Professional Documents
Culture Documents
METABOLISM
CATABOLISM
EDITED BY
Liniyanti D.Oswari,MD.,MNS,MSc.
For Block 8
Medical student, Sriwijaya
University
Carbohydrate Metabolism
Glycolysis
2.3. Biphospoglycerate (2.3.BPG)
Glycogenesis
Glycogenolysis
HMP shunt
Gluconeogenesis
REGULATION OF METABOLISM BY
HORMONES
Carbohydrate Metabolism
Overview
glycogen
pentose
GLUCOSE
other sugars
pyruvate
lactate
acetyl CoA
EtOH
Glucose
Utilization
Adipose
Energy
Stores
Glycogen
Glucose
Pentose
Phosphate
Pathway
Ribose-5-phosphate
Glycolysis
Pyruvate
GLYCOLYSIS
Glucose can also be available from
food intake.
Glucose is also stored as glycogen
(glycogenesis).
After gluconeogenesis, glucose is
converted from glycogen in liver or
muscle for glycolysis.
Glycolysis is the break down of a 6 C
glucose sugar to two 3C pyruvate.
Hexokinase
ADP
Glucose
ATP
Fructose-6-phosphate
ATP
ADP
Fructose-1, 6-biphosphate
Dihydroxyacetone
phosphate (DHAP)
Glyceraldehyde-3phosphate
NAD + Pi
NADH + H+
ADP
Glyceraldehyde-1,
3-bisphosphate
ADP
Glycerol ADP
ATP
ATP
H2O Phospho
ATP
Glycerate-3phosphate
Pyruvate
Glucose-6phosphate
Glycogen
Lactate
Dehydrogenase
Glucose-1phosphate
UDP-glucose
Lactate
Glycolysis:
break down of glucose in cytoplasm
Glycerate-2phosphate
-enolpyruvate
H2 O
Glycolysis: Phase 3
Phase 3: Oxidation and ATP formation
The 3-carbon sugars are oxidized (reducing
NAD+); i.e., 2 Hs + NAD
NADH2
Inorganic phosphate groups (Pi) are
attached to each oxidized fragment
The terminal phosphates are cleaved and
captured by ADP to form four ATP
molecules
The final products are:
Two pyruvic acid molecules
Two NADH + H+ molecules (reduced NAD+)
A net gain of two ATP molecules
GLYCOLYSIS
Glucose
ATP
hexokinase
ADP
Glucose 6-phosphate
phosphoglucoisomerase
Fructose 6-phosphate
ATP
phosphofructokinase
ADP
Fructose 1.6-bisphosphate
aldolase
triose phosphate isomerase
Dihydroxyacetone
Glyceraldehyde
Glyceraldehyde 3-phosphate
glyceraldehyde
NAD+ + Pi
3-phosphate
NADH +
H+
dehydrogenase
1,3-Bisphosphoglycerate
ADP
phosphoglycerate kinase
ATP
3-Phosphoglycerate
phosphoglyceromutase
2-Phosphoglycerate
enolase
H2O
Phosphoenolpyruvate
ADP
pyruvate kinase
ATP
hexokinase or glucokinase
phosphofructokinase
pyruvate kinase
These enzymes will be shown to be
regulate glycolysis as well.
Hexokinase Vs
Glucokinase
Hexokinase
Glucokinase
Site
Most tissues
Hepatocytes
Islet cells (pancreas)
Kinetics
Low Km
Low Vmax
High Km
High Vmax
Regulation
G-6-phosphate
F-6-phosphate
Insulin: Induction
Function
-- REGULATION OF GLYCOLYSIS
1.HEXOKINASE and
GLUCOKINASE
HEXOKINASE
GLUCOKINASE
2.
PHOSPHOFRUCTOKINASE
rate limiting for glycolysis
an allosteric multimeric regulatory
enzyme.
