NATURAL MEDICAMENTS DERIVED FROM ACETIC ACID
POLYKETIDES
Large group of structurally very different compounds
Initial compound is acetylcoenzyme A, which is formatted by
• activation of acetic acid (with help of coenzyme A and ATP)
CH3–COOH + HS–CoA + ATP → CH3CO~CoA + AMP + diphosphate
• oxidative decarboxylation of pyruvic acid
Pyruvic acid is in living organisms formed by decomposition of sugars via reaction chain of
glycolysis.
Aerobic conditions → acetylcoenzyme A
CH3–CO–COOH + HS – CoA + NAD → CH3–CO~S–CoA + CO2 + NADH2
Anaerobic conditions → reduction – lactic acid (in muscles and during milk fermentation)
decarboxylation (alcohol fermentation)
TWO FUNCTIONAL PROPERTIES OF ACETYLCOENZYME A
Via activation of α-hydrogen atoms of acetyl methyl group (enzymatic
deprotonation) acquire carbon atom anionic character.
Extraordinary electrophillic character of carbonyl group of thioester provides site
for nucleophilic attack; at polyketides it is anionic C atom (carbanion) of
deprotonated ester.
CH3
CO SCoA
-H+
..C CO SCoA
-
CH3
CO SCoA
H CH2
CO SCoAB CH2CO SCoA
+ CoA SH
CH3
CO
FORMATION OF β-POLYCARBONYL SUBSTANCES
CH3
SCoA
O
CH2
SCoA
O
O O H
CH3
O
C
H2
SCoA
SCoA
O
CO2
C
H2
SCoA
OO
CH3
CH2
SCoA
O
O O H
C
H2
SCoA
OO
CH3 n
CO2
CH3
COCH2
CO SCoA
CH3
CO SCoA
CH3
COCH2
COCH2
CO SCoA + CoA-SH
Nucleophilic attack at carbonyl,
simultaneous loss of CO2
Claisen reaction
Acetoacetyl-CoA
Malonyl-CoA
Repeated
Claisen
reaction
Poly-β-ketoester
POLYKETO SUBSTANCES ARE VERY REACTIVE
(ethylene group located between two carbonyl groups)
O
OH
O
CH3
O
C5
alkylation or hydroxylation
of methylene group
O O
O O O O
coupling via oxidative reaction of enols
including cyclisations leading to
a pannel of structurally very different compounds
CH2
CO CH2
CH2
CH2CHOH
reduction of of ketogroup to an alcohol
RCOCH2COOH RCOCH3
RCOCH2COOH RCOCH2CO SCoA
-CO2
decarboxylation leading to formation of compounds with odd number of carbon atoms
activation of COOH group via formation of thioester
DIVISIONS OF ACETOGENINS
ALIPHATIC
• Satturated fatty acids
• Unsattuated fatty acids
• Polyacetylene substances
• Prostaglandins
CYCLIC
• Phenols and their derivatives
• Anthraquinones
• Tetracyclines
• Griseofulvine
• Lichen acids
• Phloroglucinol derivatives
• Macrolides
ALIPHATIC ACETOGENINES
SATURATED FATTY ACIDS
CH3
CO SCOA
COOH
CH2
CO SCoA
RCH2
CO SCoA
CHCH2
CO SCoA
OH
RCH2
RCH2
CH CHCO SCoA RCH2
CH2
CH2
CO SCoA
RCH2
CH2
CH2
COOHn
RCH2
CO CH2
CO-SCoA
CO2 ATP
biotine, enzyme
x
x
malonylcoenzyme A
ROLE OF BIOTINE DURING CARBOXYLATION OF ACETYLCOENZYME A
NNH
S
COOH
O
COOH NHNH
S
COOH
O
CH3CO SCoA
CH2CO SCoA
COOH +
malonyl-CoA
biotineN-carboxylic acid of biotine
SYNTHESIS OF FATTY ACIDS
protein acyl carrier – fatty acids synthase
CH3CO SCoA CH2COHOOC SCoA
CH2COHOOC SE
RCH2CO SE
RCH2
COCH2
CO SE ESH CO2
NAD
NADH
RCH2
CH
OH
CH2
CO SE
RCH2CH CHCO SE
RCH2 CH2 CH2CO SE
FADFADH CoASH
RCH2CH2CH2CO SCoA ESH
(2)
enzyme containing
SH group = ESH
(3)
+ +
+
(4)
(5)
intering raection
(6)
+
final product (free acid, glyceride etc.)
