NATURAL PRODUCTS

PRIMARY AND SECONDARY

METABOLISM

A TYPICAL PLANT
h
EN
E

Glycolysis

RG
Y

Photosynthesis
(daytime)

CO2

Respiration
(nighttime)

H 2O

O2
N2
bacteria

TRACE METALS

Na, Ca, K, Mg
Fe, Cu, Co, Mo

NO2-/NO3-/NH4+
H2 O

PRIMARY METABOLISM
Primary metabolism comprises the chemical processes
that every plant must carry out every day in order to
survive and reproduce its line.
Photosynthesis
Glycolysis
Citric Acid Cycle
Synthesis of amino acids
Transamination
Synthesis of proteins and enzymes
Synthesis of coenzymes
Synthesis of structural materials
Duplication of genetic material
Reproduction of cells (growth)
Absorption of nutrients

SECONDARY METABOLISM
Secondary metabolism comprises the chemical processes
that are unique to a given plant, and are not universal.
Secondary metabolism is the chemistry that leads to the
formation of a natural product.
Sometimes portions of this chemistry are common to a number
of different plants or plant families, but the actual chemical
produced (natural product) is usually different in one plant
than in another.
Common chemical precursors can lead to different results.
Secondary metabolites (in most cases) do not appear to be
necessary to the survival of the plant, but they may give it
a competitive advantage.

CO2 + H2O
PRIMARY METABOLISM

Photosynthesis

Glucose

SECONDARY
METABOLISM
Building Blocks
Phenylpropanoids
Flavonoids
Alkaloids

Amno Acids
Proteins
synthesis
enzymes
regulation
Nucleic
Acids
reproduction
RNA DNA

G
L
Y
C
O
L
Y
S
I
S

Carbohydrates
SECONDARY
METABOLISM

Fatty Acids
Lipids
Acetyl CoA
Citric Acid
Cycle

CO2 + H2O + ATP

Acetogenins
Terpenes
Steroids

(photosynthesis)

Polysaccharides
Glycosides
Nucleic Acids
phosphoenol
pyruvate

Shikimate pathway
Aromatic Compounds
Lignans

Shikimate
pyruvate

acetyl
CoA CH3COSCoA

aromatic amino acids

aliphatic amino acids
CITRIC
ACID
CYCLE
CH3COSCoA

O2CCH2COSCoA

CH3COCH2COSCoA
CH3COSCoA

CH3COSCoA

Alkaloids
Peptides
Penicillins
Cyclic Peptides

(3)
Isoprenoids (terpenes,
steroids, carotenoids)

mevalonate

Polyketides, Fatty Acids

Prostaglandins, Macrocyclic Antibiotics

(3)Isoprenepathway:Terpenes
(3)

Mevalonate

Terpenes, Steroids
-- made from 5-carbon units

- C6 compound
that loses CO2
to form C5 units

phytane (C20)

-pinene (C10)

cholesterol
(missing 3 Cs)

IsopreneBiosynthesis

decarboxylates

DMAP

to yield IPP

IPP

- Result: two isomeric 5-carbon molecules, IPP + DMAP

- Pyrophosphates: high-energy group powers biosynthetic rxns..
natures leaving group

ParentsCompoundsandType

white board !...

BiosynthesisofMonoterpenes(C10)
DMAP

IPP

Geranyl pyrophosphate (C10)

Prenyl transferase +

-OR-

Cyclase
enzymes

Farnesyl pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

cyclic monoterpenes (C10)

White board.

Fig. 24.07

BiosynthesisofMonoterpenes(C10)
(1) DMAP ionizes to form
electrophilic carbocation
(2) Nucleophilic attack by
IPP forms geranyl-PP
(3) Stereospecific loss of
HR, forming double bond
(4) Geranyl-PP ionizes,
rearranges to form a
carbocation intermediate
- Cyclic monoterpenes then form via enzyme-catalyzed
stereospecific rearrangements, functionalizations

Monoterpenes

thujone

Overview of
isoprenoid
biosynthesis and
the role of
prenyltransferase in
higher plants
Abbreviations:
IPP:
Isopentenyldiphosphate
DMAPP:
Dimethylallyldiphosphate
FPP:
Farnesyldiphosphate
GGPP:
Geranylgeranyldiphosphate
GPP:
Geranyldiphosphate
OPP:
Diphosphate moisty

