Inhibitor from microbial sources

FPP Ki = 2 nM) and uncompetitive with the Ras substrate Ki = 32 nM) [69]. While numerous reports of FPP competitive inhibitors derived from microbial sources are available none are peptidic vide infra). The... 

Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W. (2003) Salinosporamide A A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42 355-357. 

The squalestatins represent the first novel class of squalene synthase inhibitors to be isolated from a microbial source. Numerous attempts have been made to synthesise inhibitors chemically, but the most active of these is still 10-fold less potent than the squalestatins. 

Microbial - Some of the most interesting protease inhibitors have been derived from bacterial sources such as actlnomycetes. 8 of particular importance to inhibition of neutral proteases and collagenases are elastatinal, chymostatin, leupeptlns, and phosphoramidon. 

Eight classes of natural products that are inhibitors of FPTase have been described from a variety of microbial sources. Mechanistically, these compounds are competitive with FPP. All compounds, with the exception of manumycins, possess negative charges in the form of one or more carboxylic, sulfuric or phosphoric acids, and are not active in cell-based assays. The lack of cell-based activities for these classes of natural products is linked to the negative charge present in these compounds that appears to be detrimental for cell wall penetration. Manumycin, in contrast, is not only active in cell-based assays but is also active in animal models. 

Figure 1 Bulk drugs from natural sources Paclitaxel (antileukemic and antitumor) and lovastatin (inhibitor of cholesterol biosynthesis) are examples of the diverse and complex structures made by plant and microbial cell biosyntheses, respectively. In most instances of such compounds having desirable biological activities, their structural and chiral complexities make chemical synthesis not competitive with isolation from biosynthesis.

Commercial sources of enzymes are any living organism, i.e., animals, plants, and microbes. These naturally occurring enzyme sources are quite readily available for the commercial productivity of sufficient quantities for food applications and/or other industrial uses. Table 4.1 shows some important representative industrial enzymes from animal, plant, and microbial sources. Of the number of these industrial enzymes, the majority (more than half come from fungi and yeast and a third from bacteria) come from microorganisms and the reminder, a minority, from animals (8%) and plants (4%). A number of enzymes have found use, also, in chemical analyses and medical diagnosis. However, enzymes from microbes are preferred than from animals and plants because (1) they are cheaper to produce (2) they are more predictable and controllable (3) they are reliable supplies of raw materials of constant composition and (4) plant and animal tissues contain more harmful materials (phenolics, inhibitors, etc.)... 

Selective 3-phosphoinositide-dependent kinase 1 (PDKl) inhibitors Dissecting the function and pharmacology of PDKl 13JMC2726. Staurosporine analogues from microbial and synthetic sources and their biological activities 13CMD3872. 

Fig. 34. 3. Structures of selected sterols. Sources animal - lanosterol, cholesterol and ergosterol (also microbial) plant - all others. (From Warner, K., Su, C, and White, P.J. "Role of Antioxidants and Polymerization Inhibitors in Protecting Frying Oils" in Frying Technology and Practices, M.K. Gupta, K. Warner, and P.J. White (Eds.), pp. 37-49, AOCS Press, Champaign, IL 2004. With permission.)...

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