Medical Chemistry (1 st year – GM) Lecture III MUDr. Vlastimil Kulda October 16 th , 2012

1. Medical Chemistry (1st year – GM)Lecture IIIMUDr. Vlastimil KuldaOctober 16th, 2012

2. Elements of group V

3.  adenine, guanine Nitrogen N (Nitrogenium) N2 78% of the atmosphere - chemically rather inert • principal bioelement: organic compounds ( "NH3 derivatives" ) AMINO ACIDS  PROTEINS many heterocyclic compounds  uracil, thymine, cytosine pyrimidine NUCLEIC ACIDS (DNA, RNA) purine

4. toxic properties for animals NH3ammonia - sharp odour NH4+ammonium ion N2O Nitrous oxide [ Dinitrogen oxide ] = "laughing gas" - surgery: inhalation  insensibility to PAIN = anaesthetic and analgetic effects (without muscle relaxation) obstetrics - pain relief during childbirth NO Nitric oxide [ Nitrogen monoxide ] NO2Nitrogen dioxide - reddish-brown gas • in the environment • toxic gases • (Photochemical smog)

5. Endothelial cell NO Smooth muscle cell diffusion NO synthesis relaxation Biological functions of NO = important gaseous signaling molecule !!! EDRF = endothelium-derived relaxing factor = NO Nitroglycerin vasodilator - treatment of angina pectoris NO (a lack of blood suply of heart muscle  chest pain) Nitroglycerin = glyceryl trinitrate - oily explosive liquid [ DYNAMITE ]

6. Arginine (amino acid) NO enzyme: NO synthase Citrulline Biochemical formation of NO halflife: ~ 4 sec. Functions of NO: 1) dilation of blood vessels  vasodilator ( = EDRF ) 2) neurotransmitter 3) in macrophages and neutrophils – immune response (NO is toxic to bacteria) 4) role in penile erection

7. HNO2Nitrous acid (INN: Acidum nitrosum) - weak acid, not stable salts: nitrites NaNO2 Sodium nitrite (INN: Natrii nitris) - toxic ! food additive: alters the color of preserved meat prevents growth of Clostridium botulinum (botulinum toxin  botulism) organic nitrites = esters of nitrous acid HNO3Nitric acid (INN: Acidum nitricum) - strong acid - oxidazing agent ! salts: nitrates AgNO3 Silver nitrate (INN: Argenti nitras) Amyl nitrite – treatment of angina pectoris

8. nitrites METHEMOGLOBIN FeIII HEMOGLOBIN FeII Toxicity of NO2- (NO3-) intestinal bacteria can reduce nitrates to nitrites: NO3- NO2- Limits for drinking water: NO3- 50 mg/l adults 15 mg/l infants 1) Methemoglobinemia "blue baby syndrom" unable to transfer O2 methemoglobin reductase "protective enzyme" - insufficient in infants !

9. 2) Nitrosamines Nitrites can react with secondary amines  Nitrosamines CARCINOGENS ! Nitrites in food - meat and cheese products preserved with nitrite pickling salt !!!

10. Phosphorus P • principal bioelement H3PO4 Phosphoric acid (INN: Acidum phosphoricum) - in biochemistry: "phosphates" = esters of H3PO4 • Bone and tooth mineral: hydroxyapatite Ca5(PO4)3OH • Anions in body fluids: H2PO4- / HPO42- • Nucleotides, DNA, RNA • Structural lipids (phospholipids) - membranes ! • Metabolic intermediates (Glucose–6–phosphate, ...) • High energy compounds ATP

11. ATP + H2O ADP + Pi + energy ATP + H2O AMP + PPi + energy pyrophosphate ester bond phosphoanhydride bonds ATP = adenosine triphosphate DE = - 30.5 kJ/mol

12. hexokinase ADP ATP glucose glucose-6-P ATP = adenosine triphosphate ATP is used to drive many energy consuming reactions ! ATP is used as "energy" for active transport ("pumps") ATP is often used to "activate metabolites": ATP is formed from ADP when "fuel molecules" are oxidized. glucose  CO2 + H2O up to 36-38 ATP / molecule of glucose (majority of this ATP production: oxidative phosphorylation in mitochondria)

13. Sarin, soman, tabun - "nerve gases" - extremely toxic substances !!! - chemical weapons of mass destruction Sarin Organophosphate neurotoxins very potent insecticid also highly toxic ! Parathion inhibition of the enzyme acetylcholinesterase !

