Chemistry of The World- How Nature Makes Molecules

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 - e.g the humble poppy produces the alkaloid clinically known as morphine, 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, 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.

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 precursors,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 protein. This leads to further investigation of 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-ß-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 ß-carbon in the polyketide pathway, 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 further reactions and morphological changes occur. Evidence for the involvement of acetate in the pathway was provided by the feeding of C-14 labeled acetate into plants and the labeled C-14 being found throughout the chain of the product [4] as C-14 is a ß- emitter it is easy to identify labels in compounds in extracted metabolites using autoradiography.

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.

Mevalonic acid is made of three acetate units CH3CO2, the first two units join are joined by a Claisen ester condensation reaction and the final acetate unit is added by a Aldol to give the central hydroxy unit, the phosphorylation of mevalonic acid with ATP forms isopentenyl pyrophosphate (IPP) and then IPP is converted into dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate the precursor for rose oil a perfume is made by joining IPP and DMAPP by a cation/anion pair interaction, from this allylic cation rearrangement can form a number of other terpenes such as limonene. Studies have shown that limonene has pathogen selective antimicrobial activity specifically (-) - limonene is the more active isomer with higher sensitivities for five out of the 8 pathogens tested against however subsequent studies have shown that the influence of stereochemistry on antimicrobial activity is pathogen specific.

Conclusion

Secondary metabolite can technically not be essential to life, they have become a very important part of day to day like and these compounds are keeping many people alive or the knowledge gained by studying the adverse metabolites such as the aflatoxin which was over-looked for centuries has helped prevent food spoilage and saved lives in doing so. The purpose of the secondary metabolites still remains uncertain, do these non-sentient organisms evolve to produce beneficial chemicals so that they are grown in large numbers by humans or are they being made due to an environmental stimulus, do the secondary metabolites benefit the host organism be deterring predators? We may never know but I’m sure we’ll do our best to find out!