BIOGENESIS OF NATURAL COMPOUNDS
PHOTOSYNTHESIS SUGARS
primary
ACIDS metabolites
AMINOACIDS BIOGENIC
COMPOUNDS
SPECIALIZED secondary
COMPOUNDS metabolites
(both in genera and species)
BETWEEN PRIMARY AND SECONDARY METABOLITES IS NOT ALWAYS
EASILY DISTINGUISHED BORDER
O
CH3
OMe
O
CH3
O
CH3
NMe2
O
CH3
O
CH2
OH
glucose
oleandrose quinovose
desosamine
primary metabolite
secondary metabolites
D-digitoxose
BETWEEN PRIMARY AND SECONDARY METABOLITES IS NOT
ALWAYS EASILY DISTINGUISHED BORDER
N
H
H
CO2H
CH2-CH(NH2)-CO2H
N
H
H
CO2H N
H
H
CO2H
O
O
CH2CH(NH2)CO2HHO2C
CH2
CH2CH(NH2)CO2H
L-proline
L-phenylalanine
L-pipecolic acid baikiaine
hypoglycine A stizolobic acid
primary metabolites secondary metabolites
L-PIPECOLIC ACID
(S)-2-piperidinecarboxylic acid; L-homoproline
Widely dispersed in plants: apples, date,
hops (Humulus lupulus),
beans (Phaseolus vulgaris)
white clover (Trifolium repens).
Part of some macrolide antibiotics, for example RAPAMYCINE.
N
H
COOH
RAPAMYCINE (SIROLIMUS, RAPAMUNE)
O
OHH
OMe
O OH
OMe
O
O
H
OH
OMe
O
O
O
N
H
31-membered peptide lactone,
chain of carboxlic acid is cyclised
with L-pipecolic acid as a bridge.
Produced by Streptomyces
hygroscopicus.
Posses antifungal, antineoplastic
and immunosuppressive activity.
In combination with cyclosporine
and tacrolimus in transplantation
medicine.
HYPOGLYCINE
Blighia sapida Kon. – ackee (unripe fruits)
West Africa → Jamaica (intoxications)
α-amino-β-(2-methylencyclopropyl)propionic acid. Hypoglycemic and
teratogennic effect. It decreases blood glucose levels 3-4 hours after
administration.
Active metabolite is (methylencyclopropyl)phormyl-CoA, impacts on metabolism
of fatty acids, disrupts their β-oxidation. In DM therapy did not find its place, its
biological activity is intensively studied from toxicological and experimental point
of view (studies of fatty acids metabolism).
CH2
NH2
COOH
BAIKIAINE
Baikiaea plurijuga (Fabaceae), Caesalpinia tinctoria, red algae
Baikianine inhibits the neurotransmittory activity of glutamic acid.
3-Hydroxybaikianine is highly concentrated found in fruiting bodies of
toxic fungus Russula subnigricans.
N
H
OH
COOHN
H
COOH
Baikiaine
(1,2,3,6-tetrahydropyridine-2-carboxylic
acid)
STIZOLOBIC ACID
Stizolobium hassjoo (Fabaceae)
Amanita pantherina, A. muscaria, A. gemmata
Toxicological importance.
O
O
NH2
HOOC COOH
H
O
O
NH2
HOOC
COOH
H
Stizolobic acid Stizolobinic acid
All life forms contain the same molecules of organic and anorganic
compounds. Differences are found their inter-ratio.
BIOPOLYMERS
are built up from many identical or similar sub-units
Basic biopolymers:
• Proteins made of 21 different aminoacids. Function: catalytic
(enzymes), regulatory (chosen hormones), nutrition, structural.
Combined glycoproteins (prevalence of monosaccharide units)
• Polysaccharides – linear or branched chains (starch, cellulose,
glycogen). At plants basic building and storage material. Metabolic
changes of these bring „chemical“ energy.
• Lipids made biological membranes (phospholipids), storage
compounds. Combined are lipopolysaccharides and lipoproteins.
• Nucleic acids composed of nucleotides (nitrogenous base,
monosaccharide (Rib, deRib) a phosphoric acid.
RNA: A, G, C, U; DNA: A, G, C, T
A X I O M E S
PRIMARY METABOLISM POSSESES BASIC IMPORTANCE,
on which has variability of organic systems very low influence.
SECONDARY METABOLITES
1. They posses limited taxonomical occurrence.
2. They are produced under specific conditions.
3. Their biochemical function is not fully elucidated.
One of the basic characteristics of secondary metabolism is that they use
only limited selection of precursors and these precursors have
special importance in primary metabolism.
