Lecture 2 Carbohydrate and Glucose metabolism
Glucose
160-200 gr glucose used a day, of which 120-150 goes to the brain. Stored as glycogen in liver (190).
Neuronal cells have no beta-oxidation because they cannot absorb long chain fatty acids. Sugars can
change conformation from cyclic to linear. These 3D changes are large and enzymes are specific for
them. Carbohydrates are obtained from food, mostly starch, dairy. The polymers need several
enzymes to be degraded because of complex structure. Sometimes the undegradable compounds
can be used by bacteria in the gut.
Intestinal epithelium uses active uptake, because this goes against the gradient. Glucose entering
the brain etc. goes via glucose transporters only back-up is ketone bodies.
Disease
Lactose intolerance is a problem in small intestines Generation of lots of lactic acid, which attracts
water from the blood causing diarrhea. Galactosemia = galactose metabolized in liver not used to
make glucose Too much galactose causes enlarged liver, brain damage, kidney damage etc.
Nonclassical = no galactokinase, trap of galactose
Classical = lack of phosphate because of trap in galactose-1-phosphate fatigue
Fructosemia = fruit intolerance, fructokinase mutation causes fructose build up can be secreted
by kidneys.
Glycogen
Branched molecule with lots of end points. Storage in liver (for whole body) and muscle (only
for itself). Synthesis starts with glucose converted to glucose-6-phosphate glucose-1-p,
glycogen synthase needed for the whole process. Glycogen phosphorylase needed for the
breakdown of glycogen to glucose. The glycogen starts with core and new molecules are
added, transferase makes new branches if they become too long. During breakdown, when
there are less than 4 in the branches it gets transferred to the end and branch is removed.
Regulation of glycogen is done by insulin, glucagon (muscle does not respond) and
epinephrine. Stress and muscle activity reinforce each other, muscle phosphorylase is regulated at 2
levels:
allosteric = intern control by metabolites
phosphorylation = external control by hormones
blood glucose levels
insulin promotes storage glycogen, fatty acid, triglyceride synthesis and
liver glycolysis. When levels drop, the glucagon is released glycogenolysis,
gluconeogenesis, lipolysis and liver glycolysis. Glucagon production is
stimulated by amino acids and nerve actions, also by stress hormones. Insulin
production by beta-cells depend on glucose levels. Uptake rates follow
enzyme kinetics.
Brain needs glucose transporter that takes up very low concentrations, the liver needs a higher level
one. The muscle and adipose GLUT-4 is insulin sensitive, only active when there is glucose left.
, Liver and pancreas glucokinase = high Km and high Vmax
Other cells hexokinase = low Km and low Vmax
Meaning higher Km is less active enzyme, therefore leaving glucose for
other tissue. Hexokinase is inhibited by glucose-6-p, glucokinase is not
inhibited. After this the liver takes up excess glucose, immediately
synthesizing glycogen.
Gluconeogenesis
Only occurs in the liver, during starvation stimulated by glucagon. G6Pase is
needed for this process and only present in liver. Lactate pyruvate
glucose, or AA pyruvate glucose. The preferred substrate is always an amino acid. Fatty acids
cannot be used because acetyl CoA cannot be converted.
Pyruvate is decision point for gluconeogenesis or lipogenesis. Depends on activity of:
Pyruvate carboxylase = glucose making, stimulated by glucagon
pyruvate dehydrogenase = fatty acid making, stimulated by insulin (acetyl
CoA is irreversible)
At different glucose levels:
Glucose is low: pyruvate gluconeogenesis by carboxylase
Glucose is high: pyruvate TCA by PDC
Insulin activates PDC (glucose into Acetyl CoA), glucagon inactivates PDC (glucose into
gluconeogenesis).
glucose-6p inhibits binding of glucose to hexokinase. Signals that peripheral cells have enough
glucose liver can take the rest.
F-2,6-BP stimulates glycolysis and blocks gluconeogenesis. When glucose levels are low there won’t
be much F-6P and no F-2,6-BP.
Combined: low glucose glucagon increased enzyme phosphorylation (PKA) activation
FBPase and inactivation PFK-2 F-2,6-BP drops inactivation PFK and activation FBPase
gluconeogenesis
, Lecture 3 Protein and Amino acid metabolism
There is no amino acid storage in the body, surplus in dietary amino acids is not needed for protein
synthesis.
