Transcript ATP - Mhanafi123`s Blog

Dr.H.MOHAMMAD HANAFI, MBBS (Syd).MS.
MEDICAL FACULTY UNAIR
Blog : http//mhanafi123.wordpress.com
INTRODUCTION
Carbohydrate is a staple food of
Indonesian, as many others, specially of
Asian and African countries. In general,
the source of carbohydrate in food
derived from rice, but some are derived
from corn, sago, cassava, potatoes,
sweet potatoes, and bananas.
 In rice amylum is the major
component. Others are minerals,
vitamins, and fibers
 Amylum : amylopectin and
amylose
 Classification of Carbohydrate
• Hetero polysaccharides
• Homo polysaccharides
• Oligosaccharides
• Disaccharides
• Monosaccharide's
Digestion and absorption
• Amylase pancreas (alfa amylase)
• Endopolysaccharidase : break up alfa link
( 1  4 ), except on the tip of polymers,
and near the branch points.
• Result of digestion : glucose, maltose,
maltotriose, iso maltose, and
oligosaccharides (limit dextrins)
• Intestinal enzymes : maltase, lactase,
sucrase, limit dextrase etc.
• Active absorption : glucose and galactose
Blood & guts: Putting it together for
glucose transport…
glucose
Fig. 11-44
Transfer of Glucose and Other Sugars
Through The Lipid Bilayer
• Because the lipid bilayer of the eucaryotic plasma
membrane is impermeable for hydrophilic molecules,
glucose is transported across the plasma membrane
by membrane associated carrier proteins, glucose
transporters. There are 2 different types of
transporter proteins, which mediate the transfer of
glucose and other sugars through the lipid bilayer:
+
• Na -coupled carrier system (SGLT)
• The facilitative glucose transporters
(GLUT)
PATH WAYS IN CARBOHYDRATE
METABOLISM
 Glycolysis
 Glycogenesis
 Glycogenolysis
 Pyruvate oxidation
 TCA Cycle
(final common pathway)
 Hexose Mono-phosphate
Shunt or Pentose
Phosphate Pathway
 Gluconeogenesis
 Uronic Acid pathway
 Fructose and Galactose
metabolism
 Hexosamine
GLYCOLYSIS
• Change : glucose  pyruvate
glucose  lactic acid
• Function : produce ATP
• Site : cytoplasm
• Aerobic glycolysis forms 7 ATP
• Anaerobic glycolysis forms 2 ATP
Pyruvate
Lactate
G
 G 6P
HEXOKINASE
 Found in all cells
except pancreas
 Inhibited by ( G 6P )
 Km for glucose low
 Catalyze the reaction
Fructose (F)  F 6P
GLUCOKINASE
• Found in liver and
pancreas
• G 6P has no effect
• Km for glucose high
• The only enzyme for
G  G 6P
G 6P  F 6P
Phosphofructokinase
6 CH OPO 2
2
3
O
H
5
H
4
OH
6 CH OPO 2
2
3
1CH2OH
O
ATP ADP
HO
2
3 OH
H
fructose-6-phosphate
5
Mg2+
1CH2OPO32
H
H
4
OH
HO
2
3 OH
H
fructose-1,6-bisphosphate
Regulator enzyme
PFK-1
F 6P  F 1,6 BP One way reaction
PHOSPHO FRUCTO KINASE 1
( PFK 1 )
Activators :
• ADP
• AMP
• Pi
• NH3
• F 2,6 BP
( fructose 2,6 Bis
Phosphate )
• F6P
Inhibitors
 ATP
 Citric acid
 2,3 BP Glycerate
( in erythrocytes)
 Free Fatty Acid
 Acetyl-CoA
 Ketone bodies
Ketone bodies :
Acetoacetate
Betahydroxy Butyrate
Acetone
O
||
CCCCOOH
OH
|
CCCCOOH
O
||
CCC
UNIQUE ROLE OF 2,6 BP
In the liver
 The most potent positive allosteric
activator for enzyme
Phosphofructokinase-1 (PFK-1), and
 It relieves inhibition of PFK-1
by ATP, and ↑ affinity for F 6 P
 Inhibit Fructose 1,6-bisphosphatase
( ↑ Km for F 1,6 BP )
F 6P
 F2,6 BP
PFK-2
cAMP Dependent
Protein Kinase
Protein  Protein P
( few proteins )
Phosphofructokinase-2 (PFK-2) is also
a phosphatase (bifunctional enzyme)
Bifunctional enzyme has two activities:
• 6-phosphofructo-2-kinase activity, decreased by
phosphorylation
• Fructose-2,6-bisphosphatase activity, increased by
phosphorylation
kinase
ATP
ADP
fructose-2,6-bisphosphate
fructose-6-phosphate
Pi
phosphatase
2
CH
OPO
1
2
3
2C
O
HO 3C
H 4C
H
H
5
C
H
Aldolase
2
CH
OPO
2
3
3
OH
2C
OH
1CH2OH
2
CH
OPO
2
3
6
fructose-1,6bisphosphate
O
+
O
1C
H 2C OH
2
CH
OPO
3
2
3
dihydroxyacetone glyceraldehyde-3phosphate
phosphate
Triosephosphate Isomerase
F 1,6 BP
Gld 3P + DHAP
Triosephosphate Isomerase
H
H
C
OH
C
O
+
H H
CH2OPO32
dihydroxyacetone
phosphate
+
H
OH
H H
C
C
+ +
H
OH
CH2OPO32
enediol
intermediate
O
C
H
C
OH
CH2OPO32
glyceraldehyde3-phosphate
In Glycolysis DHAP is converted into
glyceraldehyde -3P
Glyceraldehyde-3-phosphate
Dehydrogenase
H
O
1C
H
2
C
OH
OPO32
+ H+ O
NAD+ NADH
1C
+ Pi
H C OH
2
CH
OPO
2
3
3
glyceraldehyde3-phosphate
2
2
CH
OPO
2
3
3
1,3-bisphosphoglycerate
6. Glyceraldehyde-3-phosphate Dehydrogenase
catalyzes:
glyceraldehyde-3-P + NAD+ + Pi 
1,3-bisphosphoglycerate + NADH + H+
If oxygen available Respiratory Chain
in function, by mean of Malate shuttle
system oxidizes NADH
in the resp. syst ; 2.5 ATP released
NAD+ recovered, catalyzed by
malate dehydrogenase
Enzyme glyceraldehyde 3P dehydrogenase
required NAD+ in function
If R. C. not in function,
NADH will reduces Pyruvate into Lactate
Exergonic oxidation of the aldehyde
in glyceraldehyde-3-phosphate, to a
carboxylic acid, drives formation of
an acyl phosphate, a "high energy"
bond (~P).
This is the only step in Glycolysis in
which NAD+ is reduced to NADH.
Phosphoglycerate Kinase
O
OPO32 ADP ATP O
O
1C
H 2C OH
2
CH
OPO
2
3
3
1,3-bisphosphoglycerate
C
1
Mg2+
H 2C OH
2
CH
OPO
2
3
3
3-phosphoglycerate
This phosphate transfer is reversible (low ∆G), since
one ~P bond is cleaved & another synthesized.
The enzyme undergoes substrate-induced conformational
change similar to that of Hexokinase.
Phosphoglycerate Mutase
O
O