PRECURSORS
OH
OH
OH
CO2H
2
shikimic acid
squalene
Ilicium religiosum
Star anyse
IMPORTANCE OF PRIMARY METABOLISM FOR
PRODUCTION OF NATURAL COMPOUNDS
IN REGARDS TO INTER SOUVISLOSTI AND CONSEQUENTIONAL
RELATIONS OF METABOLIC PROCESSES IN LIVING PLANTS, IT IS NOT
POSSIBLE TO NADŘAZOVAT FROM THE POINT OF VIEW OF NATURAL
COMPOUNDS PRODUCTION ON PROCESS OF PRIMARY METABOLISM
UPON ANOTHER ONE.
CONSEQUNTIONALLY IT WILL BE TARGETED ON CHOSEN BIOSYNTHETIC
MECHANISMS WITH DURECT IMPORTANCE FOR PRODUCTION OF
SECONDARY METABOLITES.
Important inter-relations in plant metabolism
from the pharmaceutically important compounds point of view
CO2 + H2O + Hν
Chlorophyll
SUGARS
POLYSACCHARIDES
NUCLEIC ACIDS
GLYCOSIDES
DERIVATIVES OF SUGARS
HETEROGLYCOSIDES
Glycolysis Pentose cycle
PHOSPHOENOLPYRUVATE
PYRUVIC ACID
ACETYL-CoA
MALONYL-CoA
ACETOACETYL-CoA
Krebs cycle
SHIKIMIC ACID
AROMATIC AMINOACIDS
PROTEINS
MEVALONATE
SQUALENE
PHENYLPROPANOIDS, COUMARINS,
B-RING OF FLAVONOIDS, CINNAMIC ACID DERIVATIVES
ISOFLAVONOIDS, GALLIC AND BENZOIC ACID DERIVATIVES,
CATECHINE AND ITS DIMERS AND POLYMERS
DEPSIDES…
ALKALOIDS
PEPTIDES…
POLYKETIDS
ALIPHATIC POLYKETIDES:
OILS, FATS, WAXES…
AROMATIC POLYKETIDES:
A-RING OF FLAVONOIDS
TETRACYCLINES
ANTHRAQUINONES
CANNABINOIDS…
ISOPRENOIDS:
TERPENES, STEROIDS
CAROTENOIDS…
Metabolism of carbon Primary metabolites Secondary metabolites
ALIPHATIC AMINOACIDS
FATTY ACIDS
NOVOBIOCIN
from the „biogenetic parents“ point of view
O O
OH
O
O
NH2
CH3
CH3
O
CH3
O
OH
N
H
O
OH
novobiosa – sugar derived from glucose
carbonamid- group – derived from nitrogen metabolism
C-methyl, O-methyl – several C1 sources (phormyl, hydroxymethyl, it is a
pathway of methionine, glycine and serine)
3-amino-4-hydroxycoumarin – from shikimic acid via tyrosine
p-hydroxybenzyl – from shikimic acid
isopentenyl – via mevalonate
FIVE CATEGORIES OF NATURAL COMPOUNDS
ACCORDING TO THEIR BIOSYNTHETIC ORIGIN
1. Specific sugars, polysaccharides, sugar part of glycosides
2. Shikimates
3. Metabolites derived from aminoacids
4. Polyketides
5. Isoprenoids
Ribulose-1,5-diphosphate + CO2 3-phosphoglycerate
3-phosphoglyceraldehyde
Fructosa-1,6-diphosphate
Glucose
Starch
Cellulose
SPECIFIC SUGARS
Pyruvic acid
Intermediates of citrate cycle
PRODUCTS OF
SECONDARY METABOLISM
CONSEQUENCES OF SUGAR METABOLIS WITH CITRATE CYCLE
METABOLISM OF SUGARS
PHOTOSYNTHESIS – ABSORPTION OF CO2 AND A REDUCTION TO
SUGAR
CH2 O P
C
C
O
H OH
CH OH
C
H2
O P
CH2 OH
C
C
O
H OH
CH OH
C
H2
O P
ATP
ADP
CO2
CH2 O P
C
C
CH OH
C
H2
O
OH
COOH
O P
C
C
C
H2
O
H
H OH
O P
CH2 O P
COH H
COOH
CH2 O P
COH H
COOH
ATP
ADP + P
NADP + H
NADP
ribulose-5-P
+
+
+
triose-3-P
phosphoglycerate
ribulose-1,5-diP
PRODUCTION OF GLYCOSIDES
(transglycosylation)
1. Production of aglycones
2. Connection to sugar residues
CONNECTION OF SUGAR TO AN OXYGEN OF FURTHER SUGAR OR TO A OXYGEN
ATOM OF ALCOHOLIC HYDROXYL, SULPHUR, NITROGEN, OR CARBON IS
MOST OFTEN ARRANGED BY URIDINEDIPHOSPHOGLUCOSE (UDPG)
N
NO
OH
O
O
OH OH
H2CO P O P O
OH
O O
OH
CH2OH
OH
OH
OH
uridine diphospho glucose
UDPG

CHANGES OF C-1 CONFIGURATION
O
OH
OH
OOH
CH2OH
UDP
H
O
R
O
OH
OH
OR
OH
CH2
OH
UDP

 +
Release of UDP by nucleophil atack at C-1 of sugar residue shows
as a consequence A CHANGE OF CONFIGURATION AT C-1
and a production of ß-glucopyranoside
FUNCTION OF SUGAR NUKLEOTIDES DURING THE SUGAR
CHANGES
UDP-glucose
oxidation at C-6
UDP-glucuronic acid
- CO2
UDP-xylose
epimerisation at C-4
UDP-galactose
reaction with galactose-
-1-phosphate
UDP-galactose +
glukose -1-phosphate+
THREE-CARBON COMPOUNDS OF PRIMARY METABOLISM
Key compounds of primary metabolism – sugars entering CO2
fixation
(triosophosphate, phosphoglycerate, sugars of pentose cycle).