CO2 ATP
biotine - enzyme
(1)
(3)
SUBSTITUTION OF ACETYLCOENZYME A FOR
DIFFERENT ACYL-CoA
(CoA esters of propionic acid, isobutyric, isovaleric etc.)
CH3COOH CH3
(CH2
CH2
)7
COOH
CH3
CH2
COOH CH3
CH2
(CH2
CH2
)7
COOH
CH3
CH2
CH(CH3
)COOH CH3
CH2
CH(CH3
)(CH2
CH2
)6
COOH
CHCOOH
CH3
CH3
CH(CH2
CH2
)7
COOH
CH3
CH3
Initial reactant
as acetyl-CoA
Produced acid Number of C atoms
16
17
17
18
THE MOST COMMON SATTURATED FATTY ACIDS
C6 CH3
(CH2
)4
COOH
C8 CH3
(CH2
)6
COOH
C10 CH3
(CH2
)8
COOH
C12 CH3(CH2)10COOH
C14 CH3
(CH2
)12
COOH
C16 CH3
(CH2
)14
COOH
C18 CH3
(CH2
)16
COOH
C20 CH3(CH2)18COOH
n-hexanoic (capronic acid)
n-octanoic (caprylic acid)
n-decanoic (caprinic acid)
n-dodecanoic (lauric acid)
n-tetradecanoic (myristic acid)
n-hexadecanoic (palmitic acid)
n-octadecanoid (stearic acid)
n-eicosanoic (arachidonic acid)
UNSATURATED FATTY ACIDS
CH3
(CH2
)14
COOH
CH3
(CH2
)16
COOH
CH3
(CH2
)7
CH CH(CH2
)7
COOH
CH3
(CH2
)4
CH CHCH2
CH CH(CH2
)7
COOH
CH3
CH2
CH CHCH2CH CHCH2CH CH(CH2)7COOH
acetate+ malonate
c
c c
c cc
palmitic acid
stearic acid
oleic acid
linoleic acid
linolenic acid
-2H
-2H
-2H
Formation of unsaturated fatty acids via direct dehydrogenation
( 9)
( 6)
( 3)
UNSATURATED FATTY ACIDS
CH3
(CH2
)7
CH2
C
H
OH
CH2
CO SCoA CH3
(CH2
)7
CH CHCH2
CO SCoA
-H2O
+ 3 x C2 units
oleic acid
Formation of unsaturated fatty acids via hydroxyacids
c
THE MOST COMMON UNSATURATED FATTY ACIDS
C18
CH3
(CH2
)7
CH=CH(CH2
)7
COOH
C18
CH3
(CH2
)4
CH=CHCH2
CH=CH(CH2
)7
COOH
C18
CH3
CH2
CH=CHCH2
CH=CHCH2
CH=CH(CH2
)7
COOH
C18
CH3
(CH2
)5
(CHOH)CH2
CH=CH(CH2
)7
COOH
C22
CH3
(CH2
)7
CH=CH(CH2
)11
COOH
cis-9-octadecenoic acid oleic acid
cis,cis-9,12-octadecadienic acid linoleic acid
cis,cis,cis-9,12,15-octadecatrienic acid linolenic acid
12-hydroxy-cis-9-octadecenoic ricinoleic acid
cis-13-docosenoic erucic acid
CH3
(CH2
)7
CH CH(CH2
)7
COOH
CH3
(CH2
)5
CH
OH
CH2
C
H
CH(CH2
)7
COOH CH3
S CH2
CH2
C
H
NH3
+
COO
C
H
C
H
CH3(CH2)7 (CH2)7COOH
CH2
C CCH3
(CH2
)7
(CH2
)7
COOH
CH2
SCoA
OCH2
H
C CCH3
(CH2
)7
(CH2
)6
COOH
CH2
oleic
acid
ricinoleic acid methionine
dihydrosterculic acid
sterculic acid
malvic acid
UNSATURATED FATTY ACIDS
MALVACEAE, STERKULIACEAE
α-oxidace
UNSATURATED CYCLIC ACIDS – HYDNOCARPACEAE
(CH2)10COOH (CH2
)12
COOH
(C12
H22
)COOH
hydnocarpic acid chaulmoogric acid
gorlic acid
COSCoA
malonyl-CoA
Esters with glycerol
