NATURAL PRODUCT CHEMISTRY

AN INTRODUCTION TO SECONDARY METABOLISM

BY

FRANK MORAH
 Natural product chemistry deals mainly with organic compounds such as

antibiotics, alkaloids, steroids and terpenoids etc. which occurs freely in nature and

are usually synthesized within the tissues of living organisms. They are mainly the

products of secondary metabolic processes in living organisms.

The main primary metabolic process in nature is photosynthesis by which

green plants synthesize sugar from carbondioxide in the presence of sunlight.

Further metabolic alteration of sugars either through glycolysis or pentose

phosphate cycle leads to a pool of other primary metabolites such as carboxylic

acids, carbohydrates, nucleic acids, amino acids, and squalene etc. These primary

metabolites are substances which could for instance be detected in all plants and

are functional constituents of the organism. They occur virtually in the same

pattern from microbes to mammoths and this expresses the fundamental unit of

living matter.

The secondary metabolisms in plants are the reactions that utilize the

products of the primary metabolic processes, which are universal in distribution, to

form some other compounds that are often unique to one plant species or family.

The secondary metabolites are of special interest to the Natural product Chemist.

Their occurrence is highly restricted to certain plants and they are genetically

controlled. They are products which are not formed in all circumstances as they are

a function of seasonal variations and geographical locations. For example, a natural

product, oruwacin, is produced in extractable amounts for only three weeks in the

year, at the end of the rainy season (November) by an African medicinal plant

(Morinda lucida). Also another African medicinal plant (Strychnos spinosa)

cultivated in Florida (U.S.A.) contained no alkaloid and its stem back extract had no

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observable effect on mice, while the stem back extract of the same plant grown in

East Africa contained a series of alkaloids and was toxic to mice. Also, these

secondary metabolites have no obvious metabolic function in the organisms

producing them. A few natural products are believed to have specialized functions

in the plants. α α- and β-amyrins, ursolic acid, oleanolic acid and their related

compounds occur in waxy coating of leaves and fruits such as apple and pear. They

are believed to serve a protective function in repelling insects and microbial attack.

Certain plants exude some natural products from their leaves and roots to prevent

other plants from growing in their vicinity. These are either volatile terpenoids or

simple phenolic acids. Natural products are also believed to be a sort of “waste

products” from metabolic processes. Except for the volatile waste products which

escape through the stomata, these other ones are removed from circulation and

stored within the plant tissues. In this way the plants prevent themselves from self

poisoning.

The main purpose of Natural products research into the medicinal plants is to

ensure diversification in the source of medicaments and codification of oral

traditional medicine in Africa which is at present still confused with our culture and

religious rites. This will reduce our dependence on imported drugs and help to

conserve foreign exchange. Research into constituents of African flora is also aimed

at sourcing for new materials for the perfumery, cosmetic and food industries etc.

Since the production of secondary constituents and macromolecules in plants

and animals is genetically controlled, knowledge of their distribution is useful in

plant classification. Application of natural products in plant taxonomy is

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chemotaxonomy (or biochemical systematic). Flavones, alkaloids, terpeniods, non-

protein fatty acids, cyanogenic glycosides and sulphur compounds etc. have been

employed in chemotaxonomy. Certain boarder plants have been placed in their

rightful genus or family etc. through analysis of their natural products.

Study of plant pigments (such as anthocyanins, flavones and carotenoids etc)

and other secondary products have played a very important role in plant genetics.

It helps in identification of hybrid plants and elucidation of their parental origin.

In plant physiology, natural product chemistry helps in determining the

chemical structures, biosynthetic origin and mode of action of plant growth

hormones such as gibberellins, abscicins, auxins and cytokinins. In plant pathology

it helps in chemical characterization of phytotoxins (produced by invading

microbes) and phytoalexins produced by higher plants in response to microbial

attack. Natural product chemistry is also widely employed in plant ecology and

paleobotany.

TERPENOIDS

The name terpene was originally given to the volatile oil of turpentine and

similar oils which contain isomeric unsaturated hydrocarbons with the general

formula C10H16. They were recognized as far back as the 16 th century. They were

used in perfumes and cosmetics. The name was later used to describe all

compounds structurally related to the original terpenes. But the name terpenoid is

now preferable since it embraces oxygenated compounds.

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 Most terpenoids are known to contain the isoprene unit and natural rubber is

a polymer of isoprene.

Isoprene rule:

Most terpeniods are built of isoprene units joined in a head-to-tail fashion.

They are then classified on the basis of this repetition of the isoprene units as

monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids etc.

The odor of flowers or freshly cut leaves is due to the presence of mainly

volatile mono-and sesquiterpenoids. These compounds are used as food flavourings

(e.g. extracts from peppermint and cloves), as solvents (e.g. turpentine oil) and as

perfumes (e.g. roses, lavender and sandalwood oils).

Monoterpenoids (C10)

Monoterpenoids are ten carbon compounds made up of two isoprene units

usually joined in a head-to-tail fashion. They can be subdivided into acyclic (open

chain), monocyclic and bicyclic ones. e.g.

(i) Chrysanthenic acid:

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Chrysanthenic acid is a monocyclic monoterpenoid. Its esters are powerful

insecticides with the cis isomer being more powerful than the trans isomer. They

occur in the flower heads of pyrethrum

(Chrysanthemum cineraria-tollium).

(ii) Grandisol:

This is a sex-attracting chemical used by the male ball weevil.

(iii) Limonene:

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 limonene occurs in oils of lemon and oranges etc.

(iv) Menthol and menthone:

Both methol and methone occur in (-) found in various peppermint oil.

(v) α-pinene:

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 α -pinene occurs in oil of most conifers and is the chief constituent of

turpentine oil. It is a bicyclic monoterpene.

(vi) Camphor:

Camphor is another example of bicyclic monoterpenoid.

(vii) Citral:

The two acyclic monoterpenoids, geranial and neral, which are geometric

isomers of each other are collectively known as citral. Citral is the major constituent

of lemon grass oil.

Sesquiterpenoids (C15):-

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 Sesquiterpenoids are fifteen carbon compounds containing three isoprene

units. Abscisic acid and β-cadinene are example of sesquiterpenoid. Abscisic acid is

a plant growth inhibitor.

Diterpenoids:

Diterpenoids are twenty carbon compounds consisting four isoprene units.

Examples include abietic acid, agathic acid and giberellic acids etc.

8
Triterpenoids:

Triterpenoids are thirty carbon compounds consisting of six isoprene units.

This includes squalene (which occurs in high concentration in shark-liver oil),

lanosterol, α -and β-amyrins, ursolic acid, uvaol and lupeol etc.

