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Gluconeogenesis: Defined as biosynthesis of glucose from non-carbohydrate precursors
-Gluconeogenesis: an intro
-Thermodynamic Barriers (Each barrier detail explanation)
- Energetics of gluconeogenesis
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These are major source of energy for living organisms.
Supplying a huge array of metabolic intermediates for biosynthetic reactions.
The structural elements in cell coat or connective tissues.
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2. Recommended intake of nutrients SAFA 5 % MUFA 20 % PUFA 5 % Essential FA: linoleic, α -linolenic Semiessential FA: arachidonic Essential AA: Phe, Trp, Val, Leu, Ile, Met, Thr, Lys, His Semiessential AK: Arg (childhood), Ala, Gln (metab . stress) 60 % 30 % 10 % Starch Lipids Proteins Percentage of energy intake/day Nutrient
3. ATP ATP ATP Phases of catabolism I II III Resp. ch. Acetyl-CoA Pyruvate Reduced cofactors NADH + H + , FADH 2 C O 2 Glucose Fatty acids Amino acids Saccharides Lipids Proteins Citric acid cycle
4.
5.
6. Compare different ways of pyruvate de c arboxyla tion pyruvate simple decarboxylation acetaldehyde acetic acid oxidative decarboxylation in vitro oxidative decarboxylation in vivo
12. Balance reaction Pyruvate dehydrogenase is allosterically inhibited by end products: ac etyl-CoA + NADH CH 3 -CO-COOH + CoA-SH + NAD + CO 2 + CH 3 -CO-S-CoA + NADH+H +
13.
14.
15. (2) Citrate Isocitrate Reaction type: isomeration Enzyme: aconitase Cofactor: Fe-S Note: two-step-reaction, intermediate is cis -aconitate C C H 2 C O O H C O O H C H 2 H O C O O H C H C H 2 C O O H C H C O O H H O C O O H tertiary hydroxyl group secondary hydroxyl group citrate isocitrate
16. (2a) Dehydration of citrate citrate C C H 2 C O O H C O O H C H O C O O H H H H 2 O C C C O O H H C H 2 C O O H H O O C cis -aconitate
17. (2b) Hydratation of cis-aconitate stereospecific rea ction C H C H 2 C O O H C H C O O H H O C O O H C C C O O H H C H 2 C O O H H O O C cis -aconitate H 2 O isocitrate
18. Aconitase is inhibited by f luor o acet ate Dichapetalum cymosum ( see also Med. Chem. II, p . 65 ) FCH 2 COOH reacts with oxaloacetate to give fluorocitrate CAC is stopped LD 50 for human is 1 mg/kg rat poison
20. (4) 2-Oxoglutarate succinyl-CoA Reaction type: oxidative decarboxylation Enzyme: 2-oxoglutarate dehydrogenase complex Cofactors: TDP, lipoate, CoA-SH, FAD, NAD + Note: irreversible , similar to pyruvate dehydrogenase reaction (five coenzymes) C H 2 C H 2 C O O H C C O O H O + N A D H + H + N A D + - C H 2 C H 2 C O O H C O S C o A + C O 2 2-oxoglutarate succinyl-coenzyme A thioester macroergic intermediate H S C o A
21. (5) Succinyl-CoA + GDP + P i Reaction type: substrate phosphorylation Enzyme: succinyl-CoA synthetase (succinate thiokinase) Cofactor: coenzyme A + C H 2 C H 2 C O O H C O S C o A + + G D P P i C H 2 C H 2 C O O H C O O H G T P succinyl-coenzyme A succinate origin of oxygen ? - coenzyme A
22.
