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Medical Chemistry (1 st year – GM) Lecture II MUDr. Vlastimil Kulda October 9 th , 2012

Medical Chemistry (1 st year – GM) Lecture II MUDr. Vlastimil Kulda October 9 th , 2012. Water. non-bonding electron pairs. O. H. H. H 2 O. 105 o. bent molecule. d -. O. -. polar character. H. H. +. d +. d +. electrical dipole. Hydrogen bonding. -.

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Medical Chemistry (1 st year – GM) Lecture II MUDr. Vlastimil Kulda October 9 th , 2012

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  1. Medical Chemistry (1st year – GM)Lecture IIMUDr. Vlastimil KuldaOctober 9th, 2012

  2. Water non-bonding electron pairs O H H H2O 105o bent molecule d- O - polar character H H + d+ d+ electrical dipole

  3. Hydrogen bonding - attractions between water molecules  HIGH melting point boiling point specific heat heat of vaporization surface tension + - + - - + + - + 0 oC 3.6 / H2O H bonds - much weaker than covalent bonds ! bond energy of H-bonds in liquid water: about 19 kJ/mol ( covalent H – O bond in water: 460 kJ/mol ) water is most dense at 3.98 °C !!! (when freezing, ice will form first on the surface)

  4. WATER - very good solvent ! Attraction between water dipoles and ions "hydrated ions" Dispersing "amphipathic" molecules "micelles"

  5. "Amphipathic" molecules – contain both highly hydrophobic and highly polar groups palmitic acid polar group = hydrophilic non-polar chain = hydrophobic (water-fearing) (water-loving) Phospholipids phosphatidylcholine (lecithin) polar groups

  6. Biological membranes - separate the cells separate the spaces (compartments) of the cell cell membrane mitochondria nucleus lysosome endoplasmic reticulum Phospholipid BILAYER hydrophilic hydrophobic hydrophilic

  7. Water in human body ~ 60 % of the body weight intracellular ~ 40 % extracellular ~ 20 % PLASMA 5 % interstitial fluid 15 % - a very complex solution of inorganic & organic components Na+K+ Ca2+ Mg2+ Phosphates Proteins Cl-HCO3- Phosphates Na+ K+Na+ Mg2+ K+ Na+/K+ pump ( = Na+/K+ -ATPase )

  8. Water balance Intake: ~ 1.5 - 2.0 l / day metabolic water(produced in human body by oxidation of food) 0.3 – 0.5 l /day Resorption: stomach, small intestine, LARGE INTESTINE Secretion: Saliva 1 500 ml / day Stomach 2 500 Bile 500 8 200 ml /day Pancreas 700 Small intestine 3 000 Excretion: Urine 60 % Skin 20 % (perspiration) Lungs 15 % Faeces 5 %

  9. Human blood plasma pH = 7.36 – 7.44 * Ca "total Ca" Ca2+ "ionized" is about ½ of "total" ~ 1.2 mmol/l

  10. Blood plasma ( extracellular fluid ) Cell fluid (cytosol) ( intracellular fluid )

  11. phospholipids cholesterol PROTEINS - enzymes - receptors - transport systems SELECTIVE permeability (membrane = barrier) The flow of molecules and ions between the cell and environment is precisely regulated by SPECIFIC TRANSPORT SYSTEMS They regulate cell volume, ionic composition, pH They concentrate metabolic fuels and building blocks from the environment The extrude toxic substances They generate IONIC GRADIENTS  essential for the excitability

  12. Transport across membrane 1) Passive transport - does not involve energy - diffusion from high to low concentration 2) Active transport - uses energy (ATP) - can transport against the concentration gradient - one direction, high specificity 3) Secondary active transport - no direct need of energy - gradient created by active transport is used ! "channels" "pumps" ATP

  13. 2 3 1 Passive transport concentration and electrochemical GRADIENT toward equilibrium 1) Simple diffusion small molecule, NO charge, solubility in lipids ! O2 CO2 2) Ion channels - pore-forming proteins - can be "GATED" 3) Facilitated diffusion ("carrier proteins") - selective ! - large molecules, insoluble in lipids "gate" is open "gate" is closed

