Download Medical Chemistry Lecture III

Elements of group V
VA
VB
N
Nitrogenium
V
P
Phosphorus
Nb
As
Arsenicum
Ta
Sb
Stibium
Bi
Bismuthum
Vanadium
Nitrogen
N2
N
78% of the atmosphere
- principal bioelement:
(Nitrogenium)
- chemically rather inert
organic compounds ( "NH3 derivatives" )
AMINO ACIDS

PROTEINS
many heterocyclic compounds
pyrimidine
 uracil, thymine, cytosine
NUCLEIC ACIDS
(DNA, RNA)
purine
 adenine, guanine
NH3
ammonia
- sharp odour
toxic properties for animals
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
NO2
Nitric oxide [ Nitrogen monoxide ]
Nitrogen dioxide - reddish-brown gas
in the environment
-toxic gases
(Photochemical smog)
Biological functions of NO
= important gaseous signaling molecule !!!
EDRF = endothelium-derived relaxing factor
=
NO
Endothelial cell
NO
Smooth muscle cell
NO synthesis
diffusion
relaxation
Nitroglycerin  vasodilator
NO
- treatment of angina pectoris
(a lack of blood suply of heart muscle  chest pain)
Nitroglycerin = glyceryl trinitrate - oily explosive liquid
[ DYNAMITE ]
Biochemical formation of NO
Arginine
(amino acid)
enzyme: NO
synthase
NO
halflife: ~ 4 sec.
Citrulline
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
HNO2
Nitrous acid (INN: Acidum nitrosum)
salts: nitrites
NaNO2
- weak acid, not stable
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
Amyl nitrite – treatment of angina pectoris
HNO3
Nitric acid
(INN: Acidum nitricum)
- strong acid
- oxidazing agent !
salts:
nitrates
AgNO3
Silver nitrate (INN: Argenti nitras)
Toxicity of NO2- (NO3-)
NO3-
intestinal bacteria can reduce nitrates to nitrites:
Limits for drinking water: NO3-
50 mg/l
1) Methemoglobinemia
HEMOGLOBIN
adults
15 mg/l
NO2infants
"blue baby syndrom"
nitrites
METHEMOGLOBIN
FeIII
FeII
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- / HPO42-
3) Nucleotides, DNA, RNA
4) Structural lipids (phospholipids) - membranes !
5) Metabolic intermediates (Glucose–6–phosphate, ...)
6) High energy compounds ATP
ATP = adenosine triphosphate
ester bond
phosphoanhydride
bonds
ATP + H2O
ADP + Pi + energy
ATP + H2O
AMP + PPi + energy
pyrophosphate
DE = - 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":
hexokinase
ATP
glucose
ADP
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, soman, tabun - "nerve gases"
Sarin
- extremely toxic substances !!!
- chemical weapons of mass destruction
very potent insecticid
Parathion
also highly toxic !
inhibition of the enzyme acetylcholinesterase !
neuronal synapse 
neurotransmitter 
receptor 
effect
receptor
synaptic cleft
2)
vesicles with
neurotransmitter
1)
Neurotransmitter must be removed from the synaptic cleft (after its job is done) !
1) REUPTAKE
2) Enzymatic breakdown into inactive fragments - ACETYLCHOLINE
(acetylcholinesterase)
Cholinergic synapses
( neurotransmitter = acetylcholine )
botulinum toxin
vesicles with
acetylcholine (ACH)
(release of ACH is blocked)
organophosphates
synaptic cleft
(acetylcholinesterase is blocked)
*
ACH receptor
ATROPINE
(ACH receptor is blocked)
* acetylcholinesterase
*
acetylcholine
choline
acetic acid
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
Chalcogens
VI B
O
Oxygenium
Cr
Chromium
S
Sulfur
Mo
Molybdaenum
Se
Selenium
W
Wolframium
Te
Tellurium
Po
Oxygen
O2
O
(Oxygenium)
21% of the atmosphere
- principal bioelement:
- OH
H2O
many functional groups in biomolecules
"hydroxyl group"
alcohols, phenols
O
"carbonyl group"
aldehydes, ketones
- COOH
"carboxyl group"
carboxylic acids
C
electron acceptor in biologically important oxidations !
O2 + 4 e-
2 O2-
+ 4 H+
2 H2O
Oxygen radicals
- TEXTBOOK (Toxicity of oxygen)
very reactive  can cause damage to most cell components !!!
O2 + e-
O2-
superoxide radical
+ H+
O2H
perhydroxyl radical
(hydroperoxyl)
H2O2 + e-
OH-
ROS = reactive oxygen species
+
OH
hydroxyl radical
"free radicals" + H2O2 , ....
