Substrate flexibility

From the active site topology it seems that there is room for substrate flexibility. Indeed, experiments with the closely related P450eryF have demonstrated that some substitutions within the macrolactone ring of the substrate are possible [28] for example, reduction of the C9 oxo to the hydroxy group is well tolerated. However, any changes with impact on the overall confonnation of the substrate, thus changing the trajectory between the reactive C-H bond and the iron-bound oxy-... 

Pelham, R.J., and Wang, Y.-L. (1997). Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Nat. Acad. Sri. USA 94, 13661-13665. 

In vitro glycorandomization (TVG) is a chemoenzymatic method that uses substrate-flexible anomeric sugar kinases and Ntfs to convert diverse sugars into their NDP-activated forms [21], The ability to enhance the promiscuity of these two... 

Salas AP, Zhu L, Sanchez C et al (2005) Deciphering the late steps in the biosynthesis of the anti-tumor indolocarbazole staurosporine sugar donor substrate flexibility of the StaG glycosyltransferase. Mol Microbiol 58 17-27... 

Enzymes involved in the short activation pathway, probably a kinase plus a pyrophosphorylase, should exhibit broad substrate flexibility. Such enzymes will be powerful tools for constructing activated deoxysugars which are needed when utilizing glycosyltransferases in enzymatic synthesis. 

These examples confirm a greater substrate flexibility of FucT III as compared to FucT VI in their recognition of non-natural substrates. Thus, a large library of sialyl-Lewis derivatives could be easily assembled [96]. 

Biosynthetically-patterned microbiological transformations exploit the substrate flexibility of enzymes involved in the biosynthesis of secondary metabohtes. These biotransformations are sometimes known as analogue biosynthesis or precursor-directed biosynthesis. This approach to biotransformation can be useful in preparing analogues of biologically-active microbial metabolites for structure-activity studies, a feature that has been exploited with penicillins using a cloned isopenicillin N synthase. The structures of the substances that are transformed and of their products can also shed light on the stereo-electronic constraints of enzymatic steps and on the nature of biosynthetic intermediates, a feature that has been exploited in studies on the cyclization of squalene to the triterpenes and steroids. 

Several biosyntheses involve assembling building blocks such as amino acids and carboxylic acids. Parts of these assembly processes can show some substrate flexibility, allowing the enzymatic synthesis of un-natural analogues of normal fungal metabolites. One of the earliest examples was the variation of the penicillin side-chain brought about by replacing the phenylacetic acid of penicillin G with phenoxyacetic acid as in penicillin V. 

In summary, the enzymes responsible for pikromycin biosynthesis represent powerful tools for the generation of novel macrolide antibiotic compounds with the unique biosynthetic capabilities of the pikromycin PKS and the substrate flexibility of the respective tailoring enzymes. In the next section, we highlight work directed at investigating and exploiting the biosynthetic enzymes encoded by pikA, des, and pikC for the production of ketolide compounds through chemoenzymatic approaches. 

It is important to note that conformational flexibility can occur in the substrate as well as the enzyme. Flexibility can allow a substrate to be tucked into an active site rotation around single bonds can position the reactive part of the substrate in proximity to catalytic groups, while allowing other parts of the molecule to avoid steric clashes. However, substrate flexibility could have been detrimental for early enzymes, as well. If a flexible substrate binds in an active site in a manner that doesn t orient the molecule properly with respect to the catalytic groups, a potential substrate becomes an inhibitor. 

This variant expanded the spectrum of 145 substrates to substrates that were not used in the screen. Although the Y317H mutation retains the stringent requirement for the C-4 galactose architecture, it exhibits enhanced substrate flexibility at all other positions. 

In a later study on the optimization of metallocene substrates for such cyclodextrin reactions we saw that the two different enantiomers (6) of a fused ring system - in which there was no substrate flexibility - was 62-fold faster for one enantiomer than the other and showed a rate 150 million times as fast for acylation as was the rate of hydrolysis in water at the same pH. We then addressed this with molecular modeling calculations, and saw that quantitative theory accounted well for these tindings. ... 

One of the advantages that a formulator has using a polyurethane adhesive is the ability to tailor the adhesive properties to match the substrate. Flexible substrates such as rubber or plastic are obvious matches for polyurethane adhesives because a tough elastomeric product can easily be produced. Polyurethanes derive much of their toughness from their morphology. 

Features Very high solids resin solvent-free offers good uncatalyzed cure response exc. low VOC capabilities, adhesion to substrate, flexibility, overbake resist. adhesion to hot dip galvanized good flow and leveling... 

Connal, L.A., Vestberg, R., Gurr, P.A., Hawker, C.J., Qiao, G.G. Patterning on nonplanar substrates flexible honeycomb films from a range of self-assembling star copolymers. Langmuir 24, 556-562 (2008)... 

LC-1213/acrylate -0.4 1,930/N/A 400-500 nm (visible), 250-380 nm (UV) 10 sec, 400-500 nm (visible), 0.28 sec (single pass), 25 Ijtm 3.336 W/cm (DUne) UV-visible deep-section curing through UV-opaque substrates, flexible bond... 

Radiation curable adhesives can be based on raw materials that are not greatly different from those used in acrylic adhesives (first, second, and third generations), epoxy adhesives, urethane adhesives, and anaerobic adhesives. The formulation approach, however, is somewhat different. Very important is that no solvents are used to thin the resins a monomer reactive diluent is used instead. The monomer must be matched with the resin to give the desired set of properties with respect to adhesion, substrate, flexibility or stiffness, cure behavior, and durability of the cured product. Most of the radiation curable adhesives have an acrylate (or methacrylate) basis many of the acrylics are modified. 

---