23. (5a) Addition of phosphate to succinyl-CoA mixed anhydride four oxygen atoms in phosphate P O O O O H C O O C H 2 C H 2 C O S C o A H S C o A C O O C H 2 C H 2 C O O P O O O succinyl-CoA succinylphosphate
24. (5b) Phosforylation of His in the active site of enzyme substituted phosphoamide N N H E n z y me C O O C H 2 C H 2 C O O P O O O C O O C H 2 C H 2 C O O succinylphosphate succinate phospho-His N N E n z y me P O O O H +
25. (5c) Phosforylation of GDP N N N N O H 2 N H O O H O H O P O O O P O O O N N E n z y me P O O O N N N N O H 2 N H O O H O H O P O O O P O O O P O O O guanosine diphosphate guanosine triphosphate N N H E n z y me H +
26. Distinguish -PO 3 2- HPO 4 2- (P i ) phosphate inorganic P O O O P O O O O H phosphoryl phosphate
27. GTP is quickly converted to ATP GTP + ADP ATP + GDP nucleoside-diphosphate kinase
28. (6) Succinate fumarate Reaction type: dehydrogenation (-CH 2 -CH 2 - bond) Enzyme: succinate dehydrogenase Cofactor: FAD C O O H C H 2 C H 2 C O O H + FAD C C C O O H H H O O C H - II - II - I - I + F A D H 2 succinate fumarate
29. M alonate is c ompetitiv e inhibitor of succinate dehydrogenase Do not confuse : malon ate × mal ate C O O C H 2 C H 2 C O O C O O C H 2 C O O succinate malonate
30. (7) Fumarate L-malate Reaction type: hydration Enzyme: fumarase Cofactor: none Notes: 1) addition of water on double bond is stereospecific 2) hydration is not redox reaction - II + H 2 O C O O H C H C H 2 H O C O O H 0 fumarate L-malate = -II = -II C C C O O H H H O O C H - I - I
31. Distinguish : hydrol ysis × hydrat ion substr a t e + H 2 O substr ate + H 2 O + Hydrol ysis = decomposition of substrate by the action of water ( typical in ester s , amid es , peptid es , gly c osid es , anhydrid es ) Hydrat ion = a d di tion of water ( to unsaturated substrates) produ c t 2 OH produ c t 1 H produ c t OH H
32. Compare : Hydration of fumarate in vivo and in vitro in vivo : ( enzymatic reaction) : only one enantiomer is formed (L-malate) in vitro: formation of racemate C C C O O H H H O O C H H H O H H O C C O O H C H 2 C O O H O H H C C O O H C H 2 C O O H H H O L-malate D-malate C C C O O H H H H O O C H O H Enzyme Substrate
33. (8) L-malate oxalacetate Reaction type: dehydrogenation Enzyme: malate dehydrogenase Cofactor: NAD + C O O H C H C H 2 H O C O O H + N A D + C O O H C C H 2 C O O H O + N A D H H + + L-malate oxaloacetate
34.
35.
36.
37. Key enzymes for regulation of citrate cycle a allosteric inhibitor b feed-back inhibito r (inhibition by a product) c allosteric a c tiv a tor succinyl-CoA b 2-OG dehydrogenase ADP c Isocitrate dehydrogenase citrate b Citrate synthase acetyl-CoA b Pyruvate dehydrogenase Other effect NADH a ATP a Enzyme
38.
39. Carboxylation of pyruvate (biotin) B i o t i n C O O H H 3 C C O C O O H B i o t i n H C H 2 C O C O O H H O O C pyruvate oxaloacetate pyruvate carboxylase
40. Reductive carboxylation of pyruvate Reaction is more important for production of NADPH for reductive synthesis ( FA , cholesterol) malic enzyme (malate dehydrogenase decarboxylating) C O O H C C H 3 O C O O NADP H + H C O O H C C H 2 H O H C O O H L-malate NADP
41.
42. Catabolic processes - entries into the cycle Leu, Ile Phe, Tyr, Lys, Trp oxaloacetate fumarate succinyl-CoA 2-oxoglutarate CC acetyl-CoA Phe, Tyr ureosynthesis purine synthesis Ile, Val, Met, Thr Arg, Glu, Gln, His, Pro Asp, Asn pyruvate Ala, Cys, Gly, Ser, Thr, Trp fatty acids glucose
43. Anabolic processes – intermediates for syntheses citrate Fatty acids, steroids Intermediates drawn off for biosyntheses are replenished by anaplerotic reactions oxaloacetate succinyl-CoA 2-oxoglutarate CC malate porphyrines, heme (collector of amino groups) pyruvate + NADPH aspartate purine pyrimidine phosphoenolpyruvate g l u co se glutamate
44. CAC a nd the synt hesis of lipid s ATP TAG malate FA synthesis CAC mitochondria citrate cytosol citrate oxaloacetate acetyl-CoA malic enzyme C O 2 N A D P H H + + + + pyruvate
45. CAC and t ransamination oxaloacetate 2-oxoglutarate CAC aspartate glutamate
46. Vitamins necessary for CAC Try to complete Pantothenic acid Thiamin Niacin Riboflavin Reaction in citrate cycle Vitamin
47. Relationships among the major energy metabolism pathways GLYCOGEN Glucose FAT STORES TRIACYLGLYCEROLS FATTY ACIDS PROTEINS Gluco genic AA ( non-essent .) Gluco genic AA ( essentia l) Keto genic AA ( essentia l) KETONE BODIES Glycerol × Pyruvate × × × × ACETYL-CoA Citrate cycle OXIDATIVE PHOSPHORYLATION ATP
48. Interconversions between nutrients × × pyruvate dehydrogenase reaction is irreversible ketogenic AA and most mixed AA are essential Lipids amino acids in excess of proteins Amino acids lipids pyruvate and CAC intermediate provide arbon skeleton for some amino acids Glucose intermediates AA most AA are glucogenic Amino acids glucose not possible, pyruvate dehydrogenase reaction is irreversible Lipids glucose very easy and quickly Sugars lipids Commentary Interconversion
49. Saccharides are the most universal nutrients – the overdose is transformed in the fat stores, carbon skelet of non-essential amino acids may originate from saccharides. Triacylglycerols exhibit the highest energetic yield – but fatty acids cannot convert into saccharides or the skelet of amino acids. Amino acids represent the unique source of nitrogen for proteosynthesis that serves as fuel rather when the organism is lacking in other nutrients - glucogenic amino acids can convert into glucose, a overdose of diet protein may be transformes in fat stores. The metabolism of nutrients is sophistically controlled with different mechanisms in the well-fed state (absorptive phase), short fasting (post-absorptive phase), and in prolonged starvation . It also depends on energy expenditure (predominantly muscular work) – either of maximal intensity (anaerobic, of short duration only) or aerobic work of much lower intensity (long duration).