OP
OH
OH
OP
O
OH
COR1
R1
COSCoA R2COSCoA
OP
O
R2COO
COR1
OH
O
R2COO
COR1
OH2
O
O
R2COO
COR1
COR3
R3
COSCoA
O
O
R2COO
COR1
P
O
OH
OR3
O
O
CH3COO
(CH2)15CH3
P
O
OH
OCH2CH2N(CH3)3
CH2
CH2
N(CH3
)3
CH2CH2NH3
CH2CHCOOH
NH2
OH
OH
OH
OH
OH
PAF
Desaturation of stearic acid
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
CO
SR
Stearic acid 18:0
Desaturation via direction
to terminal methyl
Plants
Fungi
Oleic acid 18:1 (9c) Linoleic acid 18:2 (9c, 12c) α-linolenic acid 18:3 (9c, 12c, 15c)
Desaturation via direction
to carboxyl
18:2 (9c, 6c) γ-linolenic acid 18:3 (6c, 9c, 12c) Stearidonic acid 18:4 (6c, 9c, 12c, 15c)
Eicosatetraenic acid 20:4 (8c, 11c, 14c, 17c)Dihomo-γ-linolenic acid 20:3 (8c, 11c, 14c)
Eicosapentaenic acid 20:5 (5c, 8c, 11c, 14c, 17c)
Docosapentaenic acid 22:5 (7c, 10c, 13c, 16c, 19c)Docosahexaenic acid 22:6 (4c, 7c, 10c, 13c, 16c, 19c)
R acyl carrier protein/SCoA
Zvíře Animals Animals
+C2 (malonát) +C2 (via malonate)
+C2 (via malonate)
Prostaglandines of the
1st class
Prostaglandines of the
2nd class
Prostaglandines of the
3rd class
Arachidonic acid 20:4 (5c, 8c, 11c, 14c)
Essential fatty
acids
Omega-3 mastné
kyseliny
Oenothera biennis
Borago officinalis
Fishes cod-liver oil
Enzyme of deasaturation
Disorders: age, diabetes,
alcoholism, stress, inhibition
by high intake of trans acids
Mother milk, black currant
Plants
Fungi
POLYACETYLENIC SUBSTANCES, POLYINES
ASTERACEAE, DAUCACEAE, ARALIACEAE
CH3(CH2)4 C54
C55
CH2CH CH (CH2)7COOH
C)3 CH CH CH2OH
C)3 CH CH COOCH3
C)4 CH CH CH CH2CH3 (C
CH3 (C
CH3 (C
C)3 CH CHCH3 (C CH CH (CH2)2CH2OH
oleic acid
linolenic acid
crepeninic acid
c
dehydromatricarianol
dehydromatricaria-ester
t
t
Polyines possess toxicological importance
Dahlia sp. (Asteraceae)
Occurrence: Cicuta virosa, Cowbane or Northern Water Hemlock, Apiaceae
Aethusa cynapium - Fool's Cicely or Poison Parsley (Apiaceae)
POLYACETYLENIC SUBSTANCES, POLYINES
ANTIBIOTICS
C C C C
H
C C
H
C
H
C
H
CH C CH CH2
COOH
CH C C C CH C CH CH
OH
CH2
CH2
COOH
Nocardia acidophyllus (Actinomycetes) produces MYCOMYCIN
side product = nemotinic acid
POLYACETYLENIC SUBSTANCES, POLYINES
ASTERACEAE
O
CH2
CC
CO C C C C CH3
carlina oxide
capillin (fungistatic)
Carlina acaulis [root] - stemless carline thistle
r. Artemisia - wormwood
PROSTAGLANDINS
11
9
CO2
H
O
O
O O
COOH
9
11
OH
O
OH
CO2H
11
9
CO2H
O