Mechanismofacyclicmonoterpenesynthase

Most cyclic monoterpenes have a distinctive odor

- basis of perfume & flavor industries
Stereoisomers have different characteristic smells
- demonstrates that smell receptors are 3D proteins,
i.e. chiral environments that can distinguish enantiomers

(+)-carvone = caraway seed

(-)-carvone = spearmint

(+)-limonene = oranges
(-)- limonene = lemons

BiosynthesisofSesquiterpenes(C15)
DMAP

IPP

Prenyl transferase +

Farnesyl pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

Geranyl pyrophosphate (C10)

BiosynthesisofSesquiterpenes(C15)
DMAP

IPP

Geranyl pyrophosphate (C10)

Prenyl transferase +

Farnesyl pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

- if you introduce a
labeled carbon in the
precursor, you can see
where it ends up in the
final natural product

BiosynthesisofSesquiterpenes(C15)
DMAP

IPP

Geranyl pyrophosphate (C10)

Prenyl transferase +

Farnesyl pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

- if you introduce a
labeled carbon in the
precursor, you can see
where it ends up in the
final natural product

Reaction mechanism of all Sesquiterpenes

Reaction mechanism of all Sesquiterpenes

Diterpene(C20)Biosynthesis
+
Farnesyl pyrophosphate (C15)

carbocation
intermediate

Gerenylgerenyl-PP (C20)

Diterpenes

GibberellinBiosynthesis

CH3 oxidized, then lost as CO2

Gibberellin A3, a potent C19 plant hormone

- found in most plants (though originally isolated from a fungus)

Diterpenes

Triterpene(C30)Biosynthesis
DMAP

IPP

Geranyl pyrophosphate (C10)

Farnesyl pyrophosphate (C15)

Squalene (from shark oil)

C30 compound: 2 farnesyls joined tail-to-tail

Triterpene(C30)Biosynthesis
Squalene
other C30 triterpenes
cholesterol (C27)

sex hormones
vitamin D

CholesterolBiosynthesis

19steps

- lose 3 methyl
groups

VitaminDBiosynthesis

- cholesterol from
liver is transported
to skin

- vitamin allows uptake

of essential calcium

- photochemically
converted into
vitamin D

cholesterol

24ethylcholesterol

24stigmasterol

gorgosterol

dinosterol

3methoxycholesterol

Higherterpenes(C40)
2 x geranyl geranyl-PP

Lycopene
- major antioxidant pigment in tomatoes

-carotene
- major accessory pigment in photosynthesis

The color of an egg yolk is from

the xanthophyll carotenoids
lutein and zeaxanthin

Violaxanthin is a natural xanthophyll pigment with an

orange color found in a variety of plants including
pansies. It is biosynthesized from zeaxanthin by
epoxidation.[1] As a food additive it used under the E
number E161e as a food coloring; it is not approved for
use in the EU[2] or USA however is approved in
Australia and New Zealand[3] (where it is listed under
its INS number 161e).

Vitamin A
Occurs only in the animal world.
Found in the plant world in the form of a provitamin in
a group of pigments called carotenes.

26-51

Vitamin A

The best understood role of Vitamin A is its

participation in the visual cycle in rod cells.
the active molecule is retinal (vitamin A aldehyde),
which forms an imine with an -NH2 group of the protein
opsin to form the visual pigment called rhodopsin.
the primary chemical event of vision in rod cells is
absorption of light by rhodopsin followed by
isomerization of the 11-cis double bond to the 11-trans
configuration.

26-52

Vitamin A and the Chemistry of Vision

Rhodopsin

Metarhodopsin II
26-53

Thehighestterpenes(Cbig#)
~ 1 % of plants can synthesize cis-polyisoprenoids, like rubber

H3 C
Commercially used rubber plants can convert nearly 100% of
their mevalonate into rubber

NotesonTerpenes
(1) Oxidation reactions are carried out by the enzyme
cytochrome P450
- activate oxygen to introduce -OH, carboxyl groups
- allow removal of Cs through decarboxylation
(2) Triterpenes form flexible rings (chair, boat conformations)
with many chiral centers {rings usually not aromatic}
- provides a huge number of potential 3D structures
- high degree of biological activity
(3) Pathways can be elucidated using labeled precursors,
such as mevalonate with a 13C at position 2
- carbon NMR experiments reveal where the label ends
up in the completed molecule