50. The tissues differ in their enzyme equipment and metabolic pathways * K B = keto ne bodies - - - + - +++ Gluconeogenesis +++ + +++ + +++ + Glycolysis - + +++ + + - KB oxidation * - - - - - + Ketogenesis - +++ ± ± ± +++ FA synthesis - - ++ + - ++ FA β -oxidation - + + + + + CAC Ery Adipocyte Muscles Kidneys CNS Liver Pathway
51. Cellular compartmentation of major metabolic pathways Proteosynthesis on ribosomes (translation of mRNA) Rough ER Glycolysis, gluconeogenesis, gly c ogen , pentose c ycle, transamination, synt hesis of FA / urea / urate / heme ; ethanol oxidation Cytosol Formation and decomposition of H 2 O 2 and peroxides Peroxisomes Glycosylation of proteins, sorting and export of protein s Golgi apparat. transport of molecules/ions/information = transporters/channels/ receptor s Cell membrane Non-specific hydrolysis of various substrates Lysosomes Synthesis of TAG / chol., FA desaturation, hydroxylations of xenob ioti cs Smooth ER Oxidative decarboxylation of pyruvate, CAC, RCh, FA β - oxidation, synthesis of KB / urea / heme / Gln , AST rea ction Mitochondria DNA replication, RNA synthesis (= DNA transcription) Nucleus
52. Metabolic effects of insulin Pentose phosphate cycle Synthesis of fatty acids Glycogenolysis Synthesis of glycogen Gluconeogenesis Glycolysis Glucose phosphorylation Liver Lipolysis Synthesis of TG Hydrolysis of TG in lipoproteins Ox. decarboxylation of pyruvate Pentose phosphate pathway Glycolysis Glucose uptake (GLUT 4) Adipose tissue Synthesis of proteins Glycogenolysis Synthesis of glycogen Glycolysis Glucose uptake (GLUT 4) Muscle
53. Metabolic effects of glucagon (not on muscles) Lipolysis (HSL, hormone sensitive lipase) Adipocytes Oxidation of fatty acids Synthesis of fatty acids Glycogenolysis Synthesis of glycogen Gluconeogenesis Glycolysis Liver
55. Heme Prostetic group of many proteins (hemoglobin, myoglobin, cytochromes) Synthesis in the body: 70-80 % in erythroid cells in bone marow - hemoglobin 15 % liver – cytochroms P450 and other hemoproteins Heme consists of porphyrin ring coordinated with iron cation
56.