  14. Ion transport antibiotics Gramicidin - peptide: 15 amino acids HELIX - hydrophilic groups inside "wet channel" - lipophilic groups outside increase of the permeability of bacterial cell wall inorganic ions can travel through equilibration of concentrations = NO GRADIENT "wide wet pore"

  15. K+ hydrophillic groups INSIDE = "WET cave" Valinomycin hydrophobic (lipophillic) groups OUTSIDE ( = soluble in lipids of membrane) K+ highly selective carrier for K+ ( Na+ with water coating is too big) K+ equilibration of K+ concentration = NO GRADIENT

  16. hydrophillic groups Valinomycin hydrophobic (lipophillic) groups

  17. ATP ADP + Pi Active transport = "PUMPS" Transport against GRADIENT ENERGY ! Na+/K+ ATPase (sodium potassium pump) ATP 3 Na+ INHIBITION: cardiotonic steroids 2 K+

  18. Na+/K+ ATPase in cell membrane of EVERY human cell ! electrogenic = transfers 3 Na+ out and ONLY 2 K+ into the cell  inner side of the membrane - outer side of the membrane+ inhibitors of this pump: cardiotonic steroids = cardiac glykosides (oubain, digoxin)  treatment of heart failure, cardiac arrhytmia Digitalis purpurea (foxglove)

  19. CO2 CO2 + H2O * H+ Cl- H2CO3 K+ ATP HCO3- HCO3- + H+ Cl- lumen of the stomach pH = 1 - 2 blood pH = 7.4 parietal cell H+/K+ ATPase stomach  gastric acid HCl * carboanhydrase Zn2+ 106 increase of H+ concentration !

  20. Na+ glucose Na+ Ca2+ Secondary active transport "COTRANSPORT" Na+ dependent transport of glucose, aminoacids, Ca2+ "energy" = Na+ gradient generated by Na+/K+ ATPase SYMPORT ANTIPORT

  21. glucose glucose Na+ Na+ ATP K+ Na+ - glucose symport proximal tubulus of each nephron in the kidneys resorption of glucose intestines  resorption of glucose from GI tract

  22. Na+/Ca2+ antiport = sodium–calcium EXCHANGER Ca2+ Ca2+ Na+ Na+ ATP K+ Ca2+ ATPase Na+/Ca2+ exchanger  very low concentration of Ca2+ in cytosol

  23. Endocytosis Large (polar) molecules – cannot pass through the hydrophobic membrane phagocytosis - cell ingests large object such as bacteria pinocytosis - uptake of solutes and molecules such as proteins receptor-mediated endocytosis – specific ! LDL receptor chylomicron remnant receptor receptors that mediates endocytosis of blood plasma lipoproteins cell absorbs material by engulfing it with its own membrane

  24. vesicles with neurotransmitter Exocytosis = the opposite of endocytosis Exocytosis is needed for: - secretion of large molecules from cells: glands  peptide hormones B cells  antibodies - neuronal chemical synapses: realease of the neurotransmitter receptor synaptic cleft

  25. H2O low osmolality Water transport across membranes Water moves by "simple diffusion" through membranes ? Additional mechanism for water transport: AQUAPORINS "water channels" Water transport - due to osmotic differences (osmotic gradient) OSMOSIS high osmolality

  26. The bioelements (summary) • Principal bioelements: O, C, N, H, P, S ( biomolecules: proteins, nucleic acids, lipids, saccharides ) • Water and ions ( H2O ) Na+, K+, Mg2+, Ca2+, Cl-, ( HCO3- , phosphates) • Mineral constituents of bones and teeth Ca PO43- • Microelements (trace elements) Fe, Cu, Co, Zn, I, F, Se, ... -------------------------------------------------------- 5) Contamination (intoxication): Hg, Al, ...

