1. Glucose Pyruvate Acetyl Co A Fatty Acids Amino Acids Citric acid cycle supplies NADH and FADH 2 to the electron transport chain

2. Reduced coenzymes NADH and FADH 2 are formed in matrix from: (1) Oxidative decarboxilation of pyruvate to acetyl CoA (2) Aerobic oxidation of acetyl CoA by the citric acid cycle (3) Oxidation of fatty acids and amino acids The NADH and FADH 2 are energy-rich molecules because each contains a pair of electrons having a high transfer potential.

3. Electrons of NADH or FADH 2 are used to reduce molecular oxygen to water. A large amount of free energy is liberated. The electrons from NADH and FADH 2 are not transported directly to O 2 but are transferred through series of electron carriers that undergo reversible reduction and oxidation.

4. The flow of electrons through carriers leads to the pumping of protons out of the mitochondrial matrix. The resulting distribution of protons generates a pH gradient and a transmembrane electrical potential that creates a protonmotive force.

5. ATP is synthesized when protons flow back to the mitochondrial matrix through an enzyme complex ATP synthase. The oxidation of fuels and the phosphorylation of ADP are coupled by a proton gradient across the inner mitochondrial membrane. Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from NADH or FADH 2 to O 2 by a series of electron carriers.

6. OXIDATIVE PHOSPHORYLATION IN EUKARYOTES TAKES PLACE IN MITOCHONDRIA Two membranes: outer membrane inner membrane (folded into cristae) Two compartments: (1) the intermembrane space (2) the matrix Inner mitochondrial membrane: Electron transport chain ATP synthase Mitochondrial matrix: Pyruvate dehydrogenase complex Citric acid cycle Fatty acid oxidation Location of mitochondrial complexes The outer membrane is permeable to small molecules and ions because it contains pore-forming protein (porin). The inner membrane is impermeable to ions and polar molecules. Contains transporters (translocases).

7. THE ELECTRON TRANSPORT CHAIN Series of enzyme complexes (electron carriers) embedded in the inner mitochondrial membrane, which oxidize NADH 2 and FADH 2 and transport electrons to oxygen is called respiratory electron-transport chain (ETC). The sequence of electron carriers in ETC cyt b NADH FMN Fe-S Co-Q Fe-S cyt c 1 cyt c cyt a cyt a 3 O 2 succinate FAD Fe-S

8. High-Energy Electrons: Redox Potentials and Free-Energy Changes In oxidative phosphorylation, the electron transfer potential of NADH or FADH 2 is converted into the phosphoryl transfer potential of ATP. Phosphoryl transfer potential is  G°' (energy released during the hydrolysis of activated phos- phate compound).  G°' for ATP = -7.3 kcal mol -1 Electron transfer potential is expressed as E' o, the (also called redox potential, reduction potential, or oxidation-reduction potential).

9. Components of electron- transport chain are arranged in the inner membrane of mitochondria in packages called respiratory assemblies (complexes). THE RESPIRATORY CHAIN CONSISTS OF FOUR COMPLEXES cyt b NADH FMN Fe-S Co-Q Fe-S cyt c 1 cyt c cyt a cyt a 3 O 2 succinate FAD Fe-S I III II IV I II III IV

10. Transfers electrons from NADH to Co Q (ubiquinone) Consist of: - enzyme NADH dehydrogenase (FMN - prosthetic group) - iron-sulfur clusters. NADH reduces FMN to FMNH 2. Electrons from FMNH 2 pass to a Fe-S clusters. Fe-S proteins convey electrons to ubiquinone. QH 2 is formed. Complex I (NADH-ubiquinone oxidoreductase) The flow of two electrons from NADH to coenzym Q leads to the pumping of four hydrogen ions out of the matrix.

