Homodimerizers selectivity

It is not clear why some organisms have two 14-3-3 isoforms while others have up to 12. Binding 14-3-3 inhibits the plant enzyme nitrate reductase and there appears to be no selectivity between plant 14-3-3 isoforms in fact yeast and human isoforms appear to work equally as well in vitro. The best example where selectivity has been demonstrated is human 14-3-3o. 14-3-3o Preferential homodimerizes with itself and crystallization revealed a structural basis for this isoform s dimerization properties as well as for its specific selectivity for target binding proteins. Here partner specificity is the result of amino acid differences outside of the phosphopeptide-binding cleft. 

Another reagent that has found use in pinacolic coupling is prepared from VC13 and zinc dust.264 This reagent is selective for aldehydes that can form chelated intermediates, such as (3-formylamides, a-amidoaldehydes, a-phosphinoylaldehydes,265 and 8-ketoaldehydes.266 The vanadium reagent can be used for both homodimerization and heterodimerization. In the latter case, the reactive aldehyde is added to an excess of the second aldehyde. Under these conditions, the ketyl intermediate formed from the chelated aldehyde reacts with the second aldehyde. 

In the case of horse liver alcohol dehydrogenase, a homodimeric enzyme, Subramanian et al.(202) used the relative phosphorescence of tyrosine and tryptophan to examine the effects of various ternary complexes known to selectively quench the fluorescence of the tryptophans of each subunit. One proposed quenching mechanism is the formation of a ground-state tyrosinate in a ternary complex at neutral pH.(201) This tyrosinate, by being a resonance... 

The 1 1 mixture of 24 and 20 (or 25 and 20) in aqueous media (0.5 mM each) was subjected to the same conditions used for forming 19-20. MALDl results showed that neither 24 nor 25 selectively cross-linked with 20. In sharp contrast to the exclusive formation of 19-20 or 21-22, multiple products were detected from the 1 1 mixture of 24 and 20, among which 24, formed from the self-cyclization of 24, and 20-20 from the homodimerization of 20, represented the major products (Fig. 9.16b). Product 24-20, from the cross-linking of 24 and 20, only appeared as a minor peak. Similarly, when mixed together, 25 and 20 could not be cross-linked exclusively into 25-20 (Fig. 9.16c). The observed distribution of products, that is, the self-cyclized 25, heterodimer 25-20, and homodimer 20-20, can be regarded as being a statistical one. 

Understanding the relative rates of both productive heterocoupling and homodimerization reactions allows for the judicious selection of cross-partners that can participate in a highly selective CM reaction, even when equal stoichiometries of reactants are employed. There are five relevant equilibria and 10 rate constants in CM (Scheme 4 the rate constants for olefin E/Z isomerization have been excluded for simplicity). In the simple scenario where all the rates are similar, and the reaction can achieve equilibrium, the expected statistical cross-product yield is 50%. If, however, one olefin (e.g., R CH=CH2), as a consequence of either steric or electronic factors, reacts at a slower rate k- ) than the other reactions, such that k, k/ k-, and it is assumed that the productive cross-... 

As illustrated above, various possible alkylidene intermediates and numerous primary and secondary pathways are involved in olefin CM. To simplify selective reaction design, an empirical product selectivity model was recently developed by Grubbs and co-workers, in which some degree of orthogonality amongst olefin cross-partners was established by categorizing the relative capacity of olefins to homodimerize in the presence of a given metathesis catalyst. ... 

Olefins can be divided into four categories on the basis of their propensity to homodimerize (Figure 2). Type I olefins are able to undergo rapid homodimerization and whose homodimers can equally participate in CM. A CM reaction between two olefins of this type will generally result in a statistical product mixture. Type II olefins homodimerize slowly, and, unlike type I olefins, their homodimers can only be consumed with difficulty in subsequent metathesis reactions. Type III olefins are unable to undergo homodimerization, but have the capacity to undergo CM with either type I or II olefins. As with type I olefins, the reaction between either two type II or type III olefins should result in non-selective CM. Type IV olefins are inert to olefin CM, but do not inhibit the reaction therefore, they can be regarded as spectators to CM. 