57. Synthesis of -aminolevulinate (ALA) ALA-synthase C H 2 N H 2 C O O H H O O C C H 2 C H 2 C S O C o A glycin succinyl-CoA H O O C C H 2 C H 2 C O C H 2 N H 2 H O O C C H 2 C H 2 C O C H N H 2 C O O H 2-amino-3-oxoadipate H S C o A - CO 2 -aminolevulinate (5-amino-4-oxobutanoic acid) pyridoxalphosphate is cofactor mitochondria
58. ALA-synthase is the rate-controlling enzyme of porphyrine biosynthesis ALA-synthase - is inhibited by heme (allosteric inhibition) - synthesis of enzyme is repressed by heme - is induced by some drugs (barbiturates, phenytoin, griseofulvin) Half-life about 1 hour
59. Why some drugs increase activity of ALA-synthase? For biotransformation (hydroxylation) of xenobiotics is necessary cytochrome P-450 Indu ction of enzyme synthesis
60. Condensation to substituted pyrrole δ -aminolevulinate cytosol C O O H N O H H H H O N H 2 C O O H H H - 2 H 2 O porphobilinogen N N H 2 C O O H C O O H H
61. Condensation of porphobilinogen Under physiological circumstances , due to the presence of a protein modifier called co-synthase, uroporphyrinogen III with an asymmetrical arrangement of side chains of the ring D is formed. Only traces of symmetrical uroporphyrinogen I are produced Porphobilinogen uroporphyrinogen I (minor product) uroporphyrinogen III (main product)
62. Condensation of porphobilinogen cytosol N N H 2 C O O H C O O H H porphobilinogen 4 N H 3 4 H N H N N N C O O H H O O C C O O H H O O C H O O C H O O C C O O H C O O H H H uroporphyrinogen III methylene bridge A B C D
63. Decarboxylation of four acetates – formation of methyl groups cytosol H N H N N N C O O H H O O C C O O H H O O C H O O C H O O C C O O H C O O H H H H N H N N N C H 3 H 3 C C O O H H O O C H 3 C H O O C C H 3 C O O H H H 4 CO 2 uroporphyrinogen III coproporphyrinogen III
64. Formation of vinyl groups from two propionates mitochondria H N H N N N C H 3 H 3 C C O O H H O O C H 3 C H O O C C H 3 C O O H H H coproporphyrinogen III - 4H - 2 CO 2 H N H N N N C H 3 H 3 C C O O H H O O C H 3 C C H 3 H H protoporphyrinogen IX
65. Formation of conjugated system colourless red mitochondria H N H N N N C H 3 H 3 C C O O H H O O C H 3 C C H 3 H H protoporphyrinogen IX - 6 H N N N N C H 3 H 3 C C H 3 H 3 C C O O H H O O C H protoporphyrin IX H methyne (methenyl) bridge
66. Heme is coloured chelate with Fe 2+ protoporphyrin IX F e heme H N N N N C H 3 H 3 C C H 3 H 3 C C O O H H O O C H ascorbate F e 3+ - 2H + N N N N C H 3 H 3 C C H 3 H 3 C C O O H H O O C F e 2+
67. CO and bilirubin are formed by the degradation of heme oxidative cleavage (heme oxygenase) CO + biliverdin bilirubin carbonyl-hemoglobin 3 O 2 3 NADPH+H + more details in the 4 th semest e r
68.
69. Hemoproteins Transport of O 2 in blood Store of O 2 muscle Decomposition of H 2 O 2 Decomposition of peroxides Components of resp. chain H ydroxyla tion Desatur ation of FA Fe 2+ Fe 2+ Fe 2+ Fe 3+ Fe 2+ Fe 3+ Fe 2+ Fe 3+ Fe 2+ Fe 3+ Fe 2+ Fe 3+ Hemoglobin Myoglobin Catalase Peroxidase Cytochroms Cytochrom P-450 Desaturas es of FA Function Redox state of Fe Protein
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72. Quaternary structure of hemoglobin 4 O 2 α 1 α 2 β 1 β 2 deoxygenated hemoglobin (2,3-bisphosphoglycerate) T-conformation 4 O 2 2 H + 2 H + α 2 α 1 β 2 β 1 oxyhemoglobin R-conformation α 1 O 2 α 2 O 2 β 1 O 2 β 2 O 2
73.
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75. Language note : How to express two redox states of iron -i -o Infix iron(III) chloride iron(II) chloride New English example ferr i c chloride ferr o us chloride Old English example ferr i chloridum ferr o si chloridum Latin example hem i globin (methemoglobin) hem o globin English example Fe 3+ Fe 2+
76. Heme as cofactor of oxidoreductases transfers one ele c tron Examples of hem e enzym es C atalas e : H 2 O 2 ½ O 2 + H 2 O Myeloperoxidas e : H 2 O 2 + Cl - + H + HClO + H 2 O
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78.
79.
80. Desaturation of fatty acids ∆ 9 desaturas e H 3 C C O O H C O O H H 3 C C O O H C H 3 9-10 desaturation (humans) 12-13 desaturation (plants) stearic acid 18:0 oleic acid 18:1 (9) linoleic acid 18:2 (9,12)
81. Desaturation of FA requires cytochrome b 5 h ydroxylation at C-10 dehydrat ion