  27. Elements of group I Alkali metals Alkali metals - very reactive - react with air O2 and H2O - must be stored under oil

  28. Hydrogen H biogenic element - it is present in almost all organic compounds ! H2O H+ = proton (  H3O+ ) pH = - log [H+] The pH scale 0 7 14 alkaline (basic) sol. acidic solutions neutral

  29. water is weakly ionized: H2O H+ + OH- KW = [H+] x [OH-] = 10-14 mol2 / l2 ionic product of water pH + pOH = 14 pure water: [H+] = [OH-] = 10-7 mol/lpH = pOH = 7 ----------------------------------------------------------------------- Strong acids - fully ionised: monobasic acid: HCl H+ + Cl- dibasic acid: H2SO4 2 H+ + SO42- Weak acids– do not disociate completely: CH3COOH H+ + CH3COO- Strong bases: NaOH, KOH, Ca(OH)2 Weak base: NH4OH

  30. + - human blood plasma: pH = 7.40 0.04 gastric juice: pH = 1 – 2 pancreatic juice: pH = ~ 8 ----------------------------------------------------- H+ very low concentration in blood plasma !!! pH = 7.40 H+ = 0.000 040 mmol/l (40 nmol/l) (Na+ 142 mmol/l K+ 4.5 mmol/l) extreme influence of H+ on biological systems !!!  ionisation of functional groups in PROTEINS Ionisation of amino acids

  31. Lithium Li compounds: LiCl Li2CO3 crimson (red) colour of flame Therapy of manic-depressive psychosis (bipolar affective disorder) = alternating periods of mania (euphoria) and depression The manic phase - increased activity, decresased need for sleep - persistent elevated mood - impaired normal functioning ! The depressive phase - lack of energy - pessimistic - self-destructive behavior (risk of suicide !) Li+  changes of ion transport in CNS - still in use "mood stabilizing agent"

  32. Lithium mineral water – therapy of GOUT (type of arthritis) (Li-urate  more soluble than uric acid) Uric acid- in humans - the end product of purine catabolism - poorly soluble in water - lithium urate – more soluble !

  33. Sodium Na (Natrium) Na+ the main EXTRAcellular cation (132 – 145 mmol/l) Na+ strongly binds water ionic diameter: Na+ K+ !!! in hydrated form: Na+ larger in diameter than K+ Na+ ( together with Cl- ) large fraction of osmotic pressure (osmolality) of body fluids Water and Na balance are closely interdependent !

  34. NaCl daily intake: 5 – 15 g food (common salt) Elimination: urine (95 %) sweat (perspiration) stool Kidney BLOODGlomerular filtrate (180 l H2O / day) Glomerular filtration [ 1.5 kg NaCl ] Tubular resorption URINE 2 l H2O 5 – 15g NaCl dependent on hormones (aldosteron, ADH)

  35. Hormones regulating tubular resorption Aldosteron - steroid hormone (mineralocorticoid) - produced in the adrenal gland (adrenal cortex) - acting in the distal tubule of the kidney nephron: reabsorption of Na+ into blood secretion of K+ into urine Vasopressin = antidiuretic hormone (ADH) - peptide hormone - synthesized in the hypothalamus, released into blood in the pituitary gland (posterior part) - ADH increases the permeability of the collecting duct to water  allows water reabsorption  small volume of concentrated urine deficiency of ADH: DIABETES INSIPIDUS - polyuria - excretion of large amounts of diluted urine ( 10 – 20 l /day !)

  36. Potassium K (Kalium) K+ the main INTRAcellular cation (cytosol > 100 mmol/l) • human blood plasma: only 3.8 - 5.2 mmol/l • daily intake: ~ 4g of KCl excretion: URINE • proper concentrations of K+ and Na+  functions of membranes „membrane potential“ most cells – membrane potential relatively stable neurons, muscle cells – use changes of membrane potential for function ! (nervous system – communication between neurons)  action potential

  37. Na+/K+ ATPase Ion channels 3Na+ 2K+ Na+ EXTRAcellular fluid ATP ! cell membrane K+ 2K+ INTRAcellular fluid rising phase = depolarisation ACTION POTENTIAL falling phase = repolarisation resting potential

  38. In cells K+ is bound to GLYCOGEN ! Diabetic coma ( glucose in blood ) Glycogen synthesis Binding of K+ in cells Plasma K+ depletionHEART failure !!! insulin

  39. Copper Cu (Cuprum) microelement (in human body 100 - 150 mg) dietary intake: ~ 2 mg / day Cu2+ - cofactor of some enzymes: cytochrom c oxidase (metalloenzymes) superoxide dismutase - cofactor of HEME biosynthesis CERULOPLASMIN - transport of Cu2+ in blood plasma ( 8 Cu2+ / mol. ) - a2 globulin synthesized in the liver - enzymatic activity: Fe2+  Fe3+ WILSON‘s DISEASE - accumulation of copper in tissues (hepatolenticular degeneration) - low ceruloplasmin levels - hereditary disease - neurological symptoms, liver disease

