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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

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medical chemistry 1 st year gm lecture iii mudr vlastimil kulda october 16 th 2012

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

slide3

 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

slide4

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)
slide5

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 ]

slide6

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

slide7

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

slide8

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 !

slide9

2) Nitrosamines

Nitrites can react with secondary amines  Nitrosamines

CARCINOGENS !

Nitrites in food - meat and cheese products preserved with

nitrite pickling salt !!!

slide10
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
slide11

ATP + H2O ADP + Pi + energy

ATP + H2O AMP + PPi + energy

pyrophosphate

ester bond

phosphoanhydride

bonds

ATP = adenosine triphosphate

DE = - 30.5 kJ/mol

slide12

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)

slide13

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 !

slide14

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)

slide15

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

slide16
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

slide18

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

slide19
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+

slide20

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 !

slide21

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 )

slide22

cysteine ( Cys )

Amino acids containing sulphur

methionine ( Met )

- essential amino acids

- in proteins

slide23

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

slide24

sulfate groups - modification of polysaccharides

(heparine, chondroitin sulfate, keratan sulfate, ...)

------------------------------------------------------------------------------

Vitamins containing S

important

COENZYMES

lipoic acid

biotin

vitamin B1 (thiamin)

slide25

coenzyme A

Coenzyme A - thiol

pantothenic acid

- acyl group carrier

thiol + carboxylic acid  thioester

("high energy bond")

Acetyl-CoA

important molecule in metabolism

slide26
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

slide28
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, ...)

slide29
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

slide30
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 !

slide31

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

slide32

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)

slide33
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 ?)

slide34

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 !
slide35
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

slide36

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 !)

slide37

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

slide38

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

slide39

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

slide40
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 )

slide41

Ferrum

Cobaltum

Niccolum

Elements of group VIII

Noble gases

slide42
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

slide43
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

slide44
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

slide45

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

slide46
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, ...)

slide47

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

slide48
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