Transcript Intermediary metabolism

Intermediary metabolism
Vladimíra Kvasnicová
Intermediary metabolism relationships
(saccharides, lipids, proteins)
1. after feeding (energy intake in a diet)
 oxidation → CO2, H2O, urea + ATP
 formation of stores → glycogen, TAG
Urea
Glycogen
nonreducing
end
reducing
end
The figures were found (May 2007) at http://www.wellesley.edu/Chemistry/chem227/sugars/oligo/glycogen.jpg
http://students.ou.edu/R/Ben.A.Rodriguez-1/glycogen.gif, http://fig.cox.miami.edu/~cmallery/255/255chem/mcb2.10.triacylglycerol.jpg
Intermediary metabolism relationships
(saccharides, lipids, proteins)
2. during fasting
 use of energy stores
•
glycogen → glucose
•
TAG → fatty acids
 formation of new energy substrates
•
gluconeogenesis (glycerol, muscle proteins)
•
ketogenesis (storage TAG → FFA → ketone bodies)
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
Principal metabolic pathways of the
intermediary metabolism:
• glycogenesis
• glycogenolysis
• gluconeogenesis
• glycolysis
• lipogenesis
• lipolysis
• synthesis of FA
• -oxidation
• ketogenesis
• ketone bodies degr.
• proteosynthesis
• proteolysis
• urea synthesis
• degradation of AA
CITRATE CYCLE, RESPIRATORY CHAIN
Major intermediates
acetyl-Co A
pyruvate
NADH
pyruvate (PDH) – i.e. from glucose
amino acids (degrad.) – from proteins
fatty acids (-oxidation) – from TAG
ketone bodies (degrad.) – from FA
acetyl-CoA
citrate cycle, RCH → CO2, H2O, ATP
synthesis of FA
synthesis of ketone bodies
synthesis of cholesterol
synthesis of glucose !!!
aerobic glycolysis
oxidation of lactate (LD)
degradation of some amino acids
pyruvate
acetyl-CoA (PDH)
lactate (lactate dehydrogenase)
alanine (alanine aminotransferase)
oxaloacetate (pyruvate carboxylase)
glucose (gluconeogenesis)
aerobic glycolysis
PDH reaction
-oxidation
citrate cycle
oxidation of ethanol
NADH
respiratory chain → reoxidation to NAD+
energy storage in ATP
! OXYGEN SUPPLY IS NECESSARY!
aerobic glycolysis
PDH reaction
-oxidation
citrate cycle
oxidation of ethanol
NADH
pyruvate → lactate
respiratory chain → reoxidation to NAD+
energy storage in ATP
! OXYGEN SUPPLY IS NECESSARY!
The most important is to answer the
questions:
WHERE?
WHEN?
HOW?
 compartmentalization of the pathways
 starve-feed cycle
 regulation of the processes
Compartmentalization of mtb pathways
The figure is found at http://fig.cox.miami.edu/~cmallery/150/proceuc/c7x7metazoan.jpg (May 2007)
Cytoplasm
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glycolysis
gluconeogenesis (from oxaloacetate or glycerol)
metabolism of glycogen
pentose cycle
synthesis of fatty acids
synthesis of nonessential amino acids
transamination reactions
synthesis of urea (a part; only in the liver!)
synthesis of heme (a part)
metabolism of purine and pyrimidine
nucleotides
Mitochondrion
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pyruvate dehydrogenase complex (PDH)
initiation of gluconeogenesis
-oxidation of fatty acids
synthesis of ketone bodies (only in the liver!)
