Lipscomb pathway

CARBONATO COMPLEXES MODELS FOR CARBONIC ANHYDRASE Lipscomb Pathway (Proton Transfer)... 

Halgren T A and Lipscomb W N 1977 The synchronous transit method for determining reaction pathways and locating molecular transition states Chem. Phys. Lett. 49 225... 

The Synchronous-Transit Method for determining Reaction Pathways and Locating Molecular Transition States Thomas A. Halgren and William N. Lipscomb Chemical Physics Letters 49 (1977) 225-232... 

The cytochrome P-450-dependent metabolism of trichloroethylene was studied in hepatic microsomal fractions from 23 different humans (Lipscomb et al. 1997). CYP2E1 was the predominant form of P-450 responsible for the metabolism of trichloroethylene in humans. Incubations of trichloroethylene with the microsomal preparations resulted in hyperbolic plots consistent with Michaelis-Menton kinetics. The values ranged from 12 to 55.7 pM, and were not normally distributed, and the values range from 490 to 3,455 pmol/min/mg protein and were normally distributed. The study authors concluded that the human variability in metabolism of trichloroethylene via P-450-dependent pathways was within a 10-fold range. 

Fig. 24. Snapshots of a possible CO2 diffusion pathway into the active site of carbonic anhydrase II, as calculated in a molecular dynamics simulation. Tbe CO2 molecule is represented as a stick, and its diffusion pathway is shown by dashed arrows. [Reprinted with permission from Liang, J.-Y., Lipscomb, W. N. 1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3675-3679.1...

Figure 24 shows a possible CO2 diffusion pathway into the carbonic anhydrase II active site, and Fig. 25 shows the binding of CO2 in the hydrophobic pocket (Liang and Lipscomb, 1990). Also in Fig. 25 is the binding of CO2 in this pocket as independently calculated by Merz (1990,... 

The collapse of the proteolytic tetrahedral intermediate of the promoted-water pathway requires a proton donor in order to facilitate the departure of the leaving amino group. Rees and Lipscomb (1982) considered Glu-270, but favored Tyr-248 for this role, but Monzingo and Matthews (1984) fully elaborated on a role for Glu-270 of carboxypeptidase A and Glu-143 of thermolysin as intermediate proton donors. This proposal for carboxypeptidase A is corroborated by the near-normal activity observed for the Tyr-248- Phe mutant of rat carboxypeptidase A (Garden et al, 1985 Hilvert et al, 1986) and is reflected in the mechanistic scheme of Fig. 31 (Christianson and Lipscomb, 1989). Mock (1975) considered Glu-270 a proton donor in the carboxypeptidase A mechanism, but his mechanism does not favor a Glu-270/zinc-promoted water molecule as the hydrolytic nucleophile. Schepartz and Breslow (1987) observed that Glu-270 may mediate an additional proton transfer in the generation of the Pi product carboxylate. 

Halgren, T. A., and W. N. Lipscomb (1977), The Synchronous-Transit Method for Determining Reaction Pathways and Locating Molecular Transition States, Chem. 

Halasz GJ, Vibok A, Mayer I (1999) Comparison of basis set superposition error corrected perturbation theories for calculating intermolecular interaction energies. J Comput Chem 20 274-283 Halgren TA, Lipscomb WN (1977) The synchronous-transit method for determining reaction pathways and locating molecular transition states. (3hem Phys Lett 49 225-232 Hammond GS (1955) A correlation of reaction rates. J Am Chem Soc 77 334-338... 

Conversion of the C-terminal fragment to an activation-competent conformation is the first of several rearrangements of methionine synthase that we would like to study. Computations would complement the structure determinations, in the best Lipscomb tradition, by examining not only the static pictures of various conformers but also the likely pathways for interconversion of the structures (52) and the mechanisms for activation of bound substrates (55). 

Theoretical work by Merz and co-workers" essentially follows the pathway in Scheme 8.7 and finds that the bicarbonate is bound in the Lipscomb model, with the Lindskog structure being an intermediate or transition state on the pathway to the more stable form. More recent theory" has emphasized the importance of H2O and other groups at the active site in facilitating the proton transfer reactions. It should be noted that the theoretical conclusions have changed and evolved with time" and must be viewed accordingly. Two X-ray structures with bicarbonate bound to CA I " and a CA II" mutant have been used to support the Lindskog structure. In simple models, both bidentate and monodentate HCOj" has been observed in Cu(II) complexes," while examples of bidentate Co(III)" and monodentate Ni(II)" coordination are known. These and other models have been reviewed recently." ... 

Kovaleva EG, Neibergall MB, Chakraharty S, Lipscomb JD. Finding intermediates in the O2 activation pathways of non-heme iron oxygenases. Acc. Chem. Res. 2007 40 475 83. 

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