ADMET is a step growth polymerization in which all double bonds present can react in secondary metathesis events. However, olefin metathesis can be performed in a very selective manner by correct choice of the olefinic partner, and thus, the ADMET of a,co-dienes containing two different olefins (one of which has low homodimerization tendency) can lead to a head-to-tail ADMET polymerization. In this regard, terminal double bonds have been classified as Type I olefins (fast homodimerization) and acrylates as Type II (unlikely homodimerization), and it has been shown that CM reactions between Types I and II olefins take place with high CM selectivity [142], This has been applied in the ADMET of a monomer derived from 10-undecenol containing an acrylate and a terminal double bond (undec-10-en-l-yl acrylate) [143]. Thus, the ADMET of undec-10-en-l-yl acrylate in the presence of 0.5 mol% of C5 at 40°C provided a polymer with 97% of CM selectivity. The high selectivity of this reaction was used for the synthesis of block copolymers and star-shaped polymers using mono- and multifunctional acrylates as selective chain stoppers. 

Prostaglandin (PG) H Synthase. The enzyme PGH synthase is a homodimeric protein consisting of subunits with an approximate molecular weight of 72 kDa and one Fe(III)-protoporphyrin IX (PPIXFe(III)) prosthetic group per subunit. This protein is responsible for the central reaction in the biosynthesis of prostaglandins and is selectively inhibited by antiinflammatory drugs such as aspirin and indo-... 

In principle, directed evolution procedures could be repeated indefinitely until any desired activity has been attained. At some point, however, the catalyst will be sufficiently active that the host cell grows like the wild-type strain, making selection for further improvement difficult. This is true for the modified hexamer even though it is still an order of magnitude less efficient than the homodimeric MjCM [37]. Since total activity depends on the catalyst concentration as well as specific activity, reducing the available catalyst concentration can further increase selection pressure. In practice, intracellular protein concentrations can be lowered in a variety of ways, including the use of low copy plasmids [101], weak promoters [102] and inefficient ribosome binding sites [103]. 

To explore the feasibility of such an approach for the design of active catalysts, we have systematically replaced the secondary structural elements in the homodimeric helical bundle chorismate mutase (Fig. 3.18) with binary-patterned units of random sequence. Genetic selection was then used to assess the catalytic capabilities of the proteins in the resulting libraries, providing quantitative information about the robustness of this particular protein scaffold and insight into the subtle interactions needed to form a functional active site [119]. 

It is possible to perform selective heterodimerization reactions using both cyclic ethers 71 and glycouril derivatives 68 bearing ureidyl NH groups (Equation 22) <2002JOC5817>. These reactions delivered the desired C- and S-shaped heterodimer 69 and 70 with low-to-moderate diastereoselectivities. This heterodimerization route is the method of choice in cases where the homodimerization reactions fail. 

As shown in Table 4.1, formation of the mixed adduct is favored over homodimerization of 8a with the simple styrene 13a, but this selectivity is inverted for the case of the more bulky dienophile tra 5-[3-methylstyrene 13b, presumably due to steric effects. Although the overall reaction is highly exothermic on the radical cation surface, the reaction is not insensitive to steric effects. Chemoselectivity in the radical cation cycloaddition is largely a consequence of a substrate s ability to stabilize the radical cation of the oxidized species through the formation of a weakly bound ion-molecule complex. Such complexes have been known for a long time in gas-phase... 

FGF receptor isoforms, FGFRl, FGFR2, and FGFR3, form both homodimeric and heterodimeric receptor species. The multiplicity of FGF receptors explains the selective, individual responsiveness of cells and tissues to either acid or basic FGFs. 

Although the first generations of the ruthenium catalysts were selective for less-substituted double bonds, the latest generations of catalyst allow for more highly substituted double bonds to be prepared. For example, the use of excess isobutylene - an olefin that is reluctant to homodimerize - with a simple olefin results in the formation of the corresponding isoprenoid stmcture in good yield [38]. 

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