Hydrides ternary complexes

The reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) has been analyzed extensively14 26-30 and a kinetic scheme for E. Coli DHFR was proposed in which the steady-state kinetic parameters as well as the full time course kinetics under a variety of substrate concentrations and pHs were determined. From these studies, the pKa of Asp27 is 6.5 in the ternary complex between the enzyme, the cofactor NADPH and the substrate dihydrofolate. The second observation is that, contrary to earlier results,27 the rate determining step involves dissociation of the product from the enzyme, rather than hydride ion transfer from the cofactor to the substrate. 

Figure 10. The ternary complex of the enzyme dihydrofolate reductase, the substrate and the cofactor during the transition state of the hydride ion transfer. The enzyme backbone atoms are shown alone for clarity and are colored blue. The substrate is shown in yellow and the cofactor is in red. The bond colored in light blue indicates the hydride ion being shared by both the cofactor and the substrate before the transfer to the substrate. Water molecules around the residue pteridine of the substrate and the nicotinamide ring of the cofactor alone are shown and colored in light blue. The yellow spheres represent the sodium ions and the pink spheres the chloride ions.

S. Li, R.A. Varin, O. Morozova, T. Khomenko, Controlled mechano-chemical synthesis of nanostructured ternary complex hydride Mg FeH under low-energy impact mode with and without pre-milting , J. Alloys Compd. 384 (2004) 231-248. 

Aldehyde formation during the catalytic action of the enzyme requires a net removal of two hydrogen atoms from the alcohol substrate. This dehydrogenation process is known to proceed by a mechanism of combined proton and hydride ion transfer, and it has been well established that transfer of hydride ion occurs directly between substrate and coenzyme in the productive ternary complex. 

Dunn has also proposed a mechanism involving this charge relay system in ternary complex formation, but with the substrate displacing the zinc-bound water, as shown in Scheme 9.1443 Hydride transfer from NADH, to form an alcoholate anion, has been shown to occur before protonation.1398 As well as not requiring penta-coordinate zinc, this mechanism differs from Dworschack and Plapp s in postulating the formation of an alcoholate anion. 

A key structural and mechanistic feature of lactate and malate dehydrogenases is the active site loop, residues 98-110 of the lactate enzyme, which was seen in the crystal structure to close over the reagents in the ternary complex.49,50 The loop has two functions it carries Arg-109, which helps to stabilize the transition state during hydride transfer and contacts around 101-103 are the main determinants of specificity. Tryptophan residues were placed in various parts of lactate dehydrogenase to monitor conformational changes during catalysis.54,59,60 Loop closure is the slowest of the motions. 

A Cr(VI)-catalyst complex has been proposed as the reactive oxidizing species in the oxidation of frans-stibene with chromic acid, catalysed separately by 1,10-phenanthroline (PHEN), oxalic acid, and picolinic acid (PA). The oxidation process is believed to involve a nucleophilic attack of the olefinic bond on the Cr(VI)-catalyst complex to generate a ternary complex.31 PA- and PHEN-catalysed chromic acid oxidation of primary alcohols also is proposed to proceed through a similar ternary complex. Methanol- reacted nearly six times slower than methanol, supporting a hydride transfer mechanism in this oxidation.32 Kinetics of chromic acid oxidation of dimethyl and diethyl malonates, in the presence and absence of oxalic acid, have been obtained and the activation parameters have been calculated.33 Reactivity in the chromic acid oxidation of three alicyclic ketoximes has been rationalized on the basis of I-strain. Kinetic and activation parameters have been determined and a mechanism... 

Scheme 11.1 also summarizes other impressive examples of the performance of the CBS method [1-8]. Several excellent reviews on the CBS method have appeared recently [1, 2], and no detailed discussion of the development of the process or substrate scope shall be presented in this review. Please note, however, that the oxazaborolidine-catalyzed borane reduction of ketones is a prime example of bi-functional catalysis [2, 9] - as shown in Scheme 11.2, the current mechanistic picture involves simultaneous binding of both the ketone and the borane to the Lewis-acidic (boron) and Lewis-basic (nitrogen) sites of the catalyst A. In the resulting ternary complex B, the reaction partners are synergistically activated toward hydride transfer. 

During hydride ion transfer, careful analysis of the secondary structural features of the protein in the ternary complex reveals that the overall conformational features of the protein remain undisturbed. The conformational angles of the residues in the MET loop were analyzed in detail due to its proximity to the substrate. The MET loop is composed of amino acid residues Ala9 through Leu24. Comparison of the initial, transition, and final states of the MET loop during hydride ion transfer reveals that (a) between the initial state and the transition state, the angle... 

If this interpretation is correct, then the pKa of the phenolic hydroxyl of the intermediate must be perturbed to a higher value by at least 2 pka units (i.e., a value >8.75), while the pKaofthe -CH2OH group is perturbed to a value <9 in this ternary complex. The blue-shifted spectrum of the intermediate is consistent with structure 2. Studies with other substrates (5,26,27,39) strongly support a catalytic mechanism in which the hydride transfer step involves the interconversion of innersphere-coordinated aldehyde and innersphere-coordinated al-koxide ion. The data of Kvassman et al. (39) and Sartorius et al. (26) indicate a pKa for the coordinated alcohol of 6 or 7 is not unreasonable (21,40). 

Direct hydride transfer takes place from the alcohol CH to the 4-position of the properly oriented nicotinamide ring. The resulting ternary complex is an NADH-aldehyde adduct. The polarity of the active site dramatically drops. 

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