→→→ pyruvate, phosphoenolpyruvate, acetylcoenzyme A.
These are building blocks of majority of natural compounds.
phosphoenolpyruvate + erythroso-4-phosphate → C7 acid →
shicimic acid →
→ chorismic acid → phenylpyruvic acid → phenylalanine →
→ cinnamic acid
ACETYLCOENZYME A
CH3COCOOH
- CO2
CH3CO-SCoA
fatty acids
CH3
(CH2
CH2
)nCO-SCoA
polyketides
aromatic compounds
cycle of citric acid
-hydroxy-
-methylglutarate
mevalonate
3-methyl-2-butenyldiphosphate
i s o p r e n o i d s
3-methyl-3-butenyldiphosphate
pyruvate
formation of ATP
-ketoacids
aminoacids
+ N
„ONE-CARBON METABOLISM“
METHYL GROUPS TRANSFERS TO A NUCLEOPHILLIC CENTRE MOSTLY
S-ADENOSYLMETHIONINE, WORKING AS ALKYLATION REAGENT.
AT NATURAL COMPOUNDS:
• FORMATION OF PHENOLIC ETHERS
• FORMATION OF N-METHYL AMINES
• FORMATION OF C-METHYLATED PHENOLS AND KETONES
TRANSFER OF C1 GROUP
adenosyl S
+
C
H2
CH3
C
H2
C
H
NH2
COOH
O N
O
O CH3
N
+
CH3
HO
CH3
(a)
(a)
(b)
(b) (c)
CH3
(c)
S-adenosylmethionine
adenosylhomocysteine
+
BASIC BIOSYNTHETIC REACTIONS
• Living organisms posses extraordinary diverse composition.
• Catalytic operation of enzymes
• Limited number of precursors
• Small number of reactions which find place in metabolism.
• Simple and known reactions.
FORMATION OF CARBON – CARBON BOND
Nucleophillic methylene grouping + electrophillic C-atom of ketone, ester …
C
H
C
H
C O
C O
CH2
C
H
+ C
SR
O
CH CO + RS
-
C
H
+ CO2 CH C
O
O
C
H
+ CH3
S
+
R'
R
CH CH3 + S
R
R'
FORMATION OF C-C OR C-O-C BOND VIA OXIDATION
N
CH3
OH
OH
MeO
N
CH3
O
OH
MeO
OH O O O
OH OH
O
OH
A B C
B B B A
.
.
.
- 2 H+
- 2 e
- 1 H+
- 1 e
INTRODUCTION OF OXYGEN GROUP VIA OXIDATION
OF C-H BOND, OR VIA DIRECT EPOXIDATION C=C
NH2
COOH
NH2
COOH
OH
O
O
O
O
O
phenylalanine tyrosine
squalene squalene-2,3-epoxide
2
3
OXIDATION AND REDUCTION OF C-O OR C-C BOND
(FORMATION OF CARBONYL AND UNSATTURATED COMPOUNDS)
OH O
R CH2OH R C
H
O
R C
OH
O
CH3(CH2)7CH2CH2(CH2)7COOH CH3(CH2)7CH2
CH2(CH2)7COOH
C18H36O2 C18H34O2
formation of carbonyl compounds
alcohol aldehyde carboxylic acid
stearic acid oleic acid
c
DECARBOXYLATION OF β-KETOCARBOXYLIC ACIDS
COCH2COOH COCH3
CO2+

ALKYLATION AND ACYLATION OF NUCLEOPHILLIC
ATOMS OF NITROGEN AND OXYGEN
NH CH3
S
+
R'
R
N CH3
S
R
R'
O
CH2
OPP
O
O CH3
C
O
SR
OCOCH3 R S
+ +
+
+ +
SPONTANEOUS REACTIONS
(ALDOL CONDENSATION, FORMATION OF LACTONES AND LACTAMS)
OH COOH
CH3 C
H
O
NaOH CH3 C C
H2
C
OH
H H
O
NaOH
O
O
NH2 COOH N
H O
2 + +
LACTONE
LACKTAM