β-amyrins

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R = CH3; α-amyrin

R = CO2H; ursolic acid

R = CH2OH; uvaol

EXRACTION AND ISOLATION OF NATURAL PRODUCTS

The plants to be investigated must be botanically identified by a reputable

authority or plant taxonomist. Voucher specimens of such plants are normally

deposited in recognized herbarium for future reference.

Essentially three methods are used in present day for extraction of natural

products. These include:

(a) Steam distillation

(b) Extraction with organic solvents or sometimes water.

(c) Extraction with aqueous acid or base.

Steam volatile components like the essential oils can be separated from the

non-steam volatile components by steam distillation. Essential oils are complex

mixtures of mainly monoterpenoids and sesquiterpenoids. They are relatively

volatile and steam volatile. They are responsible for the characteristic scent, odor

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and smell of many plant parts, such as flowers, fruits etc. The essential oils occur

as complex mixtures and are commercially employed as natural perfumes, flavoring

agents in food industry and as spices. Examples of useful essential oils include:

peppermint oil, citrus oil, nutmeg oil, lemon grass oil, sandalwood oil and rose

flower oil etc. The classical method of isolation of essential oils is by steam

distillation of fresh plant materials. Steam distillation may, in certain cases lead to

formation of trace amount of artefacts formed by rearrangement, and

polymerization etc. occurring at steam temperature.

Heat-labile compounds can be extracted with light petroleum (30-40 0) and

the solvent removed under reduced pressure. Solvents are commonly employed in

extraction of plant materials. The materials can be extracted fresh or in dried form.

The plant material should be dried as quickly as possible without use of high

temperatures to minimize chemical changes. It is a common practice to plunge the

fresh plant material into boiling alcohol (ethanol) a few minutes after collection to

minimize enzyme catalyzed hydrolysis or oxidation. The plant material may be

subsequently crushed in a blender before filtration.

Dried plant material is usually crushed or powdered before extraction. The

ground plant material is commonly continuously extracted with suitable solvents in

a Soxhlet extraction apparatus. The ground material is loaded in a Soxhlet extractor

and the hot solvent allowed to drop on it. As the solvent percolates through the

ground material, it extracts some of its organic constituents. The extract collects in

a flask where the solvent is distilled off. The material and the cycle is allowed to

continuously repeat itself over a period of time. Cold (i.e. batch) extraction is

sometimes carried out by soaking the plant materials in a suitable solvent for a few

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days before filtration in order to ensure maximum extraction. It is also a common

practice to extract the plant materials first with light petroleum to remove fat and

other relatively non-polar constituents. This is followed by extraction with more

polar ethanol or methanol. The extract, in each case, is concentrated in vacuo at

room temperatures or low temperatures between 30-40 0. It may also be necessary

to partition the alcohol concentrate between chloroform and water in order to

separate the very highly polar from their less polar constituents.

Aqueous sodium hydrogen carbonate is sometimes used to extract carboxylic

acids while aqueous sodium hydroxide extracts phenols and carboxylic acids.

Aqueous mineral acids (e.g. HCl) extract alkaloids which contain the free amino

and/or substituted amino group. In either case, the extract may be acidified or

basified as necessary to liberate extracted organic acid or base from a solution of

its salt.

It may be necessary to point out that there is no single recipe for extraction

of natural products. In practice, the researcher modifies the procedure to suit the

prevailing circumstances. For example, extractions of alkaloids from the alcohol

concentrate between aqueous HCl and chloroform. This removes the chloroform

soluble non-alkalodal materials. Basification of the aqueous fraction with ammonia

liberates the alkaloid from the solution of its salt. Another extraction with

chloroform will give chloroform solution of the alkaloid.

If at any point, an extract deposits some crystal on standing, such crystals

should be collected by filtration and tested for homogeneity by thin layer

chromatography or paper chromatography using several solvent systems.

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 Extraction usually gives a mixture of components. The extract is therefore

usually subjected to separation processes in order to obtain or isolate the individual

components. The separation techniques commonly employed include:

(a) Thin layer chromatography (tlc)

(b) Column chromatography

(c) Paper chromatography

(d) Gas chromatography

(e) Recrystallisation

Isolation is preceded with structural determination.

DETERMINATION OF THE STRUCTURE OF NATURAL PRODUCTS:

Structural work on natural products may begin with an elemental analysis

which gives the ratio of carbon, hydrogen, nitrogen, oxygen and sulphur etc. in the

molecule. From this, the empirical formula can be calculated. Determination of the

relative molecular mass enables the molecular formula to be calculated. The

structure can be determined using physical and chemical methods.

PHYSICAL METHODS

These are the most modern methods.

(a) Mass spectrometry (MS):-

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 The most obvious use of the mass spectrometry is in the accurate

determination of the relative molecular mass. The molecular ion has a m/z ratio

equal to the relative molecular mass.

(b) UV/Visible spectrosocopy:-

This is used to determine the presence of unstauration and the extent and

nature of conjugation

(c) Infrared spectroscopy (ir):-

This is particularly useful in identification of functional groups present in the

compound e.g.

3100 - 3600 cm-1 for N-H and free O-H

2400 - 3400 cm-1 (V.broad) for chelated OH of CO2H gp

1600 - 1800 cm-1 for C=O absorption.

Infrared gives information about hydrogen-bonding. It also gives information

about the nature of substitution on the benzene nucleus. The infrared spectrum

of any different samples of the same compound.

(d) NMR spectroscopy:-

Proton (1H) NMR spectrum gives idea about the different types of protons

present in the molecule. It also, through integration, gives idea about the ratiof

the different proteins and their different molecular environments.

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(e) Optical methods:-

Many natural products contain one or more chiral centers and are

therefore optically active. Natural products usually occur in 100% optical purity.

One can therefore measure the molecular rotation using the formula.

[M]D = [α ]D x rel. mol. mass

Optical rotatopn dispersion (ORD) is the change in the rotation power with

change in wavelength. ORD measurements are only valuable for chiral

compounds. It involves measuring molecular rotations over various

wavelengths. Plotting molecular rotation over wavelength gives the ORD curve.

It may be a plain curve or a cotton effect curve.

+ ve

- ve

-
λ
Plain curve

Peak

Amplitude
15

M
 Cotton effect curve

A curve that ascends and decends monotonically is known as a plain curve.

It may be positive or negative depending on the slope as shown in the graph.

Cotton effect curves show peaks (maxima) and troughs (minima). A cotton

effect curve is labeled positive if the peak is at a longer wavelength than the

trough. On the other hand, it is negative if the peak is at lower wavelength than the

trough.

The sign magnitude and general shape of the cotton effect curve can be

closely correlated with immediate structural and steroechemical environment of the

carbonyl group and are little affected by the structural changes remote from the

group. The position and configuration of a carbonyl group in a molecule may

therefore be found by comparing its cotton effect curve with those of suitable

analogues e.g.

