Since With each compound having its own

Since day one man has tried to mimic and understand
everything that nature does, from fire electricity and even production of
diamonds and so far, scientists have been rather successful, many physical and
chemical processes can be replicated in vitro by scientists however the
biological field is slightly lagging behind and there is still much to be
learnt about enzyme facilitated reactions and the different metabolites.

Secondary metabolites are of particular interest as they are
usually unique to a particular species 1 -e.g the humble poppy
produces the alkaloid clinically known as morphine2, and usually
have no proven effect on the organism manufacturing the chemical, however could
have an effect on potential predators. Secondary metabolites are biosynthesized
from a small number of important compounds which arise from the reactions which
produce or metabolise essential metabolites such as proteins, carbohydrates,
and nucleic acids 1, with special attention to acetate and mevalonic acid.
With each compound having its own reaction pathway, the polyketide pathway
involves acetate in the form of a thioate with a coenzyme A leaving group, the
mevalonic acid pathway has mevalonic acid as its precursor as the name suggests
however it is biosynthesised from 3 units of CH3CO2H.

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In this article the biosynthesis of secondary metabolites
from the polyketide and mevalonic acid pathways will be discussed as well as
the biological activity of the metabolites.

Polyketides

Biosynthesis is the formation of chemical compounds by
living things usually within cells, acetate the precursor to the polyketide
pathway and the source of mevalonic acid is obtained from metabolised fatty
acids

Polyketides are structurally diverse usually containing alternating
oxygen atoms that are derived from the carbonyl groups of the fatty acid
precursors3 ,and are the most common fungal secondary metabolite
and are formed via the polyketide pathway, these substances boast a range of
medicinal activities from antibiotics, antifungal, anticancer compounds, the
variety of  is matched by the variety
biosynthetic mechanisms, the enzymology of many polyketide synthases are
different from one another and only three were known buy 1985: 6-methylsalacilic
acid synthase from Penicillium patulum, naringenin chalcone synthase from the
parsley plant Petroselinum hortense and resveratrol synthase from the peanut
plant Arachis hypogaea. These three enzymes were studied and found to have the
basic traits of a polyketide synthase yet had distinctly varied properties but
did not lead to a coherent prediction of how a bacterial polyketide synthase
would be organised, largely due to the contrast in function and size of the functional
enzymes for example 6-methylsalecilic acid had a molecular mass or 800,000 Da,
it is suggested that its structure was due to its role as a tetrameric protein
with multiple functions, to which all the substrates are covalently attached in
contrast charcone synthase a homodimer whose units have a molecular mass of just
42,000 Da and act on the CoA esters of the substrates and is unable to mimic
the action of an acyl carrier protein3. This lead to further
investigation into derivatives of the polyketide pathway.

Formation or a polyketide starts with the condensation of
acetyl-CoA with the required number of malonyl-CoA units and then modification
of the poly-?-ketone
where required, in the case of aflatoxin the starter unit is a hexanoate rather
than the typical acetate started combined with nine malonoates through
subsequent condensation reactions in a similar fashion to eukaryotic fatty-acid
synthase , polyketide synthases which are multidomain proteins , both enzymes
condense short chain carboxylic acids  (acetyl coenzyme A malonyl CoA to form carbon
chains of varying length. The main difference between the fatty acid pathway
and the polyketide pathway is that there isn’t a full reduction of the ?-carbon
in the polyketide pathway 4,5, the hexanoate has malonoates
added, this is how the polyketide backbone of aflatoxin is made (noranthrone),
which is then oxidised to the anthraquinine norsolorinic acid 6 further
reactions and morphological changes occur and are shown in fig.1 and details of
these reactions can be found in4and6. Evidence for
the involvement of acetate in the pathway was provided by the feeding of C-14
labelled acetate into plants and the labelled C-14 being found throughout the
chain of the product 4 as C-14 is a ?- emitter it is easy
to identify labels in compounds in extracted metabolites using autoradiography.

Fig.1 pathway for
the synthesis of Aflatoxin B2 6

 

Aflatoxin as the name suggests is a mycotoxin which contaminates
food stuffs, the toxicity of the Aflatoxins was first witnessed in the early
1960’s when thousands of turkeys died all around London, as a result of eating
peanut meal which was heavily contaminated with a common species of mould 5.
Currently the available information doesn’t provide evidence of a complete
sequence of biochemical events leading to the life-threatening levels of toxicity
or carcinogenicity.  Biochemical changes occurring
immediately after exposure of animals and cell cultures to Aflatoxin revealed a
general pattern of responses. Aflatoxin interacts with DNA, the interaction is
expected to interfere with DNA transcription, giving rise to predicable results,
the failure of DNA transcription would result in the deterioration of DNA and
RNA synthesis leading to the inhibition of protein synthesis 7.