Dead-end mechanism

An alternative explanation of inhibition which has features in common with the dead-end mechanism, may be considered but is difficult to accept. In this... 

This general approach has, however, serious limitations. The position of the site for attack (and therefore the electron transfer distance involved) is very conjectural. In addition, the vexing possibility, which we have encountered several times, of a dead-end mechanism (Sec. 1.6.4) is always present. One way to circumvent this difficulty, is to bind a metal complex to the protein at a specific site, with a known (usually crystallographic) relationship to the metal site. The strategy then is to create a metastable state, which can only be alleviated by a discernable electron transfer between the labelled and natural site. It is important to establish that the modification does not radically alter the structure of the protein. A favorite technique is to attach (NH3)5Ru to a histidine imidazole near the surface of a protein. Exposure of this modified protein to a deficiency of a powerful reducing agent, will give a eon-current (partial) reduction of the ruthenium(III) and the site metal ion e.g. iron(III) heme in cytochrome c... 

Some further examples of the dead-end mechanism have been reported (c/. refs 52 and 53) [equations (30) and (31) Y=edta, pdta, or cydta X=CN-orPh3P]. 

There are two approaches to explain physical mechanism of the phenomenon. The first model is based on the existence of the difference between the saturated vapor pressures above two menisci in dead-end capillary. It results in the evaporation of a liquid from the meniscus of smaller curvature ( classical capillary imbibition) and the condensation of its vapor upon the meniscus of larger curvature originally existed due to capillary condensation. 

Thus it is necessary to find alternative approach to describe the physical mechanism of two-side filling of conical capillaries with hquids. Theoretical model of film flow in conical dead-end capillary is based on the concept of disjoining pressure II in thin liquid film [13]... 

Fig. 4 illustrates the time-dependence of the length of top s water column in conical capillary of the dimensions R = 15 pm and lo =310 pm at temperature T = 22°C. Experimental data for the top s column are approximated by the formula (11). The value of A is selected under the requirement to ensure optimum correlation between experimental and theoretical data. It gives Ae =3,810 J. One can see that there is satisfactory correlation between experimental and theoretical dependencies. Moreover, the value Ae has the same order of magnitude as Hamaker constant Ah. But just Ah describes one of the main components of disjoining pressure IT [13]. It confirms the rightness of our physical arguments, described above, to explain the mechanism of two-side liquid penetration into dead-end capillaries. 

Physical mechanism of two-side filling of dead-end capillaries with liquids, based on liquid film flow along the wall, is proposed for the first time. Theoretical model correlates with experimental data. 

P-site ligands inhibit adenylyl cyclases by a noncompetitive, dead-end- (post-transition-state) mechanism (cf. Fig. 6). Typically this is observed when reactions are conducted with Mn2+ or Mg2+ on forskolin- or hormone-activated adenylyl cyclases. However, under- some circumstances, uncompetitive inhibition has been noted. This is typically observed with enzyme that has been stably activated with GTPyS, with Mg2+ as cation. That this is the mechanism of P-site inhibition was most clearly demonstrated with expressed chimeric adenylyl cyclase studied by the reverse reaction. Under these conditions, inhibition by 2 -d-3 -AMP was competitive with cAMP. That is, the P-site is not a site per se, but rather an enzyme configuration and these ligands bind to the post-transition-state configuration from which product has left, but before the enzyme cycles to accept new substrate. Consequently, as post-transition-state inhibitors, P-site ligands are remarkably potent and specific inhibitors of adenylyl cyclases and have been used in many studies of tissue and cell function to suppress cAMP formation. 

Enzyme kinetics. Consider a mechanism for an enzymatic reaction in which the E S complex is a dead end ... 

The example of methotrexate points out that the inhibition modality of dead end inhibitors, with respect to a specific substrate, will depend on the reaction mechanism of the target enzyme. Thus a complete understanding of inhibition mechanism requires an understanding of the underlying reaction mechanism of the target enzyme. A comprehensive discussion of these issues has been provided by Segel (1975). Table 3.6 summarizes the pattern of dead-end inhibition observed for competitive inhibitors of one substrate in the common bisubstrate reaction mecha-... 

The determination of bisubstrate reaction mechanism is based on a combination of steady state and, possibly, pre-steady state kinetic studies. This can include determination of apparent substrate cooperativity, as described in Chapter 2, study of product and dead-end inhibiton patterns (Chapter 2), and attempts to identify... 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Competitive, 249, 123, 146, 190 [partial, 249, 124 progress curve equations for, 249, 176, 180 for three-substrate systems, 249, 133, 136] competitive-uncompetitive, 249, 138 concave-up hyperbolic, 249, 143 dead-end, 249, 124 [for bireactant kinetic mechanism determination, 249, 130-133 definition of kinetic constants, 249, 220-221 effects on enzyme progress curves, nonlinear regression analysis, 249, 71-72 inhibition constant evaluation, 249, 134-135 kinetic analysis with, 249, 123-143 one-substrate systems, 249, 124-126 unireactant systems, theory,... 

Despite the increasing munber of theoretical studies of individual steps, a full picture of the gas-phase chemistry has not yet been deduced. Both the physical transport effects as well as the gas-phase chemistry have to be taken into consideration. Even the most elaborate mechanisms [83-86] rely on the possibly erroneous experimental activation energies for GaMes pyrolysis in the gas phase. Neither GaN etching [96] at high temperatures nor pressure-dependent rates [95] have been included in the mechanisms. In addition, the cyclic oligomers [Mc2GaNH2]x with x = 2,3 are taken either as dead ends or as direct precursors to GaN via further methane elimination, whereas a rad-... 

From the effect of the R substituent on the mechanism and products of the reduction of 28+ (R = Me or Ph), it was concluded that reductive cleavage of the N=N bond of a ix-r] r] coordinated organodiazene might occur only in particular cases. Therefore, this type of coordination might be a dead-end as far as the N=N bond cleavage is... 

In addition, a noncompetitive mechanism has also been observed in some peptides, and this means that the peptide can combine with an enzyme molecule to produce a dead-end complex, regardless of whether a substrate molecule is bound or not. For example, LIY (Nakagomi et al.,... 

Figure 25.1 Heterogeneity is one of the main properties of porous media it not only characterizes the scales shown in the figure, but also occurs on larger scales up to the size of the whole porous system. Three important mechanisms of transport and mixing in porous media are (a) interpore dispersion caused by mixing of pore channels (b) intrapore dispersion caused by nonuniform velocity distribution and mixing in individual channels (c) dispersion and retardation of solute transport caused by molecular diffusion between open and dead-end pores as well as between the water and the...

It may be possible to do a membrane autopsy to identify the foulant(s) and fouling mechanism. For microporous membranes the blocking law analysis [1], which uses permeate volume (V) vs. time (t) data, can supplement the observations. The generalized relationship at constant pressure and in dead-end filtration mode gives,... 

Furthermore, the selection of a given rule from the set of applicable rules may lead to a dead end road in the reasoning process. This necessitates a mechanism to go back to the most recent branching point and to take an alternative choice from the set of applicable rules (if there is one). This is referred to as backtracking. 

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