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 The ketone derived from the sesquiterpene lactones “a” is either “b” or “c”. it

has negative cotton effect curve but the steroidal ketone “d” has positive cotton

effect curve. The structure of the ketone is therefore “c” and not “b”.

CHEMICAL METHODS

(a) Degradation method:-]

Degradation method involves breaking down the molecule into identifiable

fragments by chemical means. This involves reacting the molecule with such

oxidizing agents like ozone, potassium tetraoxomanganate (VII), trioxonitrate (V)

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acid and chromic acid. The molecule could be fraced from the products of such

oxidations.

(b) The compound can also be converted into known derivatives and this can

help in identification.

(c) Synthesis:-

The confirmation of the structure of any natural product is through synthesis.

Any deduced structure of a natural product which has not yet been confirmed

through laboratory synthesis is merely known as a proposed structure.

BIOGENESIS OF NATURAL PRODUCTS

Biogenesis refers to a way put forward by which natural products are synthesized in

the cells of living organisms. This is based purely on theoretical grounds with no

experimental backing, whereas biosynthesis is the method of synthesis in living

tissues based on experimental evidence.

The breakdown of sugar in living tissues serves as both an energy yielding

process and as a source of metabolic intermediates. The hexose sugar is converted

during glycolysis into triose phosphate which can be oxidized (through

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phosphoenolpyruvate and pyruvate) to acetyl coenzyme A. The hexose sugar can

also be converted through pentose phosphate cycle to triose phosphate. The

reactive thioester, acetyl co-enzyme A, formed is utilized in the biosynthesis of

isoprenoids and polyketides etc. Both pentose phosphate cycle and

phosphoenolpyruvate can be utilized for formation of aromatic amino acids,

shikimic metabolites (lignans, coumarins, chalcones, phenolics and flavonyls) and

etc.

BIOSYNTHESIS OF ISOPRENE UNIT

Mevalonic acid was discovered in Lactobacillus acidophilus in form of its δ-

lactone. It is found to be incorporated into cholesterol. Formation of mevalonic acid

(M.V.A.) involves several condensations of the acetate units. Two molecules of

acetyl coenzyme A undergo a sort of Claisen ester condensation to give acetoacetyl

co-enzyme A.

One molecule of acetoacetyl coenzyme A condenses with one molecule of

acetyl coenzyme A to give hydroxylmethylglutaryl coenzyme A. This on hydrolysis

followed by reduction gives mevalonic acid.

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Formation of isoprene unit from MVA:-

Isoprene unit is formed from mevalonic acid by a series of reactions involving

phosphorylation of M.V.A. in the presence of adenosine triphosphat8e (ATP).

Mevalonic acid is phosphorylated to mevalonic acid phosphate. In the second step,

the mevalonic. acid phosphate is further phosphorylated by ATP to give mevalonic

acid pyrophosphate. Phosphorylation of the 3-hydroxy group gives an unstable

intermediate which is converted by simple process of decarboxylation to isopentenyl

pyrophosphate (i.e. 3-methyl-3-butenylpyrophosphate. This isomerizes to 3, 3-

dimethylallyl pyrophosphate (DMAPP). It is from these isoprene units that the

precursors for the different classes of terpenoids are obtained.

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Monoterpenoids:-

To form ten-carbon compounds, two C 5 compounds are required. A molecule of

isopentenyl pyrophosphate reacts with a molecule of DMAPP to give geranyl pyr

ophosphate, GPP. GPP is the precursor for all monoterpenoids.

Sesquiterpenoids:-

A molecule of isopentenyl pyrophosphate can condense with a molecule of geranyl

pyrophosphate to give farnesyl pyrophosphate, FPP. FPP is the precursor for

sesquiterpenoids.

Diterpenoids:-

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Condensation of a molecule of farnestyl pyrophosphate with one molecule of

isopentenyl pyrophosphate gives geranylgeranyl pyrophosphate, GGPP. GGPP is the

precursor for diterpenoids.

Triterpenoids:-

Condensation of two molecules of farnesyl pyrophosphate in a tail-to-tail fashion

gives squalene which is the precursor for triterpenoids and steroids.

MONOTERPENOIDS

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 Geranyl pyrophosphate can be converted directly into a series of acyclic

monoterpenoids. It can also be converted through the geranyl carbocation into the

cyclic ones.

Geraniol

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 Geraniol is obtained in nature by the enzymic hydrolysis of geranyl

pyrophosphate. It is found in the volatile oil of geranium and the oil of rose while its

isomeric alcohol, nerol, is found in neroli and bergamot oils. Geraniol can be

separated from other constituents of the oil as it forms crystalline complex with

calcium chloride. When water is added to the isolated complex, geraniol separates

out as an oil.

Oxidation of geraniol with manganese (IV) oxide, MnO 2 gives geranial (citral

a) with little amount of neral (citral b). Reduction of either geranial or neral with

sodium in ethanol gives back geraniol and nerol, respectively. The structural

identity of nerol and geraniol has been shown by ozonolysis. Ozonolysis of the two

compounds gave the same products indicating their structural similarity.

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 In the presence of acid, both alcohols cyclize to terpineol but nerol cyclizes

much faster than geraniol indicating that nerol has a cis arrangement.

Camphor:

Camphor is an important natural product. It is used extensively in medicine and as

a plasticizer in the manufacture of explosives, celluloid and photographic film. It is

a bicyclic monoterpenoid.

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 Geranyl pyrophosphate isomerizes to the cis-form which loses the

pyrophosphate group to form a primary carbocation. Electrophilic attack of this

carbocation on a double bond leads to cyclisation with resultant formation of a

tertiary carbocation. Electropallic attack of the new carbocation on the remaining

double bond results in formation of a bridged compound with a positive charge on a

secondary carbon atom.

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 Hydroxylation of this secondary carbocation followed by oxidation to a keto

function gives camphor.

Although camphor is obtained readily from nature, the demand is so high

that it is today more readily obtrained from the more-available terpenes such as α -

pinene, camphene. For instance, treatment of camphene with ethanoic acid in the

presence of H4SO4 gives isobornyl ethonate. This on hydrolysis followed by oxidation

gives camphor.

IRIDOIDS:-

Iridoids glycosides constitute a group of naturally occurring organic products. The

naturally occurring iridoids are generally characterized by the cyclopentanopyrole

ring system. In most of the compounds the β-glycosyloxy group is present on C- 1

and a double bond present between C 3 and C-4 gives rise to the characteristic enol

ether. By opening the ring skeleton between C-7 and C-8 a group of compounds

called secoiriodoids are obtained.

