Metabolic engineering of cyanobacteria has the advantage that sunlight and CO 2 are the sole source of energy and carbon for these organisms. However, as photoautotrophs, cyanobacteria generally lack transporters to move hydrophilic primary metabolites across membranes. To address whether cyanobacteria could be engineered to produce and secrete organic primary metabolites, Synechococcus elongatus PCC7942 was engineered to express genes encoding an invertase and a glucose facilitator, which mediated secretion of glucose and fructose. Similarly, expression of lactate dehydrogenase-and lactate transporter-encoding genes allowed lactate accumulation in the extracellular medium. Expression of the relevant transporter was essential for secretion. Production of these molecules was further improved by expression of additional heterologous enzymes. Sugars secreted by the engineered cyanobacteria could be used to support Escherichia coli growth in the absence of additional nutrient sources. These results indicate that cyanobacteria can be engineered to produce and secrete high-value hydrophilic products.Metabolic engineering of photosynthetic microbes is attractive because of the efficient use of light energy by these organisms and the potential for CO 2 mitigation during production (21). Conventional terrestrial plants capture solar energy at low efficiencies (about 0.1 to 0.25% for corn and up to 1% for switchgrass), while fast-growing prokaryotic and eukaryotic microalgal species are about 1 order of magnitude more productive and their photosynthetic efficiencies can be Ͼ10% (12, 13). Genetic tools for engineering cyanobacterial species, including Synechococcus elongatus PCC7942 (Synechococcus), can be applied to metabolic engineering (7). For example, Deng and Coleman (8) expressed pyruvate decarboxylase and alcohol dehydrogenase in cyanobacteria to produce small amounts of ethanol, and Atsumi et al. recently described efficient synthesis of isobutanol using a four-step pathway established in Escherichia coli (2).Much attention has been focused on metabolic engineering to produce fuels. However, fuel molecules are generally toxic to microbes even at moderate concentrations. In addition, on a per-photon basis, the actual market value of fuels is at best comparable to, and generally lower than, the market value of other commodity organic compounds, such as sugars, lactic acid, and amino acids. Engineering cyanobacteria to produce and secrete hydrophilic or charged molecules would thus be economically desirable.Commonly used metabolic engineering organisms, such as E. coli and yeast (e.g., Saccharomyces cerevisiae), express a variety of transport systems for exporting waste products as well as importing nutrients. As photoautotrophs, cyanobacteria lack many of the transporters found in these organisms. In addition, while most microbes store energy by pumping protons across the plasma membrane, cyanobacteria store energy by transporting protons across the thylakoid membrane. In fact, cyanobacteria tend to alkalinize their...
The tert-butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series of drug analogues of bosentan and vercirnon are documented as part of a comparative study of tert-butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl, and cyclopropyl-trifluoromethyl substituents.
Peptides are important in the drug discovery process. In analogy to nonpeptidic small-molecule counterparts, they can sometimes suffer from disadvantages such as their low bioavailability and poor metabolic stability. Herein, we report the synthesis of new oxetanyl dipeptides and their incorporation into Leu-enkephalin analogues as proof-of-principle studies. The modular approach that is described enables the incorporation of a variety of oxetanyl amino acids into potential peptide therapeutics.
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