Regulation of small molecules

REGULATION OF SMALL-MOLECULE DRUGS VERSUS BIOLOGICALS VERSUS BIOTECH PRODUCTS... 

Maria de los Angeles Cortes Castillo, Technology and Health Service Delivery, Pan American Health Organization, Washington, DC, Regulation of Small-Molecule Drugs versus Biologicals versus Biotech Products... 

In eukaryotes, translation initiation is rate-limiting with much regulation exerted at the ribosome recruitment and ternary complex (elF2 GTP Met-tRNAjMet) formation steps. Although small molecule inhibitors have been extremely useful for chemically dissecting translation, there is a dearth of compounds available to study the initiation phase in vitro and in vivo. In this chapter, we describe reverse and forward chemical genetic screens developed to identify new inhibitors of translation. The ability to manipulate cell extracts biochemically, and to compare the activity of small molecules on translation of mRNA templates that differ in their factor requirements for ribosome recruitment, facilitates identification of the relevant target. 

In order to judge the performance of the regulated CSE-NS method, the calculation of the potential energy curves (PECs) of small molecules such as L12 and BeH2 is very illuminating. 

In fact, tubers contain plentiful amounts of small molecules and secondary metabolites, which have roles in an array of key tuber processes from regulating tuber organogenesis to mediating... 

Ornithine decarboxylase catalyzes the transformation of ornithine to the polycationic bases, putresine, spermine, and spermidine. These compounds exert regulatory effects on cell growth. It has been shown that quercetin (10 to 30 pmol/mouse) markedly suppressed the stimulatory effect of the transporters associated with antigen processing (TPA) on ornithine decarboxylase (ODC) activity and on skin tumor formation in mice initiated with dimethylbenzanthracene. Such inhibition may be related to the activation of the catalytic site, which is under nonconventional regulation by small molecules. Also, the synthetic flavonoid flavone acetic acid was shown to inhibit the activity of ODC in stimulated human peripheral blood lymphocytes and human colonic lamina propria lymphocytes. 

Holton S, Merckx A, Burgess D et al (2003) Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition. Structure 11(11) 1329-1337... 

Two mechanisms that are commonly employed in altering enzyme activity are covalent modification and allosteric regulation. Covalent modification is an enzymatically catalyzed reaction that involves the reversible formation of a covalent bond between a small molecule and a specific amino acid side chain(s) on an enzyme that affects its activity. Allosteric regulation of an enzyme s activity involves noncovalent binding of a small molecule at a site other than the active site that alters the enzyme s activity. Unlike the limited examples of covalent modification that have been discovered (see Table 15-1), a wide variety of small molecules have been found to regulate the activity of particular enzymes allosterically. 

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