1. Intermediary metabolism
Vladimíra Kvasnicová

2. Intermediary metabolism relationships (saccharides, lipids, proteins)
after feeding (energy intake in a diet)
oxidation → CO2, H2O, urea + ATP
formation of stores → glycogen, TAG
Urea

3. Glycogen reducing end nonreducing end
The figures were found (May 2007) at

4. 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)

5. The figure was adopted from Devlin, T. M
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, ISBN 0‑471‑15451‑2

6. The figure was adopted from Devlin, T. M
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, ISBN 0‑471‑15451‑2

7. 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

8. acetyl-Co A pyruvate NADH
Major intermediates
acetyl-Co A
pyruvate
NADH

9. acetyl-CoA 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 !!!

10. degradation of some amino acids
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)

11. respiratory chain → reoxidation to NAD+ ! OXYGEN SUPPLY IS NECESSARY!
aerobic glycolysis
PDH reaction
-oxidation
citrate cycle
oxidation of ethanol
NADH
respiratory chain → reoxidation to NAD+
energy storage in ATP
! OXYGEN SUPPLY IS NECESSARY!

12. NADH pyruvate → lactate
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!

13. The most important is to answer the questions:
WHERE?
WHEN?
HOW?
compartmentalization of the pathways
starve-feed cycle
regulation of the processes

14. Compartmentalization of mtb pathways
The figure is found at (May 2007)

15. 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

16. 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)

17. 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)

18. Golgi Apparatus Nucleus
posttranslational modification of proteins
protein sorting
export of proteins (formation of vesicules)
Ribosomes
proteosynthesis
Nucleus
replication and transcription of DNA
synthesis of RNA

19. Lysosomes Peroxisomes
hydrolysis of proteins, saccharides, lipids and nucleic acids
Peroxisomes
oxidative reactions involving O2
use of hydrogen peroxide
degradation of long chain FA (from C20)

20. Starve-feed cycle
relationships of the metabolic pathways under various conditions
cooperation of various tissues
see also (Metabolic Interrelationships)

21. 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, ISBN 0‑471‑15451‑2

22. 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, 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, 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, ISBN 0‑471‑15451‑2

25. The figure was adopted from Devlin, T. M
The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 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, 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

28. 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

29. 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

30. 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

31. 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

32. =  detoxification of NH3 from degrad. of prot.
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.

33. 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

34. 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)

35. 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)

36. 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

37. 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

38. 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

39. 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

40. 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!

41. Reversible covalent modification:
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: (December 2006)

42. 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