O
O
O
COOH
O OH
O
O
O
COOH
OH
OH
OH
 8,11,14-eicosatrienic acid
cyclic endoperoxide
thromboxane B2
prostacycline
PGE1
LINOLENIC ACID
COX
PGG2
Prostaglandins
O
R1
R2
O
R1
R2
O
R1
R2
OH
R1
R2
O
O
R1
R2
OH
OH
R1
R2
OH
COOH
COOH
COOH
OH
OH
OH
R1
O OH
O
O R1
O
O
R2
R2
O
COOH
OH
PGA PGB PGC PGD PGE PGF
PGG
PGH
PGI
R1 R2
1st class
2nd class
3rd class
Acetate cyclization – formation of simple phenols
O
SCoA
O
SCoA
COOH
7
6
5
4
3
2
1 SEnz
O O O O
5
4
3
6 7
C
2
1 SEnz
OO
O
O
H
+
4
3
2
5
C
6
1
SEnz
7
O
OO
O
SEnz
OO
O
OH
H SEnzO
O O
O
SEnz
OO
O
O
O O
O
OH
OOH
OH
OH
OH O
OH
+ 3 x
Acetyl-CoA Malonyl-CoA poly-β-ketoacid
Aldol condensation Claisen reaction
Dehydrogenation Re-formation of carbonyl
made favourable by formation favourable by release from enzyme
of conjugated system
Enolization Enolizace
favourable via formation of favourable via formation
aromatic system of aromatic system
Hydrolysis
Orsellinic acid
Phloroacetophenone
Polyketide synthasa
Polyketide cyclase
meta-OH
CYCLIC ACETOGENINS
PHENOLS AND THEIR DERIVATIVES
R CO
7
CH2
6
CO
5
CH2
4
CO
3
CH2
2
CO
1
O R´
C7
CH2
6
C
5
CH2
4
C3
CH2
2
O
O
R O
C
1
O
O
R´
C1
CH2
2
C
3
CH2
4
C5
CH2
6
O
O
OR´
O
C
7
O
R
C
OR
OHOH
OH
COOR´
OHR
OH
COOR´
OHR
OHR
OH
OHCH3
OH
COOH
aldol
condenzation
(2 7) reduction at C5
C-acylation
(1 6)
acylphloroglucinolresorcinol
carboxylic acid
- CO2
resorcinol
orsellinic acid
intramolecular
intramolecular
6-methylsalycilic
acid
CH3
COOH O O
O O
O
O
O SEnz
OO
O
O
COSEnz
OHOH
OH
OH
COSEnz
OH
OH
OH
O O
7 x
2 x aldol
condenzation
Enolization
Lactone
formation
Alternariol
OHOH
COOH OHOH
COOH
OHOH
O
O
OH
COOH
Orsellinic acid Lecanoric acid
Utilization
of terminal carboxyl
Utilization
of
terminal
carboxyl
Carboxyl
termination
CYCLIC ACETOGENINS
DERIVATIVES OF PYRONES AND NAPHTOQUINONES
R CO
7
CH2CO
5
CH2CO
3
CH2CO
1
O R´
5
1
O
OCH2
COR 7
3
R
O
CH2COOR´
C
O
O O
O R
O
CO SCoA
OH
OH O
R
O
COOH
EXAMPLES OF POLY-β-KETO-SUBSTANCES
CYCLISATION
with numerous secondary transformations
O
O
O
CH3
COOH
OH
OH
CH3
COOH
O O
CH3
O
O
COOH MeO OMe
COCH2COCH3
OMe
O
CH3
O
O
O
O O
COOH
O O
OH
OH
OH
CH3
CH3O
O
O O O
O O
COOH
CH3
OH
O
OOH
OH
COOH
expected
precursor
x v(C2)x natural compound
4
5
7
8
endocrocine
alternariol
eugenone
orsellinic acid
ACETATE ORIGIN OF NATURAL COMPOUNDS
O
O
OH
CH3OH
OH
O
O
O
CH3Cl
MeO
OMe OMe
COOH
OH
COOH
CH3
COOH Penicillium spp.
