Toxicity, isoprenoid production

One of the main functions of peroxisomes is to detoxify the cell by splitting hydrogen peroxide. They contain the enzyme catalase. Catalase converts H2O2 (hydrogen peroxide, a toxic by-product of cellular metabolism) to H2O and O2, with 4H202 4H2O-I-2O2. Peroxisomes also degrade fatty acids and toxic compounds and catalyze the first two steps required in the synthesis of ether-linked phospholipids (which are later used to build membranes) and sterols. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. 

Where natural production is not at sufficient titre and biotransformation is not a viable approach, microbes must be engineered to produce the desired isoprenoid directly from central carbon intermediates. Here we will review engineering approaches for isoprenoid production, focusing on model organisms but also discussing more unusual production strains. We also review some of the economic and practical considerations for isoprenoid bioprocesses, including issues related to feedstock price/availability (particularly important for bulk bioprocesses) and product toxicity (particularly for isoprenoid hydrocarbons with fuel applications). 

Often used in concert with mass spectrometry, NMR spectroscopy remains an invaluable structural diagnostic tool of particular importance to tricyclic natural products chemistry. For example, the tricyclic phenolic compound moracin P (3) was one of eight previously known compounds identified together with two new isoprenoid-substituted flavanones in isolates of the root bark of mulberry trees <89H(29)807>. In a series of studies of 6-7-5 tricyclic natural products, ID and 2D H and l3C NMR spectroscopy were employed extensively in the structure determination of sesquiterpene lactones (4)—(8) found among the aerial natural products of toxic plants (85P1378,90P551, 90P3875). 

Statins. Statins, such as atorvastatin (Lipotor), simvastatin (Zocor) and lovastatin (Mevacor), are fungal-derived HMG-CoA reductase inhibitors. Treatment results in an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is also required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity. 

The microbial production of isoprene or isoprenoids through the MVA or MEP pathway has been reported in a variety of microorganisms. The details of the engineering strategies, especially for isoprene production, are discussed below. The preferred approach of heterologous or endogenous pathway expression is determine d by the me chanism of metabolic regulatory control, the toxicity of the intermediate metabolites, and the characteristics of the key enzymes. 

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