14. vesicles with neurotransmitter neuronal synapse  neurotransmitter  receptor  effect receptor synaptic cleft 2) 1) Neurotransmitter must be removed from the synaptic cleft(after its job is done) ! 1) REUPTAKE 2) Enzymatic breakdown into inactive fragments - ACETYLCHOLINE (acetylcholinesterase)

15. botulinum toxin (release of ACH is blocked) vesicles with acetylcholine (ACH) Cholinergic synapses ( neurotransmitter = acetylcholine ) organophosphates (acetylcholinesterase is blocked) synaptic cleft * ATROPINE (ACH receptor is blocked) ACH receptor * acetylcholinesterase * acetylcholine acetic acid choline

16. As Arsenicum - toxic in all forms dentistry – root canal therapy (devitalisation of tooth)  arsenic compounds SALVARSAN - organic compound containing As - drug that was used to treat syphilis ! - the first effective "chemotherapeutic agent" before penicillin (1940s) - severe side effects

17. Elements of group VI Chalcogens

18. electron acceptor in biologically important oxidations ! O2 + 4 e- 2 O2- 2 H2O + 4 H+ C O Oxygen O (Oxygenium) O2 21% of the atmosphere • principal bioelement: H2O many functional groups in biomolecules - OH "hydroxyl group" alcohols, phenols "carbonyl group" aldehydes, ketones - COOH "carboxyl group" carboxylic acids

19. Oxygen radicals- TEXTBOOK (Toxicity of oxygen) very reactive  can cause damage to most cell components !!! O2 + e- O2- superoxide radical O2H perhydroxyl radical (hydroperoxyl) H2O2 + e- OH- + OH hydroxyl radical ROS = reactive oxygen species "free radicals" + H2O2 , .... + H+

20. SH protein SH Sulphur S (Sulfur) • principal bioelement H2S Hydrogen sulphide - strong poison - gas with odour of rotten eggs - SH sulfhydryl groups in organic structures (often: active groups of proteins – enzymes) Toxic heavy metals ( Pb, Hg, As, ...) - block sulfhydryl groups !

21. H2SO3Sulphurous acid (INN: Acidum sulfurosum) - weak acid salts: sulphites ( ........ sulfis ) H2SO4Sulphuric acid (INN: Acidum sulfuricum) - strong acid salts: sulphates ( ........ sulfas ) H2S2O3 Thiosulphuric acid (INN: Acidum thiosulfuricum) salts: thiosulphates ( ........ thiosulfas ) H2S Hydrogen sulphide (INN: Acidum hydrosulfuricum) salts: sulphides ( ........ sulfuridum )

22. cysteine ( Cys ) Amino acids containing sulphur methionine ( Met ) - essential amino acids - in proteins

23. Redox reactions R SH R S R‘ SH R‘ S - 2 H + 2 H S S S S S S R S OH R SH disulfide bond - S – S - disulfide bonds stabilize the folded form of a protein intermolecular -S-S- bonds intramolecular -S-S- bond O oxidation "sulfates" O

24. sulfate groups - modification of polysaccharides (heparine, chondroitin sulfate, keratan sulfate, ...) ------------------------------------------------------------------------------ Vitamins containing S important COENZYMES lipoic acid biotin vitamin B1 (thiamin)

25. coenzyme A Coenzyme A - thiol pantothenic acid - acyl group carrier thiol + carboxylic acid  thioester ("high energy bond") Acetyl-CoA important molecule in metabolism

26. Selenium Se trace element - in enzymes: glutathion peroxidase(destruction of peroxides) - chemically related to sulphur  analogous amino acids selenocysteine = "rare amino acid" in some proteins: thyroid hormone deiodinases

27. Elements of group VII Halogens

28. Fluorine F (Fluorum) trace element F2 yellowish very reactive gas Ca5(PO4)3F fluorapatite - bones, teeth compounds of fluorine ( NaF ) – toothpaste  to prevent dental caries excessive consumption of F-  "fluorosis"- damage of dental enamel (white spots, mottling of enamel) Freons (chlorofluorocarbons) - destruction of O3 layer Hydrofluorocarbon derivatives - inhalational general anaesthetics halothane (isofluran, sevofluran, ...)

