Medical Chemistry (1 st year – GM) Lecture III MUDr. Vlastimil Kulda October 16 th , 2012
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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
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)
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)
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)
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.
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
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 !
2) Nitrosamines
Nitrites can react with secondary amines Nitrosamines
CARCINOGENS !
Nitrites in food - meat and cheese products preserved with
nitrite pickling salt !!!
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
ATP = adenosine triphosphate
phosphoanhydride bonds
ester bond
ATP + H2O ADP + Pi + energy
ATP + H2O AMP + PPi + energy
pyrophosphate
E = - 30.5 kJ/mol
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)
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 !
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)
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
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
Elements of group VI
VI A VI B
O Oxygenium Cr Chromium
S Sulfur Mo Molybdaenum
Se Selenium W Wolframium
Te Tellurium
Po
Chalcogens
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+
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+
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 !
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 )
Amino acids containing sulphur
cysteine ( Cys )
methionine ( Met )
- essential amino acids
- in proteins
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
sulfate groups - modification of polysaccharides
(heparine, chondroitin sulfate, keratan sulfate, ...)
------------------------------------------------------------------------------
Vitamins containing S
lipoic acid
biotinvitamin B1 (thiamin)
important
COENZYMES
coenzyme A Acetyl-CoA
important molecule in metabolism
Coenzyme A - thiol
("high energy bond")
- acyl group carrier thiol + carboxylic acid thioester
pantothenic acid
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
Elements of group VII
VII A VII B
F Fluorum Mn Manganum
Cl Chlorum Tc
Br Bromum Re
I Iodum
At
Halogens
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, ...)
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
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 !
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)
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 !
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 ?)
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 !
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
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 !)
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)
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-, ...
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
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 )
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
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
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
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
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
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, ...)
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+
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 !
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