Methanol dehydrogenase active site

TA medical therapy based on competition at the active site is used to treat patients who have ingested methanol, a solvent found in gas-line antifreeze. The liver enzyme alcohol dehydrogenase converts methanol to formaldehyde, which is damaging to many tissues. Blindness is a common result of methanol ingestion, because... 

Figure 15-23 (A) Stereoscopic view of the H subunit of methanol dehydrogenase. Eight four-stranded antiparallel 3 sheets, labeled W1-W8, form the base of the subunit. Several helices and two additional P-sheet structures (labeled Px and Py) form a cap over the base. The PQQ is located in a funnel within the cap approximately on an eight-fold axis of pseudosymmetry. Courtesy of Xia et al.ii7 (B) Schematic view of the active site. W467 is parallel to the plane of PQQ. All hydrogen-bond interactions between PQQ and its surrounding atoms, except for the three water molecules, are indicated. Courtesy of White et al.ii8...

FIGURE 20. The equatorial interactions of PQQ and the coordination of Ca +in the active site of methanol dehydrogenase (Ghosh et al., 1995). This figure also shows Asp303, which is likely to act as a base, and Arg331 which may also be involved in the mechanism.. 

Avezoux, A., Goodwin, M. G., and Anthony, C., 1995, The role of the novel disulphide ring in the active site of the quinoprotein methanol dehydrogenase from Metkylobacterium extorquens. Biochem. J. 307 7359741. 

Blake, C. C. F., Ghosh, M., Harlos, K., Avezoux, A., and Anthony, C., 1994, The active site of methanol dehydrogenase contains a disulphide bridge between adjacent cysteine residues. Nature, Structural Biology 1 1029105. 

Figure 1. (a) View of the inside of the Methanol Dehydrogenase (MDH) enzyme with the active site in stick model. The solid surface represents the solvent-accessible MDH external surface showing the binding pocket, (b) View from the binding pocket of the entire MDH active site. Amino acids labels denote their location in the sequence obtained from the entry 1W6S (Methylobacterium Extorquens W3A1 ) of the Protein Data Bank. 

The mechanism of liver alcohol dehydrogenase (LADH) has been extensively studied. For a recent overview the reader is referred to Ref [93]. Reaction field effects on the transition structure of model hydride transfer systems have been calculated at ab initio 4-3IG basis set level [93, 94]. The active site of enzymes are usually assumed to be designed to receive molecules in the transition state for the reaction they catalyze. This special sort of surrounding medium effects has been computationally documented recently [95]. From the reaction geodesic passing through the transition state for hybride transfer in the pyridium cation/methanolate model system, only the TS-structure could be fitted into the LADH active site. The normal mode analysis carried out on the TS showed an excellent agreement with isotopic substitution experiments [95]. Reaction field calculations on this model systems have also been performed. For an overview of biomolecular interactions the reader is referred to Ref [96]. 

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