29. Chlorine Cl (Chlorum) Cl2 pale green poisonous gas, suffocating odour World War I chemical weapon  destruction of lungs ! (it was soon replaced by more deadly gases – phosgene, ...) Cl2 + H2O HCl + HClO HClO HCl + O Chlorination of water - to KILL bacteria O Cl C Cl COCl2

30. Cl- important anion in body fluids the main EXTRAcellular anion (97 – 108 mmol/l) Physiologic saline solution(= isotonic = same osmolality as blood plasma) NaCl 0.9 % Inorganic acids HCl Hydrochloric acid Acidum hydrochloricum HClO Hypochlorous acid Acidum hypochlorosum HClO2 Chlorous acid Acidum chlorosum HClO3 Chloric acid Acidum chloricum HClO4 Hyperchloric acid Acidum hyperchloricum HCl - stomach !

31. phosgene ! (war gas) CHCl3 Chloroform - one of the first anesthetics (~ 1850) - inhaled vapour  insensibility  "painless sugrery" - hepatotoxic ! - 2 CHCl3 + O2 2 HCl + 2 COCl2 CCl4 Tetrachloromethane (Carbon tetrachloride) - solvent - hepatotoxic ! ( = liver damage ) CH3CH2Cl Ethyl chloride - boiling point 13o C - evaporation  cooling down the skin  pain relief - local skin anesthesia (sport injuries , ...) CH2 CHCl Vinyl chloride- is used to produce its polymer: PVC

32. best known banned pesticide (insecticide) high solubility in lipids ! DDT (dichloro-diphenyl-trichloroethane) contact poison for INSECTS only: lipids of insect cuticule  penetration to nervous ganglia  paralysis  death DDT was used with great effect to prevent insect-borne diseases ! (mosquitoes – MALARIA lice – spotted TYPHUS) environmental impact ! - long half life = persistent pollutant magnifying through the food chain  accumulation in fatty tissue (reproductive toxicity, carcinogen ?, ...) 1960s USA - DDT - major reason for the decline of the bald eagle (impaired quality of eggshells)

33. Polychlorinated biphenyls PCBs biphenyl good technical properties  were used as: insulating materials cooling fluids in transformers additives in plastics PROBLEM: very stable ! = persistent pollutants BANNED contamination of soil plants animals cumulation in lipids, milk (carcinogens ?)

34. tetrachlorodibenzo-1,4-dioxin TCDD (the most toxic dioxin) DIOXIN • general poison LD50 = 10 - 100 mg/kg ("lethal dose") • very stable, very resistant (up to 800o C)  persistent pollutant • accumulation in fatty tissues - teratogens, mutagens, carcinogens • by-product of production of herbicides • Vietnam War - Agent Orange (herbicide contaminated by TCDD) • Seveso (Italy) - industrial accident – uncontrolled reaction  • explosion of chemical reactor  cloud containing dioxin !

35. Iodine I (Iodum) trace element as element: purple – black solid sublimes into purple gas ! - solubility in water can be increased by addition of KI  Lugol‘s solution ( I2 KI water ) tincture of iodin = I2 in ethanol starch + iodine complexes of deep blue color starch = mixture of a-amylose – linear polymer of glucose amylopectin – branched polymer of glucose - polysaccharide of PLANTS  in FOOD desinfectant

36. T4 thyroxine Thyroid hormones deiodinases in tissues Se (selenocysteine) ! T3 triiodothyronine smaller quantity, greater activity! Function: stimulation of metabolism (act to increase the metabolic rate) essential to proper development (BRAIN !)