11. Complex II (succinate-ubiquinon oxidoreductase) Transfers electrons from succinate to Co Q. Form 1 consist of: - enzyme succinate dehydrogenase (FAD – prosthetic group) - iron-sulfur clusters. Succinate reduces FAD to FADH 2. Then electrons pass to Fe-S proteins which reduce Q to QH 2 Form 2 and 3 contains enzymes acyl-CoA dehydrogenase (oxidation of fatty acids) and glycerol phosphate dehydrogenase (oxidation of glycerol) which direct the transfer of electrons from acyl CoA to Fe-S proteins. Complex II does not contribute to proton gradient.

12. Ubiquinone Q: - lipid soluble molecule, - smallest and most hydrophobic of all the carriers - diffuses within the lipid bilayer - accepts electrons from I and II complexes and passes them to complex III. All electrons must pass through the ubiquinone (Q)- ubiquinole (QH 2 ) pair.

13. Complex III (ubiquinol-cytochrome c oxidoreductase) Transfers electrons from ubiquinol to cytochrome c. Consist of: cytochrome b, Fe-S clusters and cytochrome c 1. Cytochromes – electron transferring proteins containing a heme prosthetic group (Fe 2+  Fe 3+ ). Oxidation of one QH 2 is accompanied by the translocation of 4 H + across the inner mitochondrial membrane. Two H + are from the matrix, two from QH 2

14. Complex IV (cytochrome c oxidase) Transfers electrons from cytochrome c to O 2. Composed of: cytochromes a and a 3. Catalyzes a four-electron reduction of molecular oxygen (O 2 ) to water (H 2 O): O 2 + 4e - + 4H +  2H 2 O Translocates 2H + into the intermembrane space

15. A PROTON GRADIENT POWERS THE SYNTHESIS OF ATP The transport of electrons from NADH or FADH 2 to O 2 via the electron-transport chain is exergonic process: NADH + ½O 2 + H +  H 2 O + NAD + FADH 2 + ½O 2  H 2 O + FAD +  G o ’ = -52.6 kcal/mol for NADH -36.3 kcal/mol for FADH 2 How this process is coupled to the synthesis of ATP (endergonic process)? ADP + P i  ATP + H 2 O  G o ’=+7.3 kcal/mol

16. Proposed by Peter Mitchell in the 1960’s (Nobel Prize, 1978) Chemiosmotic theory: electron transport and ATP synthesis are coupled by a proton gradient across the inner mitochondrial membrane Mitchell’s postulates for chemiosmotic theory 1.Intact inner mitochondrial membrane is required 2.Electron transport through the ETC generates a proton gradient 3. ATP synthase catalyzes the phosphorylation of ADP in a reaction driven by movement of H + across the inner membrane into the matrix The Chemiosmotic Theory

17. REGULATION OF OXIDATIVE PHOSPHORYLATION Coupling of Electron Transport with ATP Synthesis Electron transport is tightly coupled to phosphorylation. ATP can not be synthesized by oxidative phosphorylation unless there is energy from electron transport. Electrons do not flow through the electron-transport chain to O 2 unless ADP is phosphorylated to ATP. Important substrates: NADH, O 2, ADP Intramitochondrial ratio ATP/ADP is a control mechanism High ratio inhibits oxidative phosphorylation as ATP allosterically binds to a subunit of Complex IV

18. Uncoupling of Electron Transport with ATP Synthesis Uncoupling of oxidative phosphorylation generates heat to maintain body temperature in hibernating animals, in newborns, and in mammals adapted to cold. Brown adipose tissues is specialized for thermogenesis. Inner mitochondrial membrane contains uncoupling protein (UCP), or thermogenin. UCP forms a pathway for the flow of protons from the cytosol to the matrix.

19. Uncouplers are lipid-soluble aromatic weak acids Uncouplers deplete proton gradient by transporting protons across the membrane Uncouplers 2,4-Dinitrophenol: an uncoupler Because the negative charge is delocalized over the ring, both the acid and base forms of DNP are hydrophobic enough to dissolve in the membrane.