Penicillium islandicum
Rumex spp.
Rhamnus spp.
3-hydroxyphtalate
griseofulvine
emodine
.
.
POLY-β-KETO CHAIN STABILISATION
RCOCH2COCH2COCH2COCH2CO SCoA
C CH C CH2
O
C
OH
CH CO SCoA
OH
RCOCH2
H
R
C
O
CH2 CH
O
C
CH2
O
K
O
CH
C
K
O
SCoA
enzyme
enzyme
ANTHRAQUINONE DERIVATIVES
CO SCoACH3
CH2
CO
CO2
H
SCoA
CH3
O
O
O O O
CO
O O
SCoA
CH3
O
H H
OH
OH
CO2
H
CH3
OHO
O
OH
OH
emodine-anthrone
emodine
dianthrone
1
7
.
.x
x xxx
x
xx
Changes in oxidation pattern
of skeleton before cyclization
Decarboxylation, oxidation,
methylation after cyclization
C-alkylation reactions
SEnz
O O O O
SEnz
OO
O
O
SCH3
Ad
R
SEnz
OO
O
O
OH
COOH
OH
OH
OH
O
O
OH
OH
O
O
OH
OH
O
O
OH
O
OH
O
O
OH
CH3
SCH3
Ad
R
OH
COOH
OH
SCH3
Ad
R
C-methylation
SAM
Aldol reaction
Aromatization
5-methylorsellinic acid
Oxidation of methyl at CH2OH
Following lactonization
Intermediate of phtalide type
Farnesyl diphosphate
Alkylation
Oxidative cleavage
O-methylation
SAM
Mycophenolic acid
ANTIBIOTICS OF POLYKETIDE TYPE
TETRACYCLINES – product of actinomycetes Streptomyces spp.
CH2CO SCoA
CONH2
CH2CO SCoA
COOH
CO
O O O O
O
O O O
SCoA
SCoA
CONH2
OH
OHOHOHOH
CONH2
OH
OOHOOH
CONH2
CH3
OH H
R2
N(CH3)2
H
H
R1
OH
1
8
R1 R2
tetracycline H H
chlorotetracycline Cl H
oxytetracycline H OH
oxidation, halogenation,
reduction, methylation,
hydroxylation
malonamide-CoA
malonyl-CoA
1
2
3
4
Dactylocyklines
OH
OH O OH O
OH
OH
OHH
O
O
R
NMe2
CONH2
MeO
OMe
Anthracycline antibiotics
O
O
OH
OHOMe O
OH
O
O
NH2OH
O
O
OH
OHOMe O
OH
O
O
NH2OH
OH
O
CoAS
O O O
OOOO
O
OEnzS
Propionyl-CoA
9 x malonyl-CoA
Daunorubicine Doxorubicine
Streptomyces peuceticus
Streptomyces coeruleorubidus
ANTIBIOTICS OF POLYKETIDE TYPE
GRISEOFULVINE – product of Penicillium griseofulvum and others,
examples of biosynthetic application of oxidative phenolic conjugation
CH3
CO SCoA
CH2
CO SCoA
COOH
SCoA
O
O
O
O
O O
CH3
O
OH
O
OH
OH
O OH
CH3
OH
O
O
O
O O
CH3
O
Cl
1
6
-CoASH
aldol condensation
-H2O
+3CH3
+Cl
griseofulvine
LICHEN ACIDS
usnic acid
OH
OH
OH
CH3
COCH3
O
O
OH
CH3
OH
CH3
OH
COCH3
COCH3
CH3
2
usnic acidsubstituted phloroglucinol
oxidativní zdvojení
z methioninu
LICHEN ACIDS
symbionts of fungi and algae, produce mainly depsides and depsidones
CH3
CO SCoA
OHOH
OH OH
CH3
CO SCoA
O OH
CH3
CO SCoA
CH3
CO
OHOH
CH3
CO SCoA
OHO
O OH
CH3
CO
CH3
CO
OHOH
+
lecanoric acid
gyrophoric acid (triester)
orsellinic acid
orsellinic acid
O-acylation
orsellinic acid
PHLOROGLUCINE DERIVATIVES PRESENT AT FERNS
OH
CH3
OH
R
OH
CH3
O
CH3
OH
R
OH
CH2
O
CH3
OH
R
OH
CH2
+
O
CH3
OH
R
OH
CH2
O
CH3
OH
R
OH
O
CH3
OH
