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Intermediary metabolism

Intermediary metabolism. Vladimíra Kvasnicová. Intermediary metabolism relationships (saccharides, lipids, proteins). after feeding (energy intake in a diet) oxidation → CO 2 , H 2 O, urea + ATP formation of stores → glycogen, TAG. Urea. Glycogen. reducing end. nonreducing end.

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Intermediary metabolism

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  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 http://www.wellesley.edu/Chemistry/chem227/sugars/oligo/glycogen.jpghttp://students.ou.edu/R/Ben.A.Rodriguez-1/glycogen.gif, http://fig.cox.miami.edu/~cmallery/255/255chem/mcb2.10.triacylglycerol.jpg

  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. (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

  7. glycogenesis gluconeogenesis lipogenesis synthesis of FA ketogenesis proteosynthesis urea synthesis glycogenolysis glycolysis lipolysis -oxidation ketone bodies degr. proteolysis degradation of AA Principal metabolic pathways of the intermediary metabolism: CITRATE CYCLE, RESPIRATORY CHAIN

  8. Major intermediates acetyl-Co A pyruvate NADH

  9. 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. 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. 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. 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 http://fig.cox.miami.edu/~cmallery/150/proceuc/c7x7metazoan.jpg (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 • 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 • 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 pathwaysunder various conditions • cooperation of various tissues • see also http://www2.eur.nl/fgg/ow/coo/bioch/#english(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, 1997. 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, 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. 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

  28. enterocyte: Gln citrulline blood  kidneys • kidneys: citrulline Arg blood  liver • liver: Arg  urea + ornithine ornithine → increased velocity of theUREA CYCLE =  detoxification of NH3 from degrad. of prot.

  29. 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

  30. 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)

  31. II. Regulation on the cell level • compartmentalization of mtb pathways • change of enzyme concentration(on the level of synthesis of newenzyme ) • change of enzyme activity(an existingenzyme is activated or inactivated)

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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!

  37. 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/JpegArt1-13/05jpeg/05_jpeg_HTML/index.htm (December 2006)

  38. Modulatorsof 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

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