20. Specific inhibitors of electron transport are invaluable in revealing the sequence of electron carriers. Rotenone and amytal block electron transfer in Complex I. Antimycin A interferes with electron flow thhrough Complex III. Cyanide, azide, and carbon monoxide block electron flow in Complex IV. ATP synthase is inhibited by oligomycin which prevent the influx of protons through ATP synthase. Specific inhibitors of electron transport chain and ATP-synthase

21. Translocation of 3H + required by ATP synthase for each ATP produced 1 H + needed for transport of P i. Net: 4 H + transported for each ATP synthesized For NADH: 10 H + / 4H + ) = 2.5 ATP For FADH 2 : 6 H + / 4 H + = 1.5 ATP ATP Yield Ten protons are pumped out of the matrix during the two electrons flowing from NADH to O 2 (Complex I, III and IV). Six protons are pumped out of the matrix during the two electrons flowing from FADH 2 to O 2 (Complex III and IV). 3 4 2 4

22. DIGESTION OF CARBOHYDRATES Glycogen, starch and disaccharides (sucrose, lactose and maltose) are hydrolyzed to monosaccharide units in the gastrointestinal tract. The process of digestion starts in the mouth by the salivary enzyme  –amilase. The time for digestion in mouth is limited. Salivary  - amilase is inhibited in stomach due to the action of hydrochloric acid. Another  - amilase is produced in pancreas and is available in the intestine.

23.  -amilase hydrolyzes the  -1-4-glycosidic bonds randomly to produce smaller subunits like maltose, dextrines and unbranched oligosaccharides.  -amilase

24. The intestinal juice contains enzymes hydrolyzing disaccharides into monosaccharides (they are produced in the intestinal wall) Sucrase hydrolyses sucrose into glucose and fructose Sucrose sucrase Fructose Glucose

25. Lactose lactase Maltase hydrolyses maltose into two glucose molecules Lactase hydrolyses lactose into glucose and galactose Maltose maltase Galactose Glucose

26. ABSORPTION OF CARBOHYDRATES Only monosaccharides are absorbed The rate of absorption: galactose > glucose > fructose Glucose and galactose from the intestine into endothelial cells are absorbed by secondary active transport Na + Glucose Protein

27. Transport of glucose from blood into cells of different organs is mainly by facilitated diffusion. The protein facilitating the glucose transport is called glucose transporter (GluT). GluT are of 5 types. GluT 2 is located mainly in hepatocytes membranes (it transport glucose into cells when blood sugar is high); GluT 1 is seen in erythrocytes and endothelial cells; GluT 3 is located in neuronal cells (has higher affinity to glucose); GluT 5 – in intestine and kidneys; GluT 4 - in muscles and fat cells.

28. Glucose The fate of glucose molecule in the cell Glucose-6- phosphate Pyruvate Glycogen Ribose, NADPH Pentose phosphate pathway supplies the NADPH for lipid synthesis and pentoses for nucleic acid synthesis Glycogenogenesis (synthesis of glycogen) is activated in well fed, resting state Glycolysis is activated if energy is required

29. Catabolism of glucose in aerobic conditions via glycolysis and the citric acid cycle

30. Glycolysis (10 reactions) can be divided into three stages In the 1 st stage (hexose stage) 2 ATP are consumed per glucose In the 3 rd stage (triose stage) 4 ATP are produced per glucose Net: 2 ATP produced per glucose

31. Stage 1, which is the conversion of glucose into fructose 1,6-bisphosphate, consists of three steps: a phosphorylation, an isomerization, and a second phosphorylation reaction. The strategy of these initial steps in glycolysis is to trap the glucose in the cell and form a compound that can be readily cleaved into phospho- rylated three- carbon units.

32. Stage 2 is the cleavage of the fructose 1,6-bisphosphate into two three-carbon fragments dihydroxyacetone phosphate and glyceraldehyde 3- phosphate. Dihydroxyacetone phosphate and glyceraldehyde 3- phosphate are readily interconvertible.