R
OH
C
H2
O
CH3
OH
R
OH
CH3
OH
R
OH
CH2
OH
CH3
OH
R
OH
MeO
(-2e, -2H+)
margaspidine R=COC3H7
MACROLIDES OF ERYTHROMYCINE GROUP
formed via incorporation of propionic acid in form of methylmalonylcoenzyme A
RCO SCoA CH CO
CH3
SCoA
CO2
H
RCO CH
CH3
CO SCoA
CH2
CH
CH3
C
CH3
OH
CH
OH
CH
CH3
CO CH
CH3
CH2
C
OH
CH3
CH
5
OR
CH
CH3
CH
3
OR'
CH
2
CH3
CO
1
O
O
O 1
2
3
4
5
O
O
OH
OH
OH
O
O
N(CH3)2
OH
O
OH
OMe
+
erythromycine (R=desosamine, R'=cladinose)
erythromycine
acyl-CoA
methylmalonyl-CoA
O
SCoA
O
SCoA
COOH
O
OH
OH
OH
OH
SEnz
O
O
O
O
OH
OH
OH
O
O
O
OH
O
O
OHOH
O
OH NMe2
O
OH
MeO
+ 6 x Carbonyls „fate“
Reduced
Reduced
ReducedReduced
Reduced
Dehydrated
Reduced
Non-reduced
Saccharopolyspora erythrea
COMPOSITE ACETOGENINS
formed except of acetogenine from constituent of other biogenetic origin
CoAS
O
O
SEnz
O
OO
O
O O
O
OH
OOHO
O
OH
OH
OHO
O
OH
OH O
O
H
OHO
O
OH
OH O
OH
O
O
OHO
O
OH
OH O
O
OHOOH
OH O
O
OH
HOOC
O
O
OO
O
MeO
O
O
O
O
O
MeO
O
O
O
MeO
OO
O
Aldol and Claisen condenzation,
Aromatization, oxidation
Series of reactions ensuring
cyclization with formation
of ketal
Baeyer
-Viliger
oxidation
Hydrolysis,
Formation of furane
Baeyer-Viliger oxidation
ensuring ring cleavage
Series of reactions
ensuring rotation and
formation of ether
bridge, formation of
xanthone
Oxidative
cleavage of
aromatic ring, re-
cyclization
Baeyer
-Viliger
oxidation
Aflatoxine G1
Aflatoxine B1
Hexanoyl-CoA
Sterigmatocystin
COMPOSITE ACETOGENINS
formed except of acetogenine from constituent of other biogenetic origin
NH2
O
SCoA
NH2
O
O
SCoA
NH2
O O
O
O
CoAS
N
H
OH
O
N
H
O OH
OH
SCoA
O
O
OO
EnzS
O
OH
HOOC
OH
OH
CoAS
O
O
O
O
SEnz
O
COOH
OH
OH
OPP
COOH
OH
OH
COOH
OH
OH
COOH
OH
OH
H
COOH
OH
OH
COOH
OH
O
OH
OH
OH
O
COOH
OH
O
OH
O
COMPOSITE ACETOGENINS
formed except of acetogenine from constituent of other biogenetic origin
Hexanoyl-CoA
3 x malonyl-CoA Olivetolcarboxylic acid
Aldol
condensation
C-alkylation
Oxidation with
Substituents rotation
Electrophilic
cyclization
a
a
b
b
Nucleophilic
cyclization
Cannabidiolic
acid
Tetrahydrocannabinolic
acid
Cannabinolic
acid
Cannabinol
CBN
Tetrahydrocannabinol THC
Cannabidiol CBD
Decarboxylation
Cannabigerolic acid
R5
R4
OH
R1
R2OR3 O
R3
OH
R1
R2
OH
R1
R2
O R3
O
OH
R1
R2
H
H
R3
O
OH
R1
H
H
O
OH
R1
R2
H H
H
R1
R2
O
OH
R3
OH
H
H
O
O
R2
R3
R1
OH
R1
OH
OH
R4O
OR2
R1 R3
O
O
OH
OH
OH
O
O
OH
OH
OH
OMe
CBG-type cannabinoids CBC-type cannabinoids CBD-type cannabinoids delta9-trans-THC-type cannabionoids
delta8-trans-THC-type cannabionoids CBL-type cannabinoids CBE-type cannabinoids CBN-type cannabinoids