Sulphur
S
(Sulfur)
- principal bioelement
H2S
- SH
Hydrogen sulphide
- strong poison
- gas with odour of rotten eggs
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)
salts: sulphites
H2SO4
Sulphuric acid
( ........ sulfis )
(INN: Acidum sulfuricum)
salts: sulphates
H2S2O3
- weak acid
Thiosulphuric acid
- strong acid
( ........ sulfas )
(INN: Acidum thiosulfuricum)
salts: thiosulphates
( ........ thiosulfas )
H2S
Hydrogen sulphide
salts: sulphides
(INN: Acidum hydrosulfuricum)
( ........ sulfuridum )
Amino acids containing sulphur
cysteine ( Cys )
methionine ( Met )
- essential amino acids
- in proteins
Redox reactions
R
SH
-2H
R‘
SH
+
R
2H
S
disulfide bond
-S–S-
R‘ S
disulfide bonds stabilize the folded form of a protein
S
S
S
S
S
S
intermolecular -S-S- bonds
R
SH
oxidation
R
intramolecular -S-S- bond
O
S
O
OH
"sulfates"
sulfate groups - modification of polysaccharides
(heparine, chondroitin sulfate, keratan sulfate, ...)
------------------------------------------------------------------------------
Vitamins containing S
important
lipoic acid
vitamin B1 (thiamin)
COENZYMES
biotin
Coenzyme A - thiol
pantothenic acid
- acyl group carrier
thiol + carboxylic acid  thioester
("high energy bond")
coenzyme A
Acetyl-CoA
important molecule in metabolism
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
Halogens
VII B
F
Fluorum
Mn
Cl
Chlorum
Tc
Br
Bromum
Re
I
At
Iodum
Manganum
Fluorine
trace element
Ca5(PO4)3F
F
(Fluorum)
F2
fluorapatite
yellowish very reactive gas
- 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
Cl2
Cl
(Chlorum)
pale green poisonous gas, suffocating odour
World War I
chemical weapon  destruction of lungs !
(it was soon replaced by more deadly gases – phosgene, ...)
O
COCl2
Cl
Cl2 + H2O
HClO
HCl
HCl
Chlorination of water
+
+
HClO
O
- to KILL bacteria
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 !
phosgene !
- 2 CHCl3 + O2
2 HCl + 2 COCl2
(war gas)
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
DDT
(dichloro-diphenyl-trichloroethane)
best known banned pesticide
(insecticide)
high solubility in lipids !
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)
Polychlorinated biphenyls PCBs
biphenyl
good technical properties  were used as: insulating materials
cooling fluids in transformers
additives in plastics
PROBLEM: very stable ! = persistent pollutants
contamination of soil
plants
animals
BANNED
cumulation in lipids, milk
(carcinogens ?)
DIOXIN
tetrachlorodibenzo-1,4-dioxin
TCDD
(the most toxic dioxin)
general poison
LD50 = 10 - 100 mg/kg
very stable, very resistant (up to 800o C)
("lethal dose")
 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 )
desinfectant
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
Thyroid hormones
T4
thyroxine
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 !)
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 !!!
FOOD
THYROID
GLAND
BLOOD
I-, IO3-, ...
very effective in
uptake of Ifrom blood !!!
thyroid
peroxidase
2 I-
I2
iodination
THYREOGLOBULIN
TSH (Thyroid-stimulating hormone)
proteolysis
hormone release into the blood
Thyroid gland is composed of spherical "follicles"
uptake of I-
I-
thyreoglobulin
I2
T4, T3 release
into blood
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
Noble
gases
VIII B
Ferrum
He
Fe
Co
Ni
Cobaltum
Ne
Ru
Rh
Pd
Niccolum
Ir
Pt
Ar
Kr
Xe
Rn
Os
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
HbF
("adult")
a2b2
("fetal")
a2g2
Myoglobin - "O2 store" in muscle cell
Cytochromes
heme
- electron transport
- their function is based on:
Fe2+ (reduced)
Fe3+ (oxidized)
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
Overview of iron metabolism
FOOD
tissues
CYTOCHROMES
Fe-S proteins
liver
FERRITIN
HEMOSIDERIN
muscles
MYOGLOBIN
blood plasma
TRANSFERRIN
bone marrow
FERRITIN
spleen
FERRITIN
red blood cells
HEMOGLOBIN
BLEEDING (Fe losses)
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
Iron deficiency - microcytic anemia
Iron overload
- mestrual bleeding)
"iron deficiency anemia"
- 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
reduction
Fe2+
Fe3+
apoferritin
BLOOD
ferritin
(Fe3+)
INTESTINAL MUCOSA CELL
Fe2+
transferrin (Fe3+)
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
gastric parietal cells
B12
intrinsic factor
complex B12 – intrinsic factor
absorption in terminal ileum