33. In stage 3, ATP is harvested when the three- carbon fragments are oxidized to pyruvate.

34. Each chemical reaction prepares a substrate for the next step in the process Glycolysis Has 10 Enzyme-Catalyzed Steps 1. Hexokinase Transfers the  -phosphoryl of ATP to glucose C-6 oxygen to generate glucose 6-phosphate (G6P) Four kinases in glycolysis: steps 1,3,7, and 10 All four kinases require Mg 2+ and have a similar mechanism

35. Converts glucose 6-phosphate (G6P) (an aldose) to fructose 6-phosphate (F6P) (a ketose) Enzyme preferentially binds the a-anomer of G6P (converts to open chain form in the active site) Enzyme is highly stereospecific for G6P and F6P Isomerase reaction is near-equilibrium in cells 2. Glucose 6-Phosphate Isomerase

36. Catalyzes transfer of a phosphoryl group from ATP to the C-1 hydroxyl group of F6P to form fructose 1,6- bisphosphate (F1,6BP) PFK-1 is metabolically irreversible and a critical regulatory point for glycolysis in most cells A second phosphofructokinase (PFK-2) synthesizes fructose 2,6-bisphosphate (F2,6BP) 3. Phosphofructokinase-1 (PFK-1)

37. 4. Aldolase Aldolase cleaves the hexose F1,6BP into two triose phosphates: glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP) Reaction is near-equilibrium, not a control point

38. Conversion of DHAP into GAP Reaction is very fast, only the D-isomer of GAP is formed Reaction is reversible. At equilibrium, 96% of the triose phosphate is DHAP. However, the reaction proceeds readily from DHAP to GAP because the subsequent reactions of glycolysis remove this product. 5. Triose Phosphate Isomerase (TPI)

39. Fate of carbon atoms from hexose stage to triose stage

40. Conversion of GAP to 1,3-bisphosphoglycerate (1,3BPG) Molecule of NAD + is reduced to NADH 6. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) Energy from oxidation of GAP is conserved in acid- anhydride linkage of 1,3BPG Next step of glycolysis uses the high-energy phosphate of 1,3BPG to form ATP from ADP

41. Transfer of phosphoryl group from the energy-rich mixed anhydride 1,3BPG to ADP yields ATP and 3-phosphoglycerate (3PG) Substrate-level phosphorylation - Steps 6 and 7 couple oxidation of an aldehyde to a carboxylic acid with the phosphorylation of ADP to ATP 7. Phosphoglycerate Kinase (PGK)

42. 8. Phosphoglycerate Mutase Catalyzes transfer of a phosphoryl group from one part of a substrate molecule to another Reaction occurs without input of ATP energy

43. 9. Enolase: 2PG to PEP 2-Phosphoglycerate (2PG) is dehydrated to phosphoenolpyruvate (PEP) Elimination of water from C-2 and C-3 yields the enol- phosphate PEP PEP has a very high phosphoryl group transfer potential because it exists in its unstable enol form

44. 10. Pyruvate Kinase (PK) Catalyzes a substrate-level phosphorylation Metabolically irreversible reaction Regulation both by allosteric modulators and by covalent modification Pyruvate kinase gene can be regulated by various hormones and nutrients PEP + ADP  Pyruvate + ATP

45. Net reaction of glycolysis Two molecules of ATP are produced Two molecules of NAD + are reduced to NADH Glucose + 2 ADP + 2 NAD + + 2 P i 2 Pyruvate + 2 ATP + 2 NADH + 2 H + + 2 H 2 O During the convertion of glucose to pyruvate:

46. 1. Aerobic conditions: oxidation to acetyl CoA which enters the citric acid cycle for further oxidation 2. Anaerobic conditions (muscles, red blood cells): conversion to lactate 3. Anaerobic conditions (microorganisms, yeast): conversion to ethanol The Fate of Pyruvate The sequence of reactions from glucose to pyruvate is similar in most organisms and most types of cells. The fate of pyruvate is variable. Three reactions of pyruvate are of prime importance:

47. Metabolism of Pyruvate to Ethanol Ethanol is formed from pyruvate in yeast and several other microorganisms in anaerobic conditions. Two reactions required: The first step is the decarboxylation of pyruvate to acetaldehyde. Enzyme - pyruvate decarboxylase. Coenzyme - thiamine pyrophosphate (derivative of the vitamin thiamine B 1 ) The second step is the reduction of acetaldehyde to ethanol. Enzyme - alcohol dehydrogenase (active site contains a zinc). Coenzyme – NADH.