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 Iridoiods are highly oxygenated monoterpenoids which occur mainly as

glycosides in plants. Plant feeding experiments with radioactive precursors

confirmed that iridoid and secoiridoid glycosides are formed through the mevalonic

pathway. Iridodial is the first isolated product. Iridodial undergoes a series of

modification reactions to give other iridoiods. It is first converted to 7-deoxyloganic

acid which is oxidized to loganin and verbenalin.

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MODIFICATION REACTIONS:-

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30
 Loganin may be further dehydrogenated to give 10-deoxygeniposide which

undergoes allylic oxidation at C-10 to afford geniposide. Geniposide and loganin can

also undergo a series of other modification reactions to give a series of other

iridoiod and secoiridoiod glycosides.

Another interesting modification reaction which occurs after cyclisation is the

biosynthesis of plumieride (a plant glycoside). It has been shown through tracer

experiments that a terpenoid related to skeleton. Plumieride is therefore a

degraded sesquiterpenoid.

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 Iridoiods are used as bitter tonic, sedative febrifuge, cough medicine, remedy

for wounds, against skin diseases and because of their insecticidel or hypotensive

effect. Acubin is used as cough medicine and for dressing wounds. Valmane

produced in Germany by Kali-Chemie and used as a mild sedative is made up of

nonglycosidic iridoiods from roots of Valeriana officianalis. Harpagoside from the

root of Harpagophytum procumbens possesses an analgesic and antiphlogistic

effect. Geniposide is the faecal softening principle of a Japanese crude drug.

The secoiridoids are also known in medicine. For example, Gentiopicroside

from Gentiana is used in bitter tonic. Oleuropein has a hypotensive action, a

coronary-dilating action and an antiarrhythonic action. Calcium salt and methyl

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ester of elenolic acid are potent broad spectrum antiviral agents. Sweroside on

heating gives nauclea which is the anriviral principle of nauclea latifolia.

DITERPENOIDS GIBBERELLINS

Gibberellins are plant growth hormones and are growth promoters. Auxins

and cytokinnins are other growth promoters while abscisic acid and ethane are

other plant hormones acting as growth inhibitors. These plant hormones occur in

very minute quantities in the plants.

Gibberellins are tetracyclic diterpenoid acids. They have two main groups.

These are the C20 and C19 gibberellins.

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 Gibberellins are made by giving them the number A 1, A2, A3,….. as they are

discovered. They can have double bonds at 1, 2, or 2, 3 positions. They can also be

hydroxylated at C-1, C-2, 3, 11, 13, 15 or 16. Each of these gives a different

giberellin. C-20 may occur at different stages of oxidation i.e. as methyl,

hydroxylmethyl (-CH2OH), carbonyl (-CHO) or carboxyl (-CO2H) group. The C20

gibberellins are always dicarboxylic or tricarboxylic acids.

REACTIONS

There are some general reactions which all gibberellins will undergo but

because of structural differences, there are also some individual reactions.

(a) The lactone ring is opened in strong base and if it is kept with an acid for

a long time, it will close back.

(b) The hydroxyl group in position 3 can easily be oxidized and after

oxidation, it can very easily be reduced to an emantiomer.

(c) The hydroxyl group at position 3 can also be dehydrated using

phosphorous oxychloride (POCL3) in pyridine or with tosylate.

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 (d) If a gibberellins is treated with a strong acid, isonerisation of the exocyclic

double bond to an endocyclic bond will occur. On the other hand, if there

is no hydroxyl group at position 13, the double bond will readily be

hydrated with dilute mineral acid to give a 16-hydroxy compound.

(e) Physiological function:

Gibberellin was first isolated as a secondary metabolite from a Fusarium species.

This fungus causes a particular disease of rice which makes the rice to grow very

high and then later die off. Gibberellins have been found to have various

physiological functions in plants.

(i) They promote extensive growth of intact plant (i.e. the whole plant).

(ii) They reverse genetic dwarfism

(iii) They affect the synthesis of some enzymes.

(iv) They reverse dormancy.

USES OF GIBBERELLIC

Gibberelic acids are produced commercially and are much used in agriculture

and industry. They are used in increasing the yield and quantity of certain fruits

such as grape and apple etc. by spraying them with gibberellic acids. Sometimes

the ripening process is delayed by spraying wth gibberellic acids. They are also

used in preservation of fruits e.g. bananas.

BIOSYNTHESIS OF GIBBERELLINS:-

The biosynthesis of gibberellins has been studied through feeding

experiments using radioactive compounds and extracting the plant at intervals to

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know the new compounds formed. They are shown to follow the normal path from

acetyl co-ezyme A. in the case of gibberellins, the first isolated product is ent-kaur-

16-ene.

Geranylgeranyl pyrophosphate undergoes an initial cyclisation catalysed by

proton to give a bicyclic intermediate. Loss of the pyrophosphate group gives an

allylic cation which cyclises to form ring C. Further cyclisation follows immediately

to form the fourth ring which undergoes a Wagner-Meerwein rearrangement to

form ring D.

There is a gradual oxidation of the C- 19 methyl to the alcohol. This oxidizes

further to analdehyde and finally to a carboxylic acid. The next stage is the

contraction of ring B to a five membered ring. The C-7 hydoxylated. It is further

oxidized to an aldehyde with contraction of ring B. further oxidation of this aldehyde

to a carboxyl group gives GA12 which is the simplest of the C20 gibberellins.

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37
TRITERPENOIDS

BIOGENESIS:-

Squalene undergoes concerted cationic cyclisation and rearrangements to

form triterpenoids. The course and mode of cyclisation depends on the way in which

the squalene molecule is folded on the enzyme surface. The different modes will

lead to formation of different types of triterpenoids such as α -amyrin, β-amyrin,

Iupeol and lanosterol etc.

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A molecule of squalene is enzymatically oxidized to oxacyclopropane squalene (an

epoxide). Enzymatic acid catalysed opening of the oxacyclopropane (i.e. epoxide)

ring gives a tertiary carbocation which is followed by a concerted cyclisations

reaction. The cyclisation involves a four sequential carbon-to-carbon bond

formation steps and leads to formation of the isoprenoid isomer of lanosterol which

undergoes a series of rearrangements with loss of a proton to afford lanostarol.

STEROIDS

Steroids are biogenetically related to triterpenoids. The most striking

difference between them is that steroids contain less than thirty carbon atoms in

the molecule. All steroids contain the hydrogenated cyclopentano-phenanthrene

skeleton. The rings are:

numbered A, B, C, D as shown and the substituent at each ring junction in plant

and animal steroids are normally in trans configuration except in very few cases

where it is cis between rings B and C only.

