Terpenes and Poliketydes

NATURAL PRODUCTSNATURAL PRODUCTS

PRIMARY AND SECONDARYPRIMARY AND SECONDARY METABOLISMMETABOLISM

ENERGY

h

CO2

O2

H2O

“N”

N2

NO2-/NO3

-/NH4+

TRACE METALS

Na, Ca, K, MgFe, Cu, Co, Mo

Photosynthesis

A TYPICAL PLANT

Glycolysis

bacteria

H2O

(daytime)

Respiration(nighttime)

PRIMARY METABOLISMPRIMARY METABOLISM

Primary metabolism comprises the chemical processesthat every plant must carry out every day in order tosurvive and reproduce its line.

PhotosynthesisGlycolysisCitric Acid CycleSynthesis of amino acidsTransaminationSynthesis of proteins and enzymesSynthesis of coenzymesSynthesis of structural materialsDuplication of genetic materialReproduction of cells (growth)Absorption of nutrients

SECONDARY METABOLISMSECONDARY METABOLISM

Secondary metabolism comprises the chemical processesthat 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 numberof different plants or plant families, but the actual chemicalproduced (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 benecessary to the survival of the plant, but they may give it a competitive advantage.

CO2 + H2O

Photosynthesis Glucose Carbohydrates

GLYCOLYS IS

Acetyl CoA

Citric Acid Cycle

Fatty AcidsLipids

AcetogeninsTerpenesSteroids

Building Blocks

Amno Acids

Proteinssynthesis

enzymes

regulationNucleicAcids

reproduction

Alkaloids

Phenyl-propanoids

RNA DNA

PRIMARY METABOLISMPRIMARY METABOLISM

SECONDARYSECONDARYMETABOLISMMETABOLISM

SECONDARYSECONDARYMETABOLISMMETABOLISM

h

CO2 + H2O + ATP

Flavonoids

PolysaccharidesGlycosidesNucleic Acids

Shikimate pathwayAromatic CompoundsLignans

aromatic amino acidsaliphatic amino acids

CH3COSCoA

CH3COSCoA

(photosynthesis)

phosphoenol pyruvate

pyruvate

acetylCoA CH3COSCoA

-O2CCH2COSCoA

CH3COSCoA

Polyketides, Fatty Acids Prostaglandins, Macrocyclic Antibiotics

Shikimate

CH3COCH2COSCoA

mevalonate

Isoprenoids (terpenes,steroids, carotenoids)

AlkaloidsPeptidesPenicillinsCyclic Peptides

CITRICACIDCYCLE

(3)

(3) Mevalonate Terpenes, Steroids

-- made from 5-carbon units

-pinene (C10) cholesterol (missing 3 C’s)

phytane (C20)

(3) Isoprene pathway: Terpenes

- C6 compound that loses CO2

to form C5 units

Isoprene Biosynthesis

DMAP IPP

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

- Pyrophosphates: high-energy group powers biosynthetic rxns.. “nature’s leaving group”

decarboxylates to yield IPP

Parents Compounds and Type

………white board !.……..

Biosynthesis of Monoterpenes (C10)

rearranged to form sesquiterpenes (C15)

Geranyl pyrophosphate (C10)

Farnesyl pyrophosphate (C15)

Prenyl transferase +

DMAP IPP

-OR-

Cyclase enzymes

cyclic monoterpenes (C10)

…White board….

Fig. 24.07

Biosynthesis of Monoterpenes (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

Overview of isoprenoid biosynthesis and the role of prenyltransferase in higher plants

Abbreviations:IPP:IsopentenyldiphosphateDMAPP:DimethylallyldiphosphateFPP:FarnesyldiphosphateGGPP:GeranylgeranyldiphosphateGPP:GeranyldiphosphateOPP:Diphosphate moisty

Mechanism of acyclic monoterpene synthaseMechanism of acyclic monoterpene synthase

(+)-carvone = caraway seed(-)-carvone = spearmint

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

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

Biosynthesis of Sesquiterpenes (C15)





DMAP IPP

Biosynthesis of Sesquiterpenes (C15)





DMAP IPP

- 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 SesquiterpenesReaction mechanism of all Sesquiterpenes

Diterpene (C20) Biosynthesis


+

Gerenylgerenyl-PP (C20) carbocationintermediate

Diterpenes

Gibberellin Biosynthesis

CH3 oxidized, then lost as CO2

Gibberellin A3, a potent C19 plant hormone

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

Diterpenes

DMAP IPP

Squalene (from shark oil)

C30 compound: 2 farnesyl’s joined tail-to-tail



Triterpene (C30) Biosynthesis

Triterpene (C30) Biosynthesis

Squalene

other C30 triterpenes

cholesterol (C27)

sex hormones

vitamin D

Cholesterol Biosynthesis

- lose 3 methyl groups

19 steps

Vitamin D Biosynthesis

- cholesterol from liver is transported to skin

- photochemically converted into vitamin D- vitamin allows uptake

of essential calcium

cholesterol24-ethylcholesterol

24-stigmasterolgorgosterol

dinosterol 3-methoxycholesterol

Higher terpenes (C40)

Lycopene

2 x geranyl geranyl-PP

- 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).

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Vitamin AVitamin 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.

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Vitamin AVitamin 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.

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Vitamin A and the Chemistry of Vitamin A and the Chemistry of VisionVision

Rhodopsin

Rhodopsin

Metarhodopsin II

Metarhodopsin II

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

H3C

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

Notes on Terpenes(1) Oxidation reactions are carried out by the enzyme cytochrome P450

- activate oxygen to introduce -OH, carboxyl groups- allow removal of C’s 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

Terpenes and Poliketydes

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