37. Deficiency of thyroid hormones = hypothyroidism metabolism  low body temperature intolerance to cold weight gain weakness, lethargy - children: mental retardation, short stature [ CRETENISM ] Excess of thyroid hormones = hyperthyroidism ( Grave‘s disease ) metabolism  intolerance to heat weight loss increased heart rate (tachycardia) GOITER (Latin STRUMA) = enlarged thyroid gland (function of the gland can be low, normal, high) Disorders

38. THYROID GLAND BLOOD FOOD very effective in uptake of I- from blood !!! I-, IO3-, ... Iodine is necessary for the synthesis of the thyroid hormones !!! thyroid peroxidase I2 2 I- iodination THYREOGLOBULIN proteolysis TSH (Thyroid-stimulating hormone) hormone release into the blood

39. thyreoglobulin uptake of I- I- Thyroid gland is composed of spherical "follicles" I2 T4, T3 release into blood follicular cells "Colloid" inside the follicles is rich in protein THYREOGLOBULIN

40. Iodine in food seafood - rich of iodine ! inland areas (Czech republic !!!) iodine deficiency  "endemic goiter"  "endemic cretenism" prevention: iodised SALT ( = table salt fortified with NaI, KI, or KIO3) ( 25 mg KI / 1 kg of salt )

41. Ferrum Cobaltum Niccolum Elements of group VIII Noble gases

42. Iron Fe (Ferrum) important microelement human body: 4–5 g Fe a) functional form - heme iron proteins hemoglobin 70 % myoglobin 5 % some enzymes - non-heme iron proteins b) tranport form (transferrin) c) storage of iron (ferritin, hemosiderin) 20 % Fe in food 10-30 mg/day absorption: only 7-10%  ~ 1 mg/day

43. HEME iron proteins Hemoglobin -O2 transport in blood - in red blood cells - tetramer = 4 subunits (each subunit: one heme + one globin) HbA ("adult") a2b2 HbF ("fetal") a2g2 Myoglobin- "O2 store" in muscle cell Cytochromes- electron transport - their function is based on: Fe2+ (reduced) Fe3+ (oxidized) heme

44. Non-heme iron proteins FeII or FeIII bound to protein SH iron–sulphur proteins (FeS proteins) Transferrin- blood plasma protein ( b1 globulin ) - transport of Fe - 1 molecule of transferrin can carry 2 iron ions in form of Fe3+ Ferritin - intracellular iron storage protein (liver, bone marrow) - 1 ferritin complex can store about 4500 Fe3+ - ferritin without iron = apoferritin Hemosiderin - "damaged (Fe-overloaded) ferritin" - Fe from it is less available

45. FOOD liver FERRITIN HEMOSIDERIN tissues CYTOCHROMES Fe-S proteins muscles MYOGLOBIN blood plasma TRANSFERRIN spleen FERRITIN bone marrow FERRITIN red blood cells HEMOGLOBIN BLEEDING (Fe losses) Overview of iron metabolism

46. Iron metabolism = unique - reutilization ! (closed system) NO regulated excretion system for Fe ! Fe absorption must be "regulated" Loss of Fe  through loss of blood (females - mestrual bleeding) Iron deficiency - microcytic anemia "iron deficiency anemia" Iron overload - hemochromatosis = accumulation of iron in the body (depositions as hemosiderin) organ dysfunction (liver, heart, ...)

47. FOOD Fe3+ STOMACH HCl pH 1-2 ascorbic acid gastroferrin - iron binding protein Iron absorption reduction Fe2+ Fe3+ BLOOD transferrin (Fe3+) ferritin (Fe3+) apoferritin Fe2+ INTESTINAL MUCOSA CELL

48. Cobalt Co (Cobaltum) trace element • central atom of vitamin B12 (cobalamin) (daily intake ~ 1 mg "the liver store": 3–5 years !) Vit. B12 deficiency megaloblastic anemia pernicious anemia– due to impaired absorption ! Absorption of vit. B12 B12 gastric parietal cells intrinsic factor complex B12– intrinsic factor absorption in terminal ileum