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 The steroids commonly have methyl substituents at positions 10 and 13 and

oxygenated at positions 3 and 17. In a good number of cases a side chain may be

found at position 17. The rings are in the more stable chair-conformation with the

atoms attached to the ring junctions in axial positions. The axial methyl groups are

also known as the angular methyl groups. Like in the case of triterpenoids, groups

above the plane of the molecules are designated as β-substituents while those

below the plane are designated as α -substitutnts. The represented steroids

molecule therefore has 3 β- OH, 10 β-Me, 8 β-H and 13 β-Me groups. It has also

got 3 α -H, 9α -H, and 14α -H.

STEROIDS OF ANIMAL ORIGIN (ZOOSTEROIDS)

There are many steroids of animal origin. Many of these steroidal derivatives have

physiological activities and frequently function as hormones in the animal body.

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Cholesterol:

Cholesterol is one of the most abundant animal steroids from which many

steroidal hormones are derived. It is present in all animal tissues particularly in the

brain and spinal cord. It is commercially isolated from the spinal cord of cattle by

extraction. Gallstones may consist of only cholesterol. It is implicated in several

circulatory and heart diseases as it is deposited in the arteries causing

arteriosclerosis and heat diseases.

Cholesterol is biogenetically derived from lanosterol. Conversion of lanosterol

to cholesterol involves removal of the three methyl groups at 4, 4 and 14 th positions

and the shift of the double bond between rings B and C to positions 5 and 6

removal of the C24-25 double bond. The methyl group at position 14 is first

removed by oxidation to a carboxyl function followed by decarboxylation to give 14-

norlanosterol. Further removal of the two methyl groups at position 4 in a similar

way gives zymosterol.

Zymosterol is converted to demosterol by shift of the double bond between

rings B and C to between C- 5 and C-6. Reduction of the C24-25 double bond of

41
desmosterol gives cholesterol. Other animal steroids that are biogenetically derived

from cholesterol can be divided into bile acids, steroidal hormones of the adrenal

cortex and the sex hormones.

Bile acids:-

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 The bile acids are biogenetically produced in the liver from cholesterol and

constitute part of a fluid delivered to the duodenum to aid emulsification, digestion

and absorption of fatty materials. Various animal species produce their own

characteristic bile acids which diiffer from each other by the number and position of

the hydroxyl groups. An example of bile acid is cholic acid.

Adrenocortical homones:-

These hormones participate in regulating the electrolyte and the water

balance in the body – as well as in protein and carbohydrate metabolism. They are

produced in the outer part (cortex) of the mammalian adrenal gland.

43
 X=R=H ; deoxycorticosterone

X = OH; R = H ; corticosterone

X == O; R = H ; 11-dehydrocorticosterone

X = H; R = OH ; 17-hydroxydeoxycorticosterone

X = OH; R = OH ; 11, 17-dihydroxycorticosterone

X = = O; R = OH ; cortisone

Cortisone, for example, is used extensively in the treatment of rheumatoid

inflammations. Synthetic analogues of the adrenocort0ical hormones are also used

in the treatment of rheumatoid and other types of inflammations.

Sex hormones:-

The sex hormones are steroidal compounds produced in the sexual glands of

higher animals and transported to the site of action where their effects are

produced. The sex-hormones are divided into three groups: androgens, estrogens

and progestin.

44
(a) Androgen:- Androgens are the male sex hormones. Testosterone is the

principal androgen produced in testis and is responsible for the masculine

characters such as the deep voice, facial hair and the general physical

constitution.

(b) Estrogens:- estrogens are the female sex hormones. An example is

estradiol. Extradiol is formed in the ovary and is responsible for the

secondary female characteristics and participate in control of menstrual

cycle.

(c) Progestins: progestins are the pregnancy hormones. An example is

progesterone which brings about proliferation of the lining of the uterus to

prepare it for implantation of the fertilized ovum.

Control of fertility:-

The menstrual cycle is controlled by three protein hormones from the

pitutary gland. These are:

i) The follicle-stimulating hormone which induces the egg growth.

45
 ii) The luteinizing hormone which induces the release of the egg from the

ovaries.

iii) Luteotropic hormone which induces formation of the ovarian tissue called

corpus luteum.

As the menstrual cycle begins, the egg growth is initiated and the tissue

around the egg secretes increasing quantities of estrogens. Once a certain level of

estrogen in the blood is reached, the production of the folicule-stimulating hormone

is turned off. At the time of ovulation the luteotropic hormone triggers the

formation of corpus luteum which in turn begins to secrete increasing amounts of

progesterone. The secreted progesterone suppresses further ovulation by turning

off the production of the luteinizing hormone. If the egg is not fertilized, the corpus

luteum and ovum are expelled and this is referred to as menstruation. On the other

hand, pregnancy leads to increased production of estrogens and progesterone to

prevent pituary hormone secretion and this prevents renewed ovulation.

The contraceptive pills contain estrogens and progestins. Most commercial

pills nowadays consist of a mixture of synthetic estrogens and progestins. This pill

when taken throughout most periods of the menstrual cycle prevents both the

development of the ovum and ovulation by turning off the production of both the

follicle-stimulating hormone and the luteinizing hormone. These pills will be seen as

tricking the female body into believing that it is pregnant.

46
STEROIDS OF PLANT ORIGIN PHYTOSTEROIDS

The typical plant steriods has at least one additional alkyl substituent on the

C-17 alkyl chain. Examples include ergosterol, sitosterol and stigmasterol etc.

47
 Ergosterol is a crystalline solid which occurs in yeast. Sitosterol and

stigamasterol are also crystalline solids widely distributed in the plant kingdom.

Lanosterol is the precursor for both cholesterol and ergosterol. Reduction of

the C24-25 double bond of desmosterol (see biogenesis of cholesterol) with

accompanying C-24 methylation gives an intermediate which is dehydrogenated at

C22-23 to give ergosterol. Ergosterol is the precursor for vitamin D 2. Sitosterol and

sigmasterol are also biogenetically derived from desmosterol.

Vitamin D

48
 Deficiency of vitamin D causes a disease known as “rickets”-this results from

improper bone formation caused by inadequate deposition of calcium phosphate

during bone formation/growth. This can be cured by administration of vitamin D.

Irradiation of ergosterol results in opeing of ring B to give vitamin D 2

(ergocalciferol). Irradiation of 7-drhydrolesterol or 22:23-dihydroergosterol gives

vitamin D3 (cholecaliferol) and D4 respectively.

49
CAROTENOIDS

Carotenoids are red, orange or yellow pigments which are widely distributed

in nature. They are essentially tetraterpenoids containing eight isoprene units. They

consist of two diterpenoid units joined in a tail-to-tail fashion. Some carotenoids are

hydrocarbons and are referred to as carotenes. Oxygenated derivatives of

carotenoid acids and esters (xabthophyll esters).

