively small
numbers of secondary messenger molecules to produce general cellular and physiological responses.
Active protein kinase
Inactive protein kinase
Active protein kinase
Inactive protein kinase
Active protein kinase
Inactive protein kinase
Active protein
Inactive protein
primary messenger
General Cellular Response
active relay molecule (second messenger)
receptor proteins