48. The conversion of glucose into ethanol is an example of alcoholic fermentation. The net result of alcoholic fermentation is: Glucose+2P i + 2ADP + 2H +  2 ethanol + 2CO 2 + 2ATP + 2H 2 O The ethanol formed in alcoholic fermentation provides a key ingredient for brewing and winemaking. There is no net NADH formation in the conversion of glucose into ethanol. NADH generated by the oxidation of glyceraldehyde 3-phosphate is consumed in the reduction of acetaldehyde to ethanol.

49. Lactate is formed from pyruvate in an animal organism and in a variety of microorganisms in anaerobic conditions. The conversion of glucose into lactate is called lactic acid fermentation. Enzyme - lactate dehydrogenase. Coenzyme – NADH. Metabolism of Pyruvate to Lactate

50. Muscles of higher organisms and humans lack pyruvate decarboxylase and cannot produce ethanol from pyruvate Muscle contain lactate dehydrogenase. During intense activity when the amount of oxygen is limiting the lactic acid can be accumulated in muscles (lactic acidosis). Lactate formed in skeletal muscles during exercise is transported to the liver. Liver lactate dehydrogenase can reconvert lactate to pyruvate. Overall reaction in the conversion of glucose into lactate: Glucose + 2 P i + 2 ADP  2 lactate + 2 ATP + 2 H 2 O  As in alcoholic fermentation, there is no net NADH formation.  NADH formed in the oxidation of glyceraldehyde 3- phosphate is consumed in the reduction of pyruvate.

51. Metabolism of Pyruvate to Acetyl CoA In aerobic conditions pyruvate is converted to acetyl coenzyme A (acetyl CoA). Acetyl CoA enters citric acid cycle where degrades to CO 2 and H 2 O and the energy released during such oxidation is utilized in NADH and FADH 2. Pyruvate is converted to acetyl CoA in the matrix of mitochondria. The overall reaction: Pyruvate + NAD + + CoA  acetyl CoA + CO 2 + NADH Reaction is catalyzed by the pyruvate dehydrogenase complex (three enzymes and five coenzymes). If pyruvate is converted to acetyl CoA, NADH formed in the oxidation of glyceraldehyde 3-phosphate ultimately transfers its electrons to O 2 through the electron-transport chain in mitochondria.

52. Lactose intolerance, or hypolactasia, is caused by a deficiency of the enzyme lactase, which cleaves lactose into glucose and galactose. Microorganisms in the colon ferment undigested lactose to lactic acid generating methane (CH 4 ) and hydrogen gas (H 2 ). The gas produced creates the uncomfortable feeling of gut distention and the annoying problem of flatulence. The lactic acid is osmotically active and draws water into the intestine, as does any undigested lactose, resulting in diarrhea. The gas and diarrhea hinder the absorption of other nutrients (fats and proteins). Treatment: - to avoid the products containing lactose; - the enzyme lactase can be ingested. Intolerance to Milk Many people are unable to metabolize the milk sugar lactose and experience gastro- intestinal disturbances if they drink milk.

53. Galactosemia The disruption of galactose metabolism is referred to as galactosemia. Classic galactosemia is an inherited deficiency in galactose 1-phosphate uridyl transferase activity. Symptoms: - vomiting, diarrhea after consuming milk, - enlargement of the liver, jaundice, sometimes cirrhosis, - cataracts, - lethargy and retarded mental development, - markedly elevated blood-galactose level - galactose is found in the urine. The absence of the transferase in red blood cells is a definitive diagnostic criterion. The most common treatment is to remove galactose (and lactose) from the diet.