50
 During the biogenesis of carotenoids, two molecules of geranylgeranyl

pyrophosphate condense in a tail-to-tail fashion to give a molecule of phytoene with

only three conjugated double bonds. This undergoes three or four successive

dehydrogenation steps at alternative ends of the conjugated chain t give

neurosporene (with nine conjugated double bonds) and lycopene (with eleven

conjugated double bonds) respectively. The mono-and bicyclic carotenoids are

biogenetically derived from neurosporene.

51
 The carotenoids have a long chain of conjugated double bonds and this is

responsible for their adsorption within the visible region of the electromagnetic

radiation. The most widely distributed carotenoid in nature is β-carotene. It serves

as a source of vitamin A in anamals and is therefore an essential dietary

requirement.

Carotenoids have two main functions in plants. They act as accessory

pigments in photosynthesis (as photosensitisers). They also act as colouring matter

flowes, fruits etc. the red colour of tomatoes is due to lycopene (an acyclic

carotenoid). It should be noted that many caroteroids are known and their

52
districbution in nature is not uniform. Specific compounds may also be synthesized

by particular plant groups.

Vitamin A:

Vitamin A is a diterpenoid alcohol having the carbon skeleton of one-half of

the β-carotene molecule. It has a terminal hydroxyl group. The β-carotene and

some other carotenoids are the precursor of vitamin is formed by cleavage of the

C40 molecule in the body. It is only the carotenoids with the β-ionone ring system

(e.g.α -carotene, γ -carotene and cryntoxanthin etc. that can act as provitamin

A. β-caretene is the most efficient provitamin A-why? Vitamin A deficiency causes

the impairing of visual acuity in dim light known as night blindness.

THE CHEMISTRY OF VISION

Vitamin A (retinol) is converted by retinol dehydrogenase in the body into

trans retinal which is converted into cis-retinal isomerase.

53
 Cis-retinal fits well into the active site of a protein called opsin where it

reacts with an amino group on opsin to form a protonated imine called rhodopsin.

When a photon strokes rhodopsin, the cis-retinal part isomerizes within 10 -12

seconds to the trans form. This includes a tremendous geometric change which

severely disrupts the entire molecular geometry. Within 10 9 seconds a series of

54
conformational changes take place in the protein molecule. The overall changes

taking place leads eventually to hydrolysis of the ill-fotting retinal unit. The entire

process initiates a nerve impulse perceived by the organism as light. The trans-

retinal reisomerises to the cis-isomer and reforms rhodopsin. All know visual

systems in nature use the retinal system for visual excitation.

ALKALOIDS

The alkaloids are naturally occurring nitrogen containing compounds found

particularly in the plant kingdom, some also occur in animals. They contain at least

one basic nitrogen atom and hence the name alkaloid (alkali-like). They used to be

defined as naturally occurring basic crystalline compounds but it is known

nowadays that some alkaloids like recinine and colhicine neutral. Also a few of them

are acidic. Although most alkaloids are crystalline solids a few of them such as

coniine and nicotine etc etc. are liquids. Most alkaloids have pharmacological

properties and a good number of them have over the years served useful drugs to

both man and live-stock. These include cuinine from chinchona bark (used in

chemotherapy of malaria), codeine, morphine, heroin, cocaine, L.S.D. and the

penocillins etc. there are several methods of classification of alkaloids. One way is

to classify them as piperidine, indole, quinoline, isoquinoline or pyridine alkaloids

etc. depending on the presence of any of these heterocyclic moieties in the alkaloid

molecule. Amino acids are the precursors of alkaloids in nature. Some are derived

from aliphatic amino acids while others are derived from aromatic amino acids.

PYROLIDINE AND PIPERIDING ALKALOIDS

55
 Pyrrolidine alkaloids contain C4N unit derived from ornithine. The actual

precursor for the pyrrolidine alkaloids is 4-amino butanal (a γ -aminoaldehyde)

obtained by decarbonxylation and oxidation deamination of ornithine. This exists in

equilibrium with the cyclic imine. Similarly piperidine alkaloids are derived from

lysine and ktheactual precursor is the δ-aminoaldehyde (5-aminopentanal). The

alkaloid in them formed by aseries of other recations following the nucleophilic

addition to the cyclic imine double bond.

56
NICOTINE

(-)-Niaotine consists of 2-8% (dry matter) of tobacco leaf. Nicotine has

effects on the nervous ganglia, stimulating it in minute doses but paralyzing it in

larger doses. Nicotine has no clinical application but it is used as an insecticide. It is

used either in fumigation especially of glasshouses or as a contact insecticide. It

acts as a paralysant of the central nervous system and death results from

respiratory failure (anabasin is also as an insecticide).

57
BIOGENESIS OF NICOTINE

Nicotine is derived from nicotinic acid and cyclic N-methyliminium ion derived

from ornithine. The nicotinic acid is first reduced to 1, 6-dihydonicotinic acid.

Nucleophilic addition of this to the iminium salt gives a bicycle intermediate which

decarboxylate to give nicotine.

Nicotine is synthesized in the laboratory from ethyl β-nicotinayte (that is

ethyl 3-pyridine-carboxylate). Claosen condensation between this ester and N-

methylpyrolinone followed by acid catalysed hydrolysis of the lactam ring gives a 3-

keto acid which decarboxylates to afford a ketone. Catalytic hydrogenation of the

ketone gives an alcohol which is converted to an iodo grouo by treatment with

hydrogen iodine. The iodo compound cyclises to racemic nicotine on treatment with

dilute base.

58
59
60
 Ornithine undergoes oxidative deamination to an aldo-amino acid which

undergoes an intramolecular condensation to a cyclic imine. Nucleophilis addition of

an acetoacetic acid molecule across the imine double bond gives an intermediate

which loses a molecule of methanoic acid (that is foemic acid) to give yet another

cyclic imine. Intramolecular nucleophilic addition across the new imine double bond

leads to an intermediate bicyclic keto-amino acid from which both atropine and

cocaine are derived. Decarboxylation of this intermediate gives secondary amino

ketone which undergoes N-methylation followed by reduction of the keto to a

hydroxyl group. Esterification of this hydroxyl group with 3-hydroxyl-2-

phenylpronoic acid affords the alkaloid atropine. On the other hand esterification

(methylation) of the carboxyl group of the bicyclic intermediate followed by N-

methylation and reduction of the keto group gives an alcohol. Esterification (that is

benzoylation) of this leads to formation of cocaine.