C
1
C
1
H 2C OH
3 CH2OPO3
O
O

H 2C OPO3
2
3-phosphoglycerate
2
3 CH2OH
2-phosphoglycerate
Phosphate is shifted from the OH
on C3 to the OH on C2.
Fluoride
(-)
Enolase
O
O

C
1
H 2 C OPO32
3 CH2OH
H

O
O

C
C
OH
O
O
1
OPO32
CH2OH
C
2C
OPO32
3 CH2
2-phosphoglycerate enolate intermediate phosphoenolpyruvate
Fluoride in tooth paste inhibits oral bacterial growth
F is also used in glucose determination
Pyruvate Kinase
O
O
ADP ATP
C
1
C
2
O
O
O
O
C
C
1
OPO32
3 CH2
phosphoenolpyruvate
C
2
1
OH
C
2
3 CH2
enolpyruvate
O
3 CH3
pyruvate
This phosphate transfer from PEP to ADP is spontaneous.
 PEP has a larger ∆G of phosphate hydrolysis than ATP.
 Removal of Pi from PEP yields an unstable enol, which
spontaneously converts to the keto form of pyruvate.
Required inorganic cations K+ and Mg++ bind to anionic residues at
the active site of Pyruvate Kinase.
Pyruvate Kinase
activity
Activators :
 F 1,6 BP
In the liver F 1,6 BP
able to abolish inhibition
of ATP and Alanine
Inhibitors :
• ATP
• Free Fatty Acid
• Acetyl CoA
• Ketone bodies
• Alanine
(in liver only)
Protein Kinase (P.K.) controls in
Glycogen.
• cAMP dependent Protein Kinase
activated by cAMP.
• cAMP synthesized from ATP
• enzyme adenylyl cyclase
• Glucagon activates adenylyl
cyclase (through G protein)
cAMP Dependent Protein Kinase
inhibits Glycolysis in two sites
1. PFK-1, with
decreasing F2,6 BP.
PFK-2-P catalyzes
F2,6 BP  F6P + Pi.
Active cAMP
Dependent P.K.
converts
PFK-2  PFK-2-P
( ATP  ADP )
2.Inactive Pyruvate
Kinase
PEP  P
Pyruvate Kinase 
PK-P
Pyruvate Kinase is
phosphorylated by
cAMP Dependent P.K.
Pyruvate Kinase
phosphate
(PK-P) is inactive
If oxygen available
for respiratory chain activity,
Pyruvate is the end product of Glycolysis
with 7 ATP as high energy phosphate.
( older textbook still counting as 8 ATP).
In unaerobic Glycolysis of certain type of muscle
for sprinters, lack of oxygen cause inactive
respiratory chain. NADH will reduces Pyruvate,
and Lactate is the final product of Glycolysis.
NAD+ is ready as coenzyme for Glyceraldehyde
3P dehydrogenase
Lactate Dehydrogenase
O
O
C
C
NADH + H+ NAD+
O
CH3
pyruvate
O
O
C
HC
OH
CH3
lactate
NAD+ is the target product. Lactate is the by product.
Lactate is one of the substrate of gluconeogenesis, will
be taken up by the liver and changed into glucose.
Glycolysis in Erythrocyte
No mitochondria
No Respiratory enzymes
NADH reduces Pyruvate into Lactate
2,3 BP Glycerate
 drives oxygen dissociation of
Oxy hemoglobin to release Oxygen
 inhibits PFK-1
In the tissue where
oxygen required
but not ATP,
1,3 BP Glycerate
is converted into
2,3 BP Glycerate
Lactate release .
Tissues that normally derive much of their
energy from glycolysis and produce
lactate include brain, gastrointestinal
tract, renal medulla, retina, and skin.
Lactate production is also increased in
septic shock, and many cancers also
produce lactate.