medical chemistry (1 st year – gm) lecture iii mudr. vlastimil kulda october 16 th , 2012
DESCRIPTION
Medical Chemistry (1 st year – GM) Lecture III MUDr. Vlastimil Kulda October 16 th , 2012. Elements of group V. adenine, guanine. Nitrogen N (Nitrogenium) N 2 78% of the atmosphere- chemically rather inert - PowerPoint PPT PresentationTRANSCRIPT
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Elements of group V
V A V B
N Nitrogenium V Vanadium
P Phosphorus Nb
As Arsenicum Ta
Sb Stibium
Bi Bismuthum
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Nitrogen N (Nitrogenium)
N2 78% of the atmosphere - chemically rather inert
- principal bioelement: organic compounds ( "NH3 derivatives" )
AMINO ACIDS PROTEINS
many heterocyclic compounds
pyrimidine
purine
uracil, thymine, cytosine
adenine, guanine
NUCLEIC ACIDS
(DNA, RNA)
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NH3 ammonia - 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 ]NO2 Nitrogen dioxide - reddish-brown gas
toxic properties for animals
in the environment
-toxic gases
(Photochemical smog)
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Biological functions of NO
= important gaseous signaling molecule !!!
EDRF = endothelium-derived relaxing factor = NO
NO synthesis
Endothelial cell
relaxation
Smooth muscle cellNO
diffusion
Nitroglycerin = glyceryl trinitrate - oily explosive liquid [ DYNAMITE ]
NO
Nitroglycerin vasodilator
- treatment of angina pectoris
(a lack of blood suply of heart muscle chest pain)
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Biochemical formation of NO
Arginine (amino acid)
Citrulline
NOenzyme: NO synthase
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
halflife: ~ 4 sec.
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HNO2 Nitrous 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
HNO3 Nitric acid (INN: Acidum nitricum) - strong acid
- oxidazing agent !
salts: nitrates AgNO3 Silver nitrate (INN: Argenti nitras)
Amyl nitrite – treatment of angina pectoris
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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"
HEMOGLOBIN
FeII
METHEMOGLOBIN
FeIII
nitrites
unable to transfer O2
methemoglobin reductase
"protective enzyme" - insufficient in infants !
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2) Nitrosamines
Nitrites can react with secondary amines Nitrosamines
CARCINOGENS !
Nitrites in food - meat and cheese products preserved with
nitrite pickling salt !!!
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Phosphorus P
- principal bioelement
H3PO4 Phosphoric acid (INN: Acidum phosphoricum)
- in biochemistry: "phosphates" = esters of H3PO4
1) Bone and tooth mineral: hydroxyapatite Ca5(PO4)3OH
2) Anions in body fluids: H2PO4- / HPO4
2-
3) Nucleotides, DNA, RNA
4) Structural lipids (phospholipids) - membranes !
5) Metabolic intermediates (Glucose–6–phosphate, ...)
6) High energy compounds ATP
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ATP = adenosine triphosphate
phosphoanhydride bonds
ester bond
ATP + H2O ADP + Pi + energy
ATP + H2O AMP + PPi + energy
pyrophosphate
E = - 30.5 kJ/mol
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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 ADP
hexokinase
glucose glucose-6-P
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)
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Organophosphate neurotoxins
Sarin
Parathion
Sarin, soman, tabun - "nerve gases"
- extremely toxic substances !!!
- chemical weapons of mass destruction
very potent insecticid
also highly toxic !
inhibition of the enzyme acetylcholinesterase !
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neuronal synapse neurotransmitter receptor effect
vesicles with neurotransmitter
synaptic cleft receptor
Neurotransmitter must be removed from the synaptic cleft (after its job is done) !
1) REUPTAKE
2) Enzymatic breakdown into inactive fragments - ACETYLCHOLINE
(acetylcholinesterase)
1)
2)
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Cholinergic synapses ( neurotransmitter = acetylcholine )
ACH receptor
vesicles with acetylcholine (ACH)
acetylcholine choline acetic acid
*
synaptic cleft
botulinum toxin (release of ACH is blocked)
ATROPINE(ACH receptor is blocked)
organophosphates(acetylcholinesterase is blocked)
*
* acetylcholinesterase
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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
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Elements of group VI
VI A VI B
O Oxygenium Cr Chromium
S Sulfur Mo Molybdaenum
Se Selenium W Wolframium
Te Tellurium
Po
Chalcogens
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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 acidsC O
electron acceptor in biologically important oxidations !
O2 + 4 e- 2 O2- 2 H2O+ 4 H+
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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+
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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)
protein SH
SH
Toxic heavy metals ( Pb, Hg, As, ...) - block sulfhydryl groups !