Both cocaine and atropine are local anaesthetics. Their anaesthetic action

was found to be associated with the amino function connected to the hydroxyl

group esterifies by an aromatic acid by a bridge of carbon atoms. Atropine has

antispasmodic (spasm = convulsion, involuntary muscular contraction), mydriatic

(mydriasis = abnormal dialation of the pupil) and central nervous system, CNS,

depressant properties. It is given before other anaesthetics to decrease secretion in

bronchial and salivary systems and to prevent cardiac depression by depressing the

vagus nerves thus quickening the heart beat.

Cocaine is a very powerful local anaesthetic. It is toxic especially to the brain.

It may cause agitation, disorientation and convulsion. Its aqueous solution is also

highly susceptible to fungal attack. Cocaine has the serious problem of addition.

61
ALKALOIDS BASED ON PHENYL-ETHYLAMINE

Several simple henyl-ethylamine bases are derived from tyrosine or phenyl-

ethylamine etc.

(i) Hordnine

(ii) Ephedrine

Ephedrine is obtained in nature from the amina acid, phenylalanine. The

phenylalanine is decarboxylated and oxidized to give 2.oxo-2-phenylethylamine.

This undergoes both N- And C- methylation followed by reduction of the keto to the

hydroxyl function to afford ephedrine. Ephedrine causes rise in blood pressure and

62
sugar. It also causes relaxation of bronchial muscles and hence it is used to relief

asthma. Its vasoconstrictor action makes it useful in the control of bleeding.

ISOQUINOLINE ALKALOIDS

Isoquinoline alkaloids are formed in nature from tyrosine via phenylethyl-

amines. The phenylethylamine condenses with an aldehyde to give an isoquinoline

condensation of the aldehyde with

Phenylethylamine gives an imimium salt at a pH of about 5. This is followed

by cyclisation with loss of a proton to give the quinoid bicyclic intermediate.

Rearrangement of this intermediate which is accompanied with aromatization

affords the isoquinoline.

PAPAVERINE SERIES (OPIUM ALKALOIDS)

The use of arylacetaldehyde (that is, arylethanal) in isoquinoline formation

gives benzylisoquinolines such as papaverine and other morphine alkaloids. The

63
parent base is norlaudanosoline. This is formed from 3,4-dihydroxyphnylamine

(dopamine) and 3,4-dohydroxyphenylethanal (that is, 3,4-

dihydroxyphenylacetaldehyde), both of which are from tyrosine via 3,4-dopa.

Papaverine is formed from norlaudanosoline through aromatosation and

complete o-methylation.

Papaverine is a smooth muscle relaxant used in spasm, asthma and

peripherial vascular disorders.

64
 Partial methylation of horlaudanosoline may occur in a specific manner to

give (-)-reticuline. Reticuline undergoes an oxidative coupling reaction ortho-with

respect to one of the phenolic hydroxyl groups and para-with respect to the other

to give salutaridine which undergoes enzymsatic reduction to dalutaridinol. The

baine is formed from satutaridinol by dehydration which results in formation of an

ether bridge. Partial hydrogenation and demethylation of thr aliphatic methoxy

group of the aromatic methoxy group of codeine affords morphine. Ethanoylation

(that is acetylation) of morphine gives the diethanoyl morphine (that is, diacetyl

morphine) known as heroine.

Codeine, morphine and heroine are narocotics. Morphine is ten to fifteen

times as potent an analgesic as codeine while heroine is about three times as

potent as morphine. The euphoric, depressant and addictive properties of these

drugs increase from codeine to morphine to heroine.

65
66
 It is believed that norlaudanosoline formed in the brain after consumption of

alcohol is responsible for delirum tremens (picture of confusion, terror, restlessness

and hallucination resulting from alcoholic intoxication) characteristic of alcoholics.

Dopamine present in the brain in normally converted to 3,4-

dihydroxyphenylethanoic acid via 3,4-dihydroxylethanal.

With much alcohol in the blood the amount of ethanol (that is, acetaldehyde

in the brain increases as some of the alcohol will be oxidized to ethanol. Ethanol

inhibits the activity of aldehyde dehydrogenase. As a result, 3, 4-dihydroxyethanal

accumulates in the brain and its concentration may reach such a level that it will,

condense with dopamine to form norlaudanosoline. It is the presence of

norlaudanosoline in the brain, which is readily converted to morphine that is

responsible for the symptoms of alcoholism.

INDOLE ALKALOIDS

Tryptophane is the precursor for most Indole alkaloids. Simple indole bases

such as Harman, serotonin and psilocybin (a hallucinogenic mushroom alkaloid) etc.

and directly derived from it. Indole alkaloids constitute a very large and complex

series of naturally occurring alkaloids. They are generally biogenetically derived

from the amino acid, tryptophane.

67
BIOSYNTHESIS OF LYSERGIC ACID DIETHYLAMINE (LSD):

Tryptophane is first decarboxylated to tryptamine. Dimethylallyl

pyrophosphate, derived from mevalonate, alkylates the tryptamine to give 4-

isopentenyltryptamine. This cyclises to give the tricyclic chanoclavine and

tetracyclic agroclavine. The methyl group of agroclaine is oxidized to a

hydroxymethylene group to form elymoclaine which isomerizes to lysergol. Further

oxidation of the hydroxymethylene group to a carboxyl group affords lysergic acid.

This is then converted to its amide, lysergic acid diethyl amide, L.S.D.

68
 LSD is about the most powerful hallucinogen known. The effective dose is

0.05mg (i.e 0.00005g or 5. Its hallucinogenic action was discovered by a Swiss

Pharmacologist, Dr. Albert Hofmann, in 1943. He stated his account as follows:

“When I was purifying lysergic acid diethylamine I experienced a strange dream-

like state which wore off after some hours…. I decided to test the compound on

myself. Being by nature a cautious man, I started my experiment with the lowest

dose which presumably could have any effect, taking 0.25mg. This first planned

experiment with LSD took a dramatic turn and led to the discovery of the

extraordinarily high psychotomimetic activity of this compound”.

69
 Other important alkaloids derived from trytophane include quinine,

cinchonamine, ajamaline, strychaine and yohimbine etc.

LIPIDS

Lipids are naturally occurring organic compounds which have the common

property of being only sparingly soluble in water but soluble in many organic

solvents especially hydrocarbon solvents. They yield monocarboxylic acids on

hydrolysis. Lipids may be divided into three main groups:

(a) Fats, oil and waxes – simple lipids

(b) Phospholipids and glycolipds – complex lipids

(c) Steroids etc – derived lipids.

Simple Lipids

Waxes, oils and waxes are all esters.

70
Waxes: waxes are esters of long chain (C 16 or greater) carboxylic acids and long

chain alcohols. Waxes are low melting solids with the characteristic “waxy” feel

e.g.

(i) Spermacile: This is a white solid with melting point of 40-50 0. It is obtained

from the head of the sperm whale, it is used in the manufacture of soap and

cosmetics.