54. Regulation of Glycolysis The rate glycolysis is regulated to meet two major cellular needs: (1) the production of ATP, and (2) the provision of building blocks for synthetic reactions. There are three control sites in glycolysis - the reactions catalyzed by  hexokinase,  phosphofructokinase 1, and  pyruvate kinase These reactions are irreversible. Their activities are regulated  by the reversible binding of allosteric effectors  by covalent modification  by the regulation of transcription (change of the enzymes amounts). The time required for allosteric control, regulation by phosphorylation, and transcriptional control is typically in milliseconds, seconds, and hours, respectively.

55. Phosphofructokinase 1 Is the Key Enzyme in the Control of Glycolysis Phosphofructokinase 1 is the most important control element in the mammalian glycolytic pathway. Phosphofructokinase 1 in the liver is a tetramer of four identical subunits. The positions of the catalytic and allosteric sites are identical.

56. Fructose 2,6-bisphosphate (F-2,6-BP) is a potent activator of phosphofructokinase 1. F-2,6-BP activates phosphofructokinase I by increasing its affinity for fructose 6-phosphate and diminishing the inhibitory effect of ATP. Fructose 2,6-bisphosphate is hydrolyzed to fructose 6- phosphate by a specific phosphatase, fructose bisphosphatase 2 (FBPase2). Both PFK2 and FBPase2 are present in a single polypeptide chain (bifunctional enzyme). Fructose 2,6-bisphosphate is formed in a reaction catalyzed by phosphofructokinase 2 (PFK2), a different enzyme from phosphofructokinase 1.

57. Regulation of Glycolysis by Fructose 2,6-bisphosphate  When blood glucose level is low the glucagon is synthesized by pancreas  Glucagon binds to cell receptors, stimulates the protein kinase A activity  Protein kinase A phosphorylates the PFK-2 inhibiting its kinase activity and stimulating its phosphatase activity  As result the amount of F-2,6-BP is decre- ased and glycolysis is slowed.

58. Regulation of Hexokinase Glucose 6-phosphate levels increase when glycolysis is inhibited at sites further along in the pathway. Glucose 6-phosphate inhibits hexokinase isozymes I, II and III. Glucokinase (isozyme IV) is not inhibited by glucose 6-phosphate. The role of glucokinase is to provide glucose 6-phosphate for the synthesis of glycogen. Hexokinase is inhibited by its product, glucose 6-phosphate (G-6-P). High concentrations of G-6-P signal that the cell no longer requires glucose for energy, for glycogen, or as a source of biosynthetic precursors.

59. Regulation of Pyruvate Kinase (PK) ATP allosterically inhibits pyruvate kinase to slow glycolysis when the energy charge is high. Finally, alanine (synthesized in one step from pyruvate) also allosterically inhibits the pyruvate kinases (signal that building blocks are abundant). Several isozymic forms of pyruvate kinase are present in mammals (the L type predominates in liver, and the M type in muscle and brain). Fructose 1,6-bisphosphate allosterically activates pyruvate kinase.

60. Inhibition 1) PFK-1 is inhibited by ATP and citrate 2) Pyruvate kinase is inhibited by ATP and alanine 3) Hexokinase is inhibited by excess glucose 6-phosphate Stimulation 1) AMP and fructose 2,6- bisphosphate (F2,6BP) relieve the inhibition of PFK-1 by ATP 2) F1,6BP stimulate the activity of pyruvate kinase Regulation of Glycolysis Alanine

61. The Pasteur Effect More ATP is produced under aerobic conditions than under anaerobic conditions, therefore less glucose is consumed aerobically.  Under anaerobic conditions the conversion of glucose to pyruvate is much higher than under aerobic conditions (yeast cells produce more ethanol and muscle cells accumulate lactate)  The Pasteur Effect is the slowing of glycolysis in the presence of oxygen.