Measures adequacy of energy levels
3. PYRUVATE KINASE
PEP + ADP Pyruvate + ATP
An allosteric tetramer
-inhibitor: ATP & acetyl CoA &
fatty
acids (alternative fuels for TCA
cycle)
Glycolysis:
Embden-Myerhof
Oxidation of
Pathway
glucose
Products:
2 Pyruvate
2 ATP
2 NADH
Cytosolic
Aerobic Vs Anaerobic
Glycolysis
Aerobic Glycolysis:
Total Vs Net ATP Production
Carbohydrate Metabolism
Primarily glucose
Fates of Glucose
Fed state
Storage as glycogen
Storage as lipids
Liver
Skeletal muscle
Adipose tissue
Fasted state
Synthesis
Synthesis and
and
breakdown
breakdown occur
occur
at
at all
all times
times
regardless
regardless of
of
state...
state...
The
The relative
relative rates
rates
of
of synthesis
synthesis and
and
breakdown
breakdown change
change
Pancreas
Muscle
Glucose
absorbed
Insulin
Glycogen
Glucose
absorbed
Adipose
Cells
Glucose absorbed
Glucose Metabolism
Pyruvate Metabolism
Cori Cycle
Lactate is
converted
to pyruvate
in the liver
Pyruvate metabolism
Convert
Glutamate
Ketoglutarate
COO
C
CH 3
COO
Alanineaminotransferase
(AAT)
Pyruvate
Keto acid
acid
HC
NH 3+
CH 3
Alanine
Amino
Aerobic Conditions
Electron
Transport
TCA
Cycle
1. Lactate Fermentation
Enzyme = Lactate
Dehydrogenase
COOC=O + NADH + H+
NAD+
CH3
pyruvate
lactate
COOH-C-OH +
CH3
glucose
glucose
glucose
glucose-6-P
glucose-6-P
glycogen
glycog
ATP
ATP
NADH
Blood
NAD
pyruvate
pyruvate
lactate
lactate
lactate
Liver
Muscle
The liver uses most of this lactate to
make glycogen. Only small amounts
of free glucose released.
Glycogen can be broken down into
glucose when needed.
2.Alcoholic Fermentation
COOC=O
CH3
CO2
CH2OH
H O
C + NADH
CH3 +
CH3
NAD+
pyruvate
acetaldehyde
ethanol
pyruvate decarboxylase-
Summary Glucose
of Reactions
2 ATP
2 NADH
2 pyruvate
2 NADH
anaerobic
2 ethanol + CO2
2 NADH
anaerobic
2 lactate
2 acetyl CoA + 2
CO2
O2
aerobic
2.3 Biphosphoglycerate(BPG)
Deficiency Hexokinase
- Genetic disease
Glycogenesis
Glycogen synthesis
Occurs in cytosol of liver,muscle& kidney
Occurs when blood glucose levels are high
Excess glucose is stored (limited capacity)
liver and muscle are major glycogen storage sites
Glycogen Synthesis
Glucose units are activated for transfer by formation of
sugar nucleotides
What are other examples of "activation"?
a phosphoanhydride exchange
Glycogen Synthase
Forms alfa-(1 4) glycosidic bonds in glycogen
Glycogenin (a protein!) forms the core of a
glycogen particle
First glucose is linked to a tyrosine -OH
Glycogen synthase transfers glucosyl units from
UDP-glucose to C-4 hydroxyl at a nonreducing
end of a glycogen strand.
Note another oxonium ion intermediate
Phosphorylation of GP and GS
Covalent control
Edwin Krebs and Edmond Fisher showed in 1956
that a "converting enzyme" converted
phosphorylase b to phosphorylase a(P)
Phosphorylation causes the amino terminus of the
protein (res 10-22) to swing through 120 degrees,
moving into the subunit interface and moving Ser14 by more than 3.6 nm
Nine Ser residues on GS are phosphorylated!
Hormonal regulation
Hormones (glucagon, epinephrine) activate
adenylyl cyclase
cAMP activates kinases and phosphatases that
control the phosphorylation of GP and GS
GTP-binding proteins (G proteins) mediate
the communication between hormone receptor
and adenylyl cyclase
Hormonal Regulation
HormonalGlucagon
Regulation
II
and epinephrine
CH2OH
CH2OH
O
........