oxidation deamination of glutamate
transamination reactions
citrate cycle
respiratory chain (inner mitochondrial membrane)
aerobic phosphorylation (inner mitoch. membrane)
synthesis of heme (a part)
synthesis of urea (a part)
Endoplasmic Reticulum
Smooth ER
• synthesis of triacylglycerols and phospholipids
• elongation and desaturation of fatty acids
• synthesis of steroids
• biotransformation of xenobiotics
• glucose-6-phosphatase
Rough ER
• proteosynthesis
(translation and posttranslational modifications)
Golgi Apparatus
• posttranslational modification of proteins
• protein sorting
• export of proteins (formation of vesicules)
Ribosomes
• proteosynthesis
Nucleus
• replication and transcription of DNA
• synthesis of RNA
Lysosomes
• hydrolysis of proteins, saccharides, lipids and
nucleic acids
Peroxisomes
• oxidative reactions involving O2
• use of hydrogen peroxide
• degradation of long chain FA (from C20)
Starve-feed cycle
• relationships of the metabolic pathways
under various conditions
• cooperation of various tissues
• see also
http://www2.eur.nl/fgg/ow/coo/bioch/#english
(Metabolic Interrelationships)
1) Well-fed
state
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
2) Early
fasting state
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
3) Fasting
state
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
4) Early
refed state
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
Changes of liver glycogen content
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
hormones
response of
the body
WELL-FED STATE
FASTING
STATE
 insulin
 glucagon,
adrenaline, cortisol
 glycemia
 lipogenesis
 proteosynthesis
 glycemia
 lipolysis
 ketogenesis
 proteolysis
WELL-FED STATE
FASTING
STATE
 insulin
 glucagon,
adrenaline, cortisol
 glycemia
 lipogenesis
 proteosynthesis
 glycemia
 lipolysis
 ketogenesis
 proteolysis
source of
glucose
from food
from stores
(glycogen)
gluconeogenesis
fate of
glucose
glycolysis
formation of stores
glycolysis
hormones
response of
the body
WELL-FED STATE
FASTING
STATE
source of
fatty acids
from food TAG
from storage TAG
fate of
fatty acids
-oxidation
synthesis of TAG
 -oxidation
ketogenesis
WELL-FED STATE
FASTING
STATE
source of
fatty acids
from food TAG
from storage TAG
fate of
fatty acids
-oxidation
synthesis of TAG
 -oxidation
ketogenesis
source of
amino acids
from food
from muscle
proteins
fate of
amino acids
proteosynthesis
oxidation
lipogenesis
gluconeogenesis
Metabolism of ammonia
- the importance of glutamine • synthesis of nucleotides ( nucleic acids)
• detoxification of amino N (-NH2 transport)
• synthesis of citrulline (used in urea cycle):
 intake of proteins in a diet (fed state)
 degradation of body proteins (starvation)
 concentration of glutamine
or
• enterocyte:
Gln  citrulline  blood  kidneys
• kidneys:
citrulline  Arg  blood  liver
• liver:
Arg  urea + ornithine
ornithine → increased velocity of the UREA CYCLE
=  detoxification of NH3 from degrad. of prot.
General Principles of Regulation
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catabolic / anabolic processes
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last step of each regulation mechanism:
change of a concentration of an active
enzyme (= regulatory or key enzyme)
•
regulatory enzymes
 often allosteric enzymes
 catalyze higly exergonic reactions
(irreverzible)
 low concentration within a cell
I. Regulation on the organism level
1.
signal transmission among cells
(signal substances)
2. signal transsduction through the cell membrane
3. influence of enzyme activity:
 induction of a gene expression
 interconversion of existing enzymes
(phosphorylation / dephosphorylation)
II. Regulation on the cell level
1.
compartmentalization of mtb pathways
2. change of enzyme concentration
(on the level of synthesis of new enzyme )
3. change of enzyme activity
(an existing enzyme is activated or
inactivated)
1. Compartmentalization of mtb patways
• transport processes between compartments
• various enzyme distribution
• various distribution of substrates and
products ( transport)
• transport of coenzymes
• subsequent processes are close to each other
2. Synthesis of new enzyme molecules:
• induction by substrate or repression by product
(on the level of transcription)
examples:
 xenobiotics  induction of cyt P450
 heme  repression of delta-aminolevulate synthase
3. Change of activity of an existing enzyme
a) in relation to an enzyme kinetics
 concentration of substrates ( Km)
 availability of coenzymes
 consumption of products
 pH changes
 substrate specificity - different Km
3. Change of activity of an existing enzyme
b) activation or inactivation of the enzyme
•
covalent modification of the enzymes
 interconversion: phosphorylation/dephosphorylation)
 cleavage of an precursore (proenzyme, zymogen)
•
modulation of activity by modulators (ligands):
 feed back inhibition
 cross regulation
 feed forward activation
Phosphorylation / dephosphorylation
• some enzymes are active in a phosphorylated
form, some are inactive
• phosphorylation:
 protein kinases
 macroergic phosphate as a donor of the phosphate
(ATP!)
• dephosphorylation
 protein phosphatase
 inorganic phosphate is the product!
Reversible covalent
modification:
A)
• phosphorylation by
a protein kinase
• dephosphorylation by
a protein phosphatase
B)
• phosphorylated enzyme
is either active or
inactive
(different enzymes are
influenced differently)
The figure is found at: http://stallion.abac.peachnet.edu/sm/kmccrae/BIOL2050/Ch1-13/JpegArt113/05jpeg/05_jpeg_HTML/index.htm (December 2006)
Modulators of enzyme activity
(activators, inhibitors)
• isosteric modulation: competitive inhibition
• allosteric modulation:
 change of Km or Vmax
 T-form (less active) or R-form (more active)
• important modulators: ATP / ADP