Intermediary metabolism

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Intermediary metabolism

• Vladimíra Kvasnicová

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Intermediary metabolism relationships(saccharides
, lipids, proteins)

• after feeding (energy intake in a diet)
• oxidation ? CO2, H2O, urea ATP
• formation of stores ? glycogen, TAG

Urea
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Glycogen
reducing end
nonreducing 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

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Intermediary metabolism relationships(saccharides
, lipids, proteins)

• 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)

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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
6
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
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Principal metabolic pathways of the intermediary
metabolism

• glycogenolysis
• glycolysis
• lipolysis
• ?-oxidation
• ketone bodies degr.
• proteolysis
• degradation of AA

• glycogenesis
• gluconeogenesis
• lipogenesis
• synthesis of FA
• ketogenesis
• proteosynthesis
• urea synthesis

CITRATE CYCLE, RESPIRATORY CHAIN
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Major intermediates

• acetyl-Co A
• pyruvate
• NADH

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• 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 !!!

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• 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)

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• aerobic glycolysis
• PDH reaction
• ?-oxidation
• citrate cycle
• oxidation of ethanol
• NADH
• respiratory chain ? reoxidation to NAD
• energy storage in ATP
• ! OXYGEN SUPPLY IS NECESSARY!

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• 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!

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The most important is to answer the questions

• WHERE?
• WHEN?
• HOW?
• compartmentalization of the pathways
• starve-feed cycle
• regulation of the processes

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Compartmentalization of mtb pathways
The figure is found at http//fig.cox.miami.edu/c
mallery/150/proceuc/c7x7metazoan.jpg (May 2007)
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• Cytoplasm
• 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

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• Mitochondrion
• 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)

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• 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)

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• 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

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• 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)

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Starve-feed cycle

• relationships of the metabolic pathwaysunder
  various conditions
• cooperation of various tissues
• see also http//www2.eur.nl/fgg/ow/coo/bioch/engl
  ish (Metabolic Interrelationships)

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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
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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
23
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
24
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
25
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
26
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
27
WELL-FED STATE FASTING STATE
hormones ? insulin ? glucagon, adrenaline, cortisol
response of the body ? glycemia ? lipogenesis ? proteosynthesis ? glycemia ? lipolysis? ketogenesis ? proteolysis


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WELL-FED STATE FASTING STATE
hormones ? insulin ? glucagon, adrenaline, cortisol
response of the body ? glycemia ? lipogenesis ? proteosynthesis ? glycemia ? lipolysis? ketogenesis ? proteolysis
source of glucose from food from stores (glycogen) gluconeogenesis
fate of glucose glycolysis formation of stores glycolysis
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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


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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
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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) or
• ? degradation of body proteins (starvation)
• ? concentration of glutamine

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• 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.

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General Principles of Regulation

• catabolic / anabolic processes
• 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

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I. Regulation on the organism level

• signal transmission among cells(signal
  substances)
• signal transsduction through the cell membrane
• influence of enzyme activity
• induction of a gene expression
• interconversion of existing enzymes
  (phosphorylation / dephosphorylation)

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II. Regulation on the cell level

• compartmentalization of mtb pathways
• change of enzyme concentration(on the level of
  synthesis of new enzyme )
• change of enzyme activity(an existing enzyme is
  activated or inactivated)

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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

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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

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3. Change of activity of an existing enzyme

• in relation to an enzyme kinetics
• concentration of substrates (? Km)
• availability of coenzymes
• consumption of products
• pH changes
• substrate specificity - different Km

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3. Change of activity of an existing enzyme

• 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

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• 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!

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• 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.peach
net.edu/sm/kmccrae/BIOL2050/Ch1-13/JpegArt1-13/05j
peg/05_jpeg_HTML/index.htm (December 2006)
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• 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