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Atip Likidlilid
METABOLISM
• Living organisms maintain complex
order in dynamic steady state by
importing food and energy from their
surroundings.
• transformation of matter and energy to
create complex molecules from simple
ones by enzyme-catalyzed reactions
METABOLIC PATHWAYS
• series of consecutive enzymatic
reactions that produce specific
products
• products of reactions
metabolites
(metabolic intermediates)
End products
Principal characteristics
of metabolic pathways
1.Metabolic pathways are
irreversible
 highly exergonic
 reactions go to completion
A
1
2
Y
X
If cells require metabolite
1
2
2
1
2
turn on
turn off
Independent
control
2. Every metabolic pathway has
a first committed step
•
irreversible ( exergonic ) reaction commits
the intermediates down the pathway
3. All metabolic pathways
are regulated
• the first committed step is too slow to
permit its substrate and product to
equilibrate
• most of other reactions in a pathway
function close to equilibrium
• committed step = rate-limiting step
4.
Metabolic pathways in
eukaryotic cells occur in
specific cellular locations
• biological membranes are selectively
permeable to metabolites
• specific transport protein
Metabolic reaction mechanisms
1. group-transfer reactions
2. oxidations and reductions
3. eliminations , isomerization and
rearrangements
4. reactions that make or break C-C
bonds
Metabolic categories
• catabolism ( degradation )
• anabolism ( biosynthesis)
complex metabolites
2-
ADP + HPO 4
NADP
+
degradation
biosynthesis
NADPH
ATP
simple products
CATABOLISM
1. digestion and absorption
starch
sucrose
lactose
cellulose
salivary amylase
starch
starch dextrin
+ glucose
+ maltose
HCl stops action of
amylase
Pancreatic amylase
starch
dextrins
+ maltose
+ isomaltose
mucosal cells
(brush border)
maltase , lactase , invertase ,
isomaltase , dextrinase
glucose , fructose , galactose
Portal circulation
liver
cellulose
galactose , frutose
from portal circulation
glucose
Glucose in systemic
circulation
peripheral tissue
Transport of monosaccherides
into tissues
• 1. Na+ - dependent glucose transport
Phlorhizin (plant glycoside) - inhibitor
• 2. Facilitated glucose transport
Cytochalasin (from mold) – inhibitor
(GLUT5)
Transporter
Tissue distribution
1. Sodium-dependent unidirectional transporter
SGLT 1 (ใช้ พลังงาน)
small intestine,kidney
2. Facilitated bidirectional transporters
GLUT1
red cells,blood brain barrier,kidney,
colon
GLUT2
liver,pancreatic B-cells,small intestine
GLUT3
neuron,placenta,testes
GLUT4
(ใช้ insulin)
GLUT5 (fructose uptake)
fat,skeletal muscle,heart
small intestine,testes
Glycolysis (Pasteur effect)
• anaerobic glycolysis (oxygen debt)
glucose
lactate
• aerobic glycolysis (oxygen load)
glucose
pyruvate
Pathway of glycolysis
(cytosol)
Stage 1 : formation of glucose 6 - P
hexose (fructose,galactose)
hexokinase
glucose
hexose 6- P
glycogen
ATP
hexokinase
phosphorylase
Pi
ADP
glucose 1- P
glucose 6- P
phosphoglucomutase
glycolysis
Stage 2 : split
G-6- P
2 Triose- P
G-6- P
Phosphohexose isomerase
Fructose-6- P
*
ATP
Phosphofructokinase-1
ADP
Fructose-1,6-bis P
Aldolase
Glyceraldehyde3- P
Triose- P isomerase
Dihydroxyacetone
phosphate
(DHAP) (95%)
Stage 3:
Glyceraldehyde-3- P
Pyruvate
Gly-3- P
Pi + NAD
+
Gly-3- P dehydrogenase
+
NADH+H
aerobic O
2
via cytochrome
1,3-bis P - glycerate
ADP
Phosphoglycerate kinase
* ATP
3- P - glycerate
Phosphoglycerate mutase
2- P - glycerate
Enolase
H2 O
2- P - enolpyruvate
ADP
* ATP
Pyruvate kinase
(couple reaction)
2- enolpyruvate
Pyruvate kinase
pyruvate
NADH+H+
Lactate dehydrogenase
NAD+
lactate
* substrate level phosphorylation
(anaerobic)
Energetics of glycolysis
ATP/mole of glucose
glycolysis
anaerobic
aerobic
1. hexokinase
2. phosphofructokinase-1
3. phosphoglycerate kinase
-1
-1
+2
-1
-1
+2
4. pyruvate kinase
+2
-
+2
+4 (+6)
+2
+6(+8)
5. 2 (NADH.H+
total
NAD+)
Inhibitors in glycolysis
1. glyceraldehyde-3- P dehydrogenase
• 1.1 Iodoacetate (ICH2COO-)
– SH group of cysteine residue in active site
of the enzyme by covalent bond
•
1.2 Arsenate (AsO43-) (uncoupler)
competitve inhibitor of Pi
– uncouple oxidation and phosphorylation
–
2. enolase : required Mg2+ for activity
–
Fluoride (F-) forms tightly bound complex
with Mg2+ at the active site
Regulation of glycolysis
•
3 allosteric enzymes
• catalyzed non equilibrium reactions
Enzymes
Inhibitors
HK
PFK-1*
-
G-6- P
ATP,citrate,PEP
( rate limiting enzyme )
PK
Activators
ATP , alanine ,
fatty acid,acetyl CoA
ADP,AMP,
cAMP
(by insulin),
FBP (F-2,6- P )
F-6- P ,
NH4+, Pi
FBP
Oxidation of pyruvate to acetyl Co A
• pyruvate transporter (mitochondria)
• pyruvate dehydrogenase complex
– pyruvate dehydrogenase ( E1) ( TPP )
– dihydrolipoamide acetyltransferase
( E2 ) ( lipoic acid )
– dihydrolipoamide reductase
( E3 ) ( FAD , NAD )
pyruvate + NAD+ + Co A
TPP
Acetyl Co A + NADH.H+ + CO2
Regulation of
pyruvate dehydrogenase complex
1. Control by product inhibitor
- NADH , acetyl Co A และ ATP
2. Comtrol by product activator
- pyruvate, ADP, Ca2+
Inhibitors of PDH complex
• arsenite ( AsO2- ) and Hg2+ (mercuric ion )
complex -SH of E2
• lactic acidosis
• neurologic disturbances