O
CH2OH
O
CH2OH
CH2
O
O
O
-[1-6] linkage
CH2OH
O
O
-[1- 4] linkages
Glycogenesis
Liver
Skeletal muscle
1% of wet weight
Glucose
Hexokinase
(muscle)
Glucokinase
(liver)
ATP
ADP
Glucose-6-phosphate
Phosphoglucomutase
(Glucose)
(Glucose)n+
Glucose-1-P
Uridyltransferase
UDP-glucose
Glucose-1-phosphate
UTP
UDP
Glycogen Synthase
PPi
Glycogen synthesis
Active
Inactive
Glycogenolysis
Glycogen degradation
Occurs in cytosol
Signal that glucose is needed is given by
hormones
Glycogen Catabolism
Glycogen
Pi
glycogen
phosphorylase
Glucose-1-phosphate
phosphoglucomutase
LIVER PATHWAY
glucose-6-phosphatase
Glucose-6-phosphate
glycolysis
(inhibited by lack of
fructose-2,6-bisP
Glucose
Pi
Glycogen
MUSCLE PATHWAY
Pi
glycogen
phosphorylase
Glucose-1-phosphate
phosphoglucomutase
Glucose-6-phosphate
glycolysis
Pyruvate
pyruvate
dehydrogenase
Acetyl CoA
anaerobic
Lactate
lactate dehydrogenase
citric acid cycle
aerobic
CO2
Glucose anabolism
Glucose storage:
glycogenesis
glycogen formation is
stimulated by insulin
glucose not needed
immediately is stored
in the liver (25%) and
in skeletal muscle
(75%)
Glucose release:
glycogenolysis
converts glycogen to
glucose
occurs between
meals, stimulated by
glucagon and
epinephrine
SIMPLISTIC SUMMARY:
-- Epinephrine and glucagon stimulate
glycogenolysis & inhibit glycogenesis
via a cAMP and a phosphorylation
cascade. release glucose
-- Glycogenesis is stimulated by
insulin in a pathway ending in the
dephosphorylation of glycogen
synthase.
-- Glycogenolysis is also inhibited
via dephosphorylation.
take up glucose
6Phosphogluconolactone
6Phosphogluconate
D-Ribulose5phosphate
RNA or
DNA
D-Ribose5phosphate
Oxidative branch
ATP
ADP
Glucose-6-P-dehydrogenase
NADP
NADPH
6-Phosphogluconate
Glucose 6-P
Glucose
NADP
6-Pgluconate dehydrogenase
Glyceraldehyde 3-P
TDP
Fructose 6-P
Transketolase
Non-oxidative branch
Ribulose 5-P
Xylulose 5-P
Glyceraldehyde 3-P
CO2
NADPH
Erythrose 4-P
Fructose 6-P
A scenario in which the cell requires NADPH but does not require ribose-5-P
Nucleic acids
Glyceraldehyde 3-P
TDP
Fructose 6-P
Transketolase
Ribulose 5-P
Xylulose 5-P
Glyceraldehyde 3-P
Erythrose 4-P
Fructose 6-P
ATP
Glucose
ADP
Glucose-6-P-dehydrogenase
NADP
NADPH
6-Phosphogluconate
Glucose 6-P
Ribulose 5-P
NADP
6-Pgluconate dehydrogenase
CO2
NADPH
Overview
Function
NADPH production
Reducing power
carrier
Synthetic pathways
Role as cellular
antioxidants
Ribose synthesis
Biosynthetic pathways
Characteristics:
Oxidative and Non-oxidative Phases
Oxidative phases
Reactions producing
NADPH
Irreversible
Non-oxidative phases
Produces ribose-5-P
Reversible reactions feed
to glycolysis
Glucose-6-P dehydrogenase
6-P-gluconate dehydrogenase
Regulation
Glucose-6-P dehydrogenase
Allosteric Regulation
First step
Rate limiting
Feedback inhibited by NADPH
Inducible enzyme
Induced by insulin
Ribose 5-phosphate
sugar used as the backbone of DNA and RNA
Cells requirement for ATP (glycolysis) or
NADPH and ribose 5-P (HMS) determines which
path it will take.
Stages of HMS
oxidation-reduction
isomerization stage
generation of NADPH
generation of ribose 5-phosphate
Production of superoxide
Antioxidant enzymes
Superoxide dismutase
Glutathione peroxidase
Glutathione reductase