Digestion
Starts in stomach where pepsin is released, cleaves only certain points. The pancreas secretes pro-
forms of the enzymes to protect epithelial cells, they become activated by pepsin in the stomach.
Ends with Di- and tri- peptides taken up by epithelial cells. Uptake is always active against the
gradient, going in to the blood is done by facilitated transporter. The intestinal cells use mainly
amino acids for energy, not the glucose.
Synthesis and degradation
Different things are done with excess amino acids:
Gluconeogenesis = using carbon skeleton to form glucose in liver
Fat storage = when there is enough glucose, making of fatty acids
Transamination reaction = conversion amino acids into other amino acids or TCA intermediates.
Used for synthesis and degradation of amino acids. PLP is needed for this, B6 is essential. Destination
of different amino acids:
3 carbon amino acid pyruvate
4 carbon amino acids oxaloacetate (TCA)
5 carbon amino acids α-ketoglutarate (TCA)
Carbon skeleton amino acids acetyl CoA (no glucose making)
Depending on where the amino acids end up they can be: glucogenic, ketogenic or both. Lysine and
leucine are strictly ketogenic, other are glucogenic or both.
If there is a defect in degradation of phenylalanine into tyrosine leads to PKU because build up of
phenylalanine. A diet with limited phenylalanine is needed. Glutamate is key component in amino
acid synthesis. Can be used for transamination reactions, or can be directly deaminated. A surplus
AA leads to glutamate synthesis:
1. Removal amino group by transamination collected by glutamate use
αKG
2. Removal of ammonium group from glutamate by glutamate
dehydrogenase
3. Enter of NH4+ to urea cycle
Regulation
Simplest conversion is from alanine to pyruvate to make glucose. Pyruvate and other TCA
components are derived from AA. If no ATP is needed, glucose or fat is made. Negative nitrogen
balance = breakdown of body proteins after fasting, AA is source of glucose during fasting. Glucose-
alanine cycle = amino acids needed for gluconeogenesis obtained from the muscle. Preferentially
use of skeletal muscles, because they contain high alanine and glutamine. Fatty acids cannot be used
but glycerol from triglycerides can be a source for gluconeogenesis.
Brain uses ketone bodies produced by liver as back up. Shortage of glucose triggers muscle
degradation before start of ketone body production.
Glucose
160-200 gr glucose used a day, of which 120-150 goes to the brain. Stored as glycogen in liver (190).
Neuronal cells have no beta-oxidation because they cannot absorb long chain fatty acids. Sugars can
change conformation from cyclic to linear. These 3D changes are large and enzymes are specific for
them. Carbohydrates are obtained from food, mostly starch, dairy. The polymers need several
enzymes to be degraded because of complex structure. Sometimes the undegradable compounds
can be used by bacteria in the gut.
Intestinal epithelium uses active uptake, because this goes against the gradient. Glucose entering
the brain etc. goes via glucose transporters only back-up is ketone bodies.
Disease
Lactose intolerance is a problem in small intestines Generation of lots of lactic acid, which attracts
water from the blood causing diarrhea. Galactosemia = galactose metabolized in liver not used to
make glucose Too much galactose causes enlarged liver, brain damage, kidney damage etc.
Nonclassical = no galactokinase, trap of galactose
Classical = lack of phosphate because of trap in galactose-1-phosphate fatigue
Fructosemia = fruit intolerance, fructokinase mutation causes fructose build up can be secreted
by kidneys.
Glycogen
Branched molecule with lots of end points. Storage in liver (for whole body) and muscle (only
for itself). Synthesis starts with glucose converted to glucose-6-phosphate glucose-1-p,
glycogen synthase needed for the whole process. Glycogen phosphorylase needed for the
breakdown of glycogen to glucose. The glycogen starts with core and new molecules are
added, transferase makes new branches if they become too long. During breakdown, when
there are less than 4 in the branches it gets transferred to the end and branch is removed.
Regulation of glycogen is done by insulin, glucagon (muscle does not respond) and
epinephrine. Stress and muscle activity reinforce each other, muscle phosphorylase is regulated at 2
levels:
allosteric = intern control by metabolites
phosphorylation = external control by hormones
blood glucose levels
insulin promotes storage glycogen, fatty acid, triglyceride synthesis and
liver glycolysis. When levels drop, the glucagon is released glycogenolysis,
gluconeogenesis, lipolysis and liver glycolysis. Glucagon production is
stimulated by amino acids and nerve actions, also by stress hormones. Insulin
production by beta-cells depend on glucose levels. Uptake rates follow
enzyme kinetics.