62. (1) Synthesis of NADPH (for reductive reactions in biosynthesis of fatty acids and steroids) (2) Synthesis of Ribose 5-phosphate (for the biosynthesis of ribonucleotides (RNA, DNA) and several cofactors) (3) Pentose phosphate pathway also provides a means for the metabolism of “unusual sugars”, 4, 5 and 7 carbons. The Role of Pentose Phosphate Pathway (phosphogluconate pathway) Pentose phosphate pathway does not function in the production of high energy compounds like ATP.

63. Occurrence of the pentose phosphate pathway Liver, mammary and adrenal glands, and adipose tissue Red blood cells (NADPH maintains reduced iron) NOT present in skeletal muscles. All enzymes in the cycle occur in the cytosol

64. Two phases: 1) The oxidative phase that generates NADPH 2) The nonoxidative phase (transketolase/ transaldolase system) that interconvert phosphorylated sugars.

65. Oxidative phase of pentose phosphate cycle

66. Nonoxidative phase of pentose phosphate cycle

67. The net reaction for the pentose phosphate pathway Glucose + ATP + 2NADP + + H 2 O ribose 5-phosphate + CO 2 + 2NADPH + 2H + + ADP The pentose phosphate pathway ends with these five reactions in some tissue. In others it continue in nonoxidative mode to make fructose 6-phosphate and glyceraldehyde 3-phosphate. These reactions link pentose phosphate pathway with glycolysis.

68. GSH also functions to eliminate H 2 O 2 and organic peroxides. Peroxides can cause irreversible damage to hemoglobin and destroy cell membranes. Glucose-6-phosphate dehydrogenase deficiency NADPH is required for the proper action of the tripeptide glutathione (GSH) (maintains it in the reduced state). GSH in erythrocytes maintains hemoglobin in the reduced Fe(II) state necessary for oxygen binding.

69. Glucose-6-phosphate dehydrogenase deficiency – the most common enzymopathy affecting hundreds of millions of people. About 10 % of individuals of African or Mediterranean descent have such genetic deficiency. Erythrocytes with a lowered level of reduced glutathione are more susceptible to hemolysis and are easily destroyed especially if they are stressed with drugs (for example, antimalarial drugs). In severe cases, the massive destruction of red blood cells causes death. Red blood cells with Heinz bodies. Dark particles (Heinz bodies) are denaturated proteins adhered to cell membranes.

70. Gluconeogenesis – synthesis of glucose from noncarbohydrate precursors Liver and kidney are major sites of glucose synthesis Main precursors: lactate, pyruvate, glycerol and some amino acids Under fasting conditions, gluconeogenesis supplies almost all of the body’s glucose Gluconeogenesis – universal pathway. It present in animals, microorganisms, plants and fungi Plants synthesize glucose from CO2 using the energy of sun, microorganisms – from acetate and propionate

71. Comparison of glycolysis and gluconeogenesis

72. Diabetes mellitus Diabetes mellitus is a disorder in which blood sugar (glucose) levels are abnormally high because the body does not produce enough insulin.Insulin - a hormone released from the pancreas, controls the amount of sugar in the blood.The levels of sugar in the blood vary normally throughout the day. They rise after a meal and return to normal within about 2 hours after eating. Once the levels of sugar in the blood return to normal

73. Types of Diabetes mellitus Type 1: In type 1 diabetes ( insulin-dependent diabetes or juvenile-onset diabetes), more than 90% of the insulin-producing cells of the pancreas are permanently destroyed. Only about 10% of all people with diabetes have type 1 disease. Most people who have type 1 diabetes develop the disease before age 30. Type 2: In type 2 diabetes ( non-insulin-dependent diabetes or adult-onset diabetes), the pancreas continues to produce insulin, sometimes even at higher-than-normal levels. However, the body develops resistance to the effects of insulin, so there is not enough insulin.

75. Glycogen Breakdown Stores of readily available glucose to supply the tissues with an oxidizable energy source are found principally in the liver, as glycogen. Glycogen is considered the principal storage form of glucose and is found mainly in liver and muscle

76. Pathways involved in the regulation of glycogen phosphorylase

77. Pathways involved in the regulation of glycogen synthase.