(hexadecyl hexadecanoate)

(ii) Bee wax): This is the material from which bees build honey comb cells. Its

melting point is 60-800. It is a mixture of esters of C26 and C28 straight chain

monocarboxy acids and C30 and C32 primary alcohols.

(iii) Caenauba wax occurs in the coating of Brazilian palm leaves. It is a mixture

of esters of C24 and C23 caeboxylic acid/C34 primary alcohol.

FATS AND OILS

Fats and oils consists primarily of esters of long chain carboxylic acids (fatty

acids) and propane-1,2,3-triol (glycerol) commonly referred to as glycerides.

71
 Oils have their melting points below room temperatures while fats have their

melting points above room temperatures. The oils are therefore liquids while fats

are solids (semi-solids) at room temperatures. There is however no basis for

chemical distinction between the two.

The difference is merely a physical one that can be removed by changing the

environment except that oils have higher degree of unsaturated than fats.

Use of the word fat to include both fats and oils is becoming common

especially among chemists. Thus both seed oil and animal fallow would be

considered as plant and animal fats respectively. This terminology avoids confusion

with non-fatty oils such as essential oils and petroleum oils etc.

Triglycerids are simple if the same fatty acid is present in all three positions

of the molecule. Natural fats are mixed glycerides in which different fatty acids are

present in all the three positions.

72
 The common fatty acid components of natural fats include:-

(a) Saturated acids:

CH3 (CH2)12 CO2H; myristic acid

CH3 (CH2)14 CO2H; palmitic acid

CH3 (CH2)16 CO2H; stearic acid

CH3 (CH2)18 CO2H; arachidic acid

(b) Unsaturated acids:

CH3 (CH2)5 CH=CH – (CH2)7 CO2H; palmitoleic acid

CH3 (CH2)7 CH=CH – (CH2)7 CO2H; oleic acid

CH3 (CH2)4 CH=CHCH2CH=CH (CH2)7 CO2H; linoleic acid

Liquid fat can be converted into solid fat by catalytic hydrogenation.

Saturated fats have been implicated as a dietary factor in atherosclerosis (that is,

hardening of the arteries). As a result the liquid fats which are highly unsaturated

are becoming increasingly popular. These liquid fats are also used in oil paints. Fats

serve as stored source of energy in the living organism and as important

component of the cell membrane.

73
PHOSPHOLIPIDS

These are triglycerides derived from fatty acids and tetraoxophosphate (v)

acid (that is, phosphoric acid). The glycerol is esterifies by two adjacent fatty acids

and a phosphate unit which bears another substituent derived from a base

(choiline, ethanolmine or serines). There are also phospholipids in which the base is

replaced by inositol. Phospholipids occur commonly in plants.

POLYKETIDS:

Polyketides are theoretically derived from β-polyketones chain (-CH 2CO-)n

where the chain is linear. In very few cases it may also be derived from the

propionate unit (-CHMe-CO-)n fatty acids cvonsists mostly of even-numbered

carbon chain because they are biogenetically derived from the acetate unit. They

are biosynthesized through the acetate and malonate systems.

74
Acetyl coenzyme A system:

In some cases the fatty acid may be derived from co-enzyme A.

Two molecules f acetyl coenzyme a$ undergo a Claisen type of condensation

to form a β-ketoester which is redcd in the resence of reducef nicotinamide adenine

dinucleotide. NADH 9that is reduced diphospyridine nucleotide, DPNH) to a β-

hydoxyester. This eliminates a molecul of water to give an α , β-unsaturated ester

which is further reduced by the reduced nicotoroamide adenine dinucleoride

phosphate, NADPH (i.e. reduced triphospyidine nucleotide, TPNH) to afford an

alkanoyl coenzyme A with two carbon atoms more than the initial one (i.e. butanoyl

co-enzyme A). A repeat of the cycle extends the chain further by two carbon atoms.

The extension may continue leading eventually to the formation of a long chain

fatty acid.

MALONATE PATHWAY

This is the most widely distributed and common mechanism of fatty acid

synthesis in living tissues. The chain extending agent, in this case, is this case, is

the malonyl co-enzyme A which is a more reactive nucleophile than acetyl co-

enzyme catalysed caboxylation.

75
 The malonyl co-enzyme A condenses with an acyl co-enzyme A molecule

referred to as the starter, which is acetyl co-enzyme A in most cases. The initial

steo involves conversion of acetyl coenzyme A and malonyl coenzyme A into the

new thioesters, acetyl-protein and maloyl protein respectively by condensation with

a special carrier protein, PSH. The acyl group of the acetyl protein becomes

transferred to the thiol group of an enzyme before finally condensing with malonyl

protein to form acetoacetyl protein.

The acetoacetyl protein is converted to butyryl proteins (that is, butanoyl protein)

by seubsequent reduction/dehydration steps and it is recycled until a long chains

fatty acid ester is obtained.

Replacement of acetyl co-enzyme A with other protein starters may lead to

branched chain and odd-numbered fatty acids via the malonate pathway e.g

76
(i) Acetyl co-enzyme starter: -

Straight chain (C16)

(ii) Propionyl starter:-

Straight chain (C17)

(iii) Isobutyryl (2-methylpropionyl) starter:-

Branched chain (C18)

Branched fatty acids:

Branched fatty acids arise from

(i) Incorporation of propionate unit during a chain extension step e.g.

(ii) Use of branched starter during the assembly process

(iii) By methylation. The methyl group can be introduced as CH 2 derived from

the –CH3 of methionine and attached to a carbon atom of an alkene

77
 double bond. It is believed to be a sort of y lip addition, followed by

reduction.

Unsaturated fatty acids:

There are several pathways to the formation of unsaturated fatty acids.

Aerobic desaturation of a proformed fatty acid in form of the acyl derivative of the

carrier protein gives unsaturated fatty acids in living tissues. For example stearic

acid to oleic and linoliec acids in the yeast cell.

An alternative pathway to unsaturated fatty acids diverges from

palmitate/stearate pathway at the G 2 stages. The α,β-unsaturated thioester

becomes reduced before addition of further C2 unit during the chain building to

form palmitic acid (16) and stearic acid (C18).

However if the β-hydroxy C12 thioester eliminates a water molecule to form a

β, γ -unsaturated thioester it may continue the chain building by addition of

further C2 units without reduction of the double bond by the system oleic acid. This

has been proved in a biosynthetic experiment using the anaerobic.

CLOSTRIDIUM BUTYRICUM

78
OTHER POLYKETIDES

Numerous other polyketides are known. These include the antibiotic

erythromycin, and tetracyclins etc, in the case of erythromycin the polyketide chain

is wholly derived from the propionate unit.

79