Brain needs glucose transporter that takes up very low concentrations, the liver needs a higher level
one. The muscle and adipose GLUT-4 is insulin sensitive, only active when there is glucose left.
, Liver and pancreas glucokinase = high Km and high Vmax
Other cells hexokinase = low Km and low Vmax
Meaning higher Km is less active enzyme, therefore leaving glucose for
other tissue. Hexokinase is inhibited by glucose-6-p, glucokinase is not
inhibited. After this the liver takes up excess glucose, immediately
synthesizing glycogen.
Gluconeogenesis
Only occurs in the liver, during starvation stimulated by glucagon. G6Pase is
needed for this process and only present in liver. Lactate pyruvate
glucose, or AA pyruvate glucose. The preferred substrate is always an amino acid. Fatty acids
cannot be used because acetyl CoA cannot be converted.
Pyruvate is decision point for gluconeogenesis or lipogenesis. Depends on activity of:
Pyruvate carboxylase = glucose making, stimulated by glucagon
pyruvate dehydrogenase = fatty acid making, stimulated by insulin (acetyl
CoA is irreversible)
At different glucose levels:
Glucose is low: pyruvate gluconeogenesis by carboxylase
Glucose is high: pyruvate TCA by PDC
Insulin activates PDC (glucose into Acetyl CoA), glucagon inactivates PDC (glucose into
gluconeogenesis).
glucose-6p inhibits binding of glucose to hexokinase. Signals that peripheral cells have enough
glucose liver can take the rest.
F-2,6-BP stimulates glycolysis and blocks gluconeogenesis. When glucose levels are low there won’t
be much F-6P and no F-2,6-BP.
Combined: low glucose glucagon increased enzyme phosphorylation (PKA) activation
FBPase and inactivation PFK-2 F-2,6-BP drops inactivation PFK and activation FBPase
gluconeogenesis
, Lecture 3 Protein and Amino acid metabolism
There is no amino acid storage in the body, surplus in dietary amino acids is not needed for protein
synthesis.
Digestion
Starts in stomach where pepsin is released, cleaves only certain points. The pancreas secretes pro-
forms of the enzymes to protect epithelial cells, they become activated by pepsin in the stomach.
Ends with Di- and tri- peptides taken up by epithelial cells. Uptake is always active against the
gradient, going in to the blood is done by facilitated transporter. The intestinal cells use mainly
amino acids for energy, not the glucose.
Synthesis and degradation
Different things are done with excess amino acids:
Gluconeogenesis = using carbon skeleton to form glucose in liver
Fat storage = when there is enough glucose, making of fatty acids
Transamination reaction = conversion amino acids into other amino acids or TCA intermediates.
Used for synthesis and degradation of amino acids. PLP is needed for this, B6 is essential. Destination
of different amino acids:
3 carbon amino acid pyruvate
4 carbon amino acids oxaloacetate (TCA)
5 carbon amino acids α-ketoglutarate (TCA)
Carbon skeleton amino acids acetyl CoA (no glucose making)
Depending on where the amino acids end up they can be: glucogenic, ketogenic or both. Lysine and
leucine are strictly ketogenic, other are glucogenic or both.
If there is a defect in degradation of phenylalanine into tyrosine leads to PKU because build up of
phenylalanine. A diet with limited phenylalanine is needed. Glutamate is key component in amino
acid synthesis. Can be used for transamination reactions, or can be directly deaminated. A surplus
AA leads to glutamate synthesis:
1. Removal amino group by transamination collected by glutamate use
αKG
2. Removal of ammonium group from glutamate by glutamate
dehydrogenase
3. Enter of NH4+ to urea cycle
Regulation
Simplest conversion is from alanine to pyruvate to make glucose. Pyruvate and other TCA
components are derived from AA. If no ATP is needed, glucose or fat is made. Negative nitrogen
balance = breakdown of body proteins after fasting, AA is source of glucose during fasting. Glucose-
alanine cycle = amino acids needed for gluconeogenesis obtained from the muscle. Preferentially
use of skeletal muscles, because they contain high alanine and glutamine. Fatty acids cannot be used
but glycerol from triglycerides can be a source for gluconeogenesis.
Brain uses ketone bodies produced by liver as back up. Shortage of glucose triggers muscle
degradation before start of ketone body production.