CBND-type cannabinoids CBT-type cannabinoids
Brevetoxins
Gymnodinium breve (Ptychodiscus
brevis)
So called red tide
Massive death of fishes
Mexican gulf, Australia, coast of
North America
Polycyclic ethers
Lipophilic
10 and 11 rings
All-trans arrangement
Relatively stabile compounds (high
and low pH cause decomposition)
Mechanism
Depolarization, opening of voltagedirected
channels Na+
Uncontrolled influx Na+ into cell
Change of voltage opening channels,
hyperexcitability
Symptoms:
Often mis-changed as intoxication
with ciguatoxins
Tingling of face, throat, fingers
Tremor, nausea, vomiting,
diarrhoea, headache
Mydriasis
Bradycardia
No death causing cases
Ciguatera toxins
Mixture of substances
Present: 24 related compounds (ciguatoxin,
maitotoxin, scaritoxin, okadaic acid)
Dinoflagellate Gambierdiscus toxicus
 On corral reefs
Found in Pacific fishes
 Tropics and subtropics
Low-molecular lipid polyethers
Temperature resistant
Stimulation of Na+
passage through membrane
Neurotoxins
4 sets of symptoms
 Neurologic 7 days
 Cardiovascular
 Gastrointestinal 1-2 days
 General 1-7 days
 Nástup otravy:
 10 minut to 12 hours after first
contact, after požití of contamined
fishes upto 36 hours
 Begging of intoxication
 Vomiting, diarrhoea, general
weakness
 Decreased sensitivity to painfull
podnětům
 Tingling and burning of fingers
 Sense of changing of cold and
heat
 Further stadia
 Hypotension, mydriasis, arhytmia
 Convulsions, circulatory colaps,
respiratory colaps, death
 Possibility of symptoms
persistance
 Bad differential diagnostics from other NSP
 First aid
 Manitol – diuresis
 Function control
 No antidote
 Curing of long-termed symtoms
 Amitriptilin, gabapentin
Domoic acid
 Nitzchia pungens
 Amnestic shellfish poisoning (ASP)
 Poisoning corresponded by neurologic disorders
 Hallucinations, time and space disorientation
 Deterioration of short-termed memory
 Symptoms of intoxication
 Vomiting, stomach convulsions, diarrhoea,
headaches
 ASP
 Cumulation of toxin in hepatopancreas, gills, so
called siphone of mollusces
 Mollusces resistant, meat becomes toxic
 New Zealand, Canada coast, Mexico
 Red tide
 Tricarboxylic acid
 Proline derivative
 Structural similarity with excitation aminoacids
(cainate, glutamate)
 Mechanism of effect:
 Excitation AMA
 100times effective than glutamate
 Ring rigidity
 Bond to NMDA receptor
 Affection of Ca channels, Ca influx
 Stimulation of processes → neuronal damage
 Loss of memory
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