  40. CuSO4 . 5 H2Ocopper (II) sulphate pentahydrate = „blue vitriol“ - in Fehling‘s solution (detection of glucose in urine) copper salts - poisonous ! ------------------------------------------- Hemocyanins - Cu2+ containing proteins - O2 transport - MOLLUSCA (snail, clam, mussel, ...) - ARTHROPODA (crabs)

  41. Silver Ag (Argentum) precious metal ( + H2S  Ag2S black ! ) AgBr - photosensitive  photography ------------------------------------------------------------------ Ag - useful in dental alloys for fittings and fillings ( Ag + Hg  amalgam ) AgNO3 - caustic effect  treatment of warts  Bartholin’s gland abscess in women (removal: silver nitrate stick insertion) - diluted solution: antiseptic properties  it was dropped into newborn‘s eyes to prevent gonococcal conjuntivitis ! (Gonorrhoea is a venereal disease caused by the bacteria Neisseria gonorrhoeae)

  42. Gold Au (Aurum) precious metal chemically and biologically resistent, inert in nature – almost exclusively in the native state pure gold – soft ! in jewellery: alloys (+ Cu, + Ag)  harder The gold content of gold alloys in carats or in thousandths pure gold: 24 carats = 1000/1000 The standard for high quality jewellery: 18 carats = 750 / 1000 What is the gold content (g) of a 100 g piece marked 18 carats? 18 24 x 100g = 75 g

  43. Elements of group II Alkaline earth metals

  44. Magnesium Mg PLANTS: Mg2+ -central atom of green pigment CHLOROPHYLL (photosynthesis) in human body: ~ 20 g Mg > ½ in bones ( Ca-Mg phosphates ) intracellular cation Mg2+ activates number of enzymes !!! ENZYMES using ATP "kinases" glucose glucose–6–phosphate (Enzymes of ATP-dependent reactions require Mg2+ as cofactor) hexokinase ADP ATP

  45. other effects of Mg2+: anti-convulsive effect (MgSO4 - prevention of eclamptic convulsions) influence on neuromuscular excitability can help to prevent kidney and gall stones "duodenal reflex" - MgSO4 delivered into the region of the sphincter of Oddi  relaxation of the sphincter + contraction of the gallbladder  expulsion of bile to intestine ( the bile release from the gallbladder is stimulated by Mg2+ ) Magnesium mineral water (Karlovy Vary)  purgative effect

  46. "burning" CaCO3 CaO + CO2 limestone, chalk quicklime "slaking" Ca(OH)2 CaO + H2O slaked lime Ca(OH)2 + CO2 CaCO3 + H2O Calcium Ca Hardening of mortar:

  47. Calcium Ca in human body ~ 1 kg (99% in bones, teeth) dietary intake: 800 - 1200 mg / day human blood plasma: "total Ca" 2.5 mmol/l (extracellular !) ionized Ca2+ 1.2 mmol/l resorption: ileum – specific protein carrier ~ 200 mg / day excretion: urine liver bile feces

  48. Hydroxyapatite Ca5 (PO4)3 OH Mineral constituents of bones and teeth Ca [ Mg, Sr, Na ] PO43- CO32- [ F-, Cl-] F - fluoroapatite enamel Enamel: - hardest substance of the body water 1-3 % organic comp. 1% mineral > 95 % (bones ~ 60 %) dentin cementum pulp

  49. Ca2+ in blood PTH Hormones regulating Ca metabolism Parathormone - peptide hormone ( 84 amino acids ) - secreted by parathyreoid glands - activation of bone mineral degradation  Ca2+ release from bones - stimulation of Ca2+ readsorption in kidney - stimulation of calcitriol formation (kidneys) - stimulation of Ca-resorption protein formation (ileum)

  50. Ca2+ in blood Calcitonin - peptide hormone ( 32 amino acids ) - produced by parafollicular cell of the thyreoid gland - inhibition of bone mineral degradation (decrease of „osteoclasts“ activity) - stimulation of Ca2+ excretion in kidney Salmon calcitonin is used for the treatment of OSTEOPOROSIS

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