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H2SO3 Sulphurous acid (INN: Acidum sulfurosum) - weak acid
salts: sulphites ( ........ sulfis )
H2SO4 Sulphuric 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 )
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Amino acids containing sulphur
cysteine ( Cys )
methionine ( Met )
- essential amino acids
- in proteins
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Redox reactions
R SH R S
R‘ SH R‘ S
- 2 H
+ 2 Hdisulfide bond - S – S -
disulfide bonds stabilize the folded form of a protein
S
S
S
S
S
S
intramolecular -S-S- bondintermolecular -S-S- bonds
R SH R S OH
O
O
"sulfates"oxidation
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sulfate groups - modification of polysaccharides
(heparine, chondroitin sulfate, keratan sulfate, ...)
------------------------------------------------------------------------------
Vitamins containing S
lipoic acid
biotinvitamin B1 (thiamin)
important
COENZYMES
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coenzyme A Acetyl-CoA
important molecule in metabolism
Coenzyme A - thiol
("high energy bond")
- acyl group carrier thiol + carboxylic acid thioester
pantothenic acid
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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
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Elements of group VII
VII A VII B
F Fluorum Mn Manganum
Cl Chlorum Tc
Br Bromum Re
I Iodum
At
Halogens
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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, ...)
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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
COCl2
O
Cl C Cl
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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 !
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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
phosgene !
(war gas)
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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)
best known banned pesticide (insecticide)
high solubility in lipids !
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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 ?)
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DIOXIN
tetrachlorodibenzo-1,4-dioxin
TCDD
(the most toxic dioxin)
general poison LD50 = 10 - 100 g/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)
1976 Seveso (Italy) - industrial accident – uncontrolled reaction
explosion of chemical reactor cloud containing dioxin !
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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 -amylose – linear polymer of glucose
amylopectin – branched polymer of glucose
- polysaccharide of PLANTS in FOOD
desinfectant
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Thyroid hormones
T4 thyroxine
T3 triiodothyronine
smaller quantity, greater
activity !
deiodinases in tissues
Se (selenocysteine) !
Function: stimulation of metabolism (act to increase the metabolic rate)
essential to proper development (BRAIN !)
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Disorders
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)
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Iodine is necessary for the synthesis of the thyroid hormones !!!
THYREOGLOBULIN
hormone release into the blood
proteolysisTSH (Thyroid-stimulating hormone)
2 I- I2
iodination
thyroid peroxidase
FOOD BLOODTHYROID GLAND
very effective in uptake of I-
from blood !!!I-, IO3-, ...
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Thyroid gland is composed of spherical "follicles"
thyreoglobulin
T4, T3 release into blood
I2
uptake of I-
I-
follicular cells
"Colloid" inside the follicles is
rich in protein
THYREOGLOBULIN
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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 )
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Elements of group VIII
VIII A VIII B
He Fe Co Ni
Ne Ru Rh Pd
Ar Os Ir Pt
Kr
Xe
Rn
Ferrum
Cobaltum
Niccolum
Noble gases
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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
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HEME iron proteins
Hemoglobin - O2 transport in blood
- in red blood cells
- tetramer = 4 subunits
(each subunit: one heme + one globin)
HbA ("adult") 22
HbF ("fetal") 22
Myoglobin - "O2 store" in muscle cell
Cytochromes - electron transport
- their function is based on: Fe2+ (reduced) Fe3+
(oxidized)
heme
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Non-heme iron proteins FeII or FeIII bound to protein SH
iron–sulphur proteins (FeS proteins)
Transferrin - blood plasma protein ( 1 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
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Overview of iron metabolism
liver
FERRITIN HEMOSIDERIN
blood plasma
TRANSFERRIN
bone marrow
FERRITIN
red blood cells
HEMOGLOBIN
spleen
FERRITIN
tissues
CYTOCHROMES
Fe-S proteins
muscles
MYOGLOBIN
BLEEDING (Fe losses)
FOOD
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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, ...)
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Iron absorption
FOOD Fe3+
STOMACH
HCl pH 1-2
ascorbic acid
gastroferrin - iron binding protein
Fe2+
reduction
INTESTINAL MUCOSA CELL
Fe3+
apoferritin ferritin (Fe3+)
BLOOD
transferrin (Fe3+)Fe2+
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Cobalt Co (Cobaltum)
trace element
- central atom of vitamin B12 (cobalamin)
(daily intake ~ 1 g "the liver store": 3–5 years !)
Absorption of vit. B12
gastric parietal cells intrinsic factor
absorption in terminal ileum
B12
complex B12 – intrinsic factor
Vit. B12 deficiency
megaloblastic anemia
pernicious anemia – due to impaired absorption !