Rearrangement enzyme catalysed

In contrast to Mori s synthesis, Pawar and Chattapadhyay used enzymatically controlled enantiomeric separation as the final step [300]. Butanone H was converted into 3-methylpent-l-en-3-ol I. Reaction with trimethyl orthoacetate and subsequent Claisen-orthoester rearrangement yielded ethyl (E)-5-methyl-hept-4-enoate K. Transformation of K into the aldehyde L, followed by reaction with ethylmagnesium bromide furnished racemic ( )-7-methylnon-6-ene-3-ol M. Its enzyme-catalysed enantioselective transesterification using vinylacetate and lipase from Penicillium or Pseudomonas directly afforded 157, while its enantiomer was obtained from the separated alcohol by standard acetylation. 

To avoid dealing with curvilinear plots of enzyme-catalysed reactions, Lineweaver and Burk introduced an analysis of enzyme kinetics based on the following rearrangement of the Michaelis-Menten equation ... 

Chorismate mutase provides an example of an enzyme where QM/MM calculations have identified an important catalytic principle at work [8], This enzyme catalyses the Claisen rearrangement of chorismate to prephenate. The reaction within the enzyme is not believed to involve chemical catalysis, and this pericylic reaction also occurs readily in solution. Lyne et al. [8] investigated the reaction in chorismate mutase in QM/MM calculations, at the AMI QM level (AMI was found to perform acceptably well for this reaction in comparisons with ab initio results for the reaction in the gas phase [8]). Different sizes of QM system were tested in the QM/MM studies (e.g. including the substrate and no, or up to three, protein side chains), and similar results found in all cases. The reaction was modelled by minimization along an approximate reaction coordinate, defined as the ratio of the forming C-C and breaking C-0 bonds. Values of the reaction coordinate were taken from the AMI intrinsic reaction coordinate for the gas-phase reaction. 

Isomerisation (catalysed by an isomerase) the intramolecular rearrangement of a molecule. This may be the transfer of a carboxyl group (C=0) from the end of a molecule (such as an aldose) to the middle (such as a ketose), or it may be the transfer of a phosphate group (the enzymes catalysing this latter sort of isomerisation are generally termed mutases). 

Figure 1 In a QM/MM calculation, a small region is treated by a quantum mechanical (QM) electronic structure method, and the surroundings treated by simpler, empirical, molecular mechanics. In treating an enzyme-catalysed reaction, the QM region includes the reactive groups, with the bulk of the protein and solvent environment included by molecular mechanics. Here, the approximate transition state for the Claisen rearrangement of chorismate to prephenate (catalysed by the enzyme chorismate mutase) is shown. This was calculated at the RHF(6-31G(d)-CHARMM QM-MM level. The QM region here (the substrate only) is shown by thick tubes, with some important active site residues (treated by MM) also shown. The whole model was based on a 25 A sphere around the active site, and contained 4211 protein atoms, 24 atoms of the substrate and 947 water molecules (including 144 water molecules observed by X-ray crystallography), a total of 7076 atoms. The results showed specific transition state stabilization by the enzyme. Comparison with the same reaction in solution showed that transition state stabilization is important in catalysis by chorismate mutase78.

An enzymic counterpart of these complex base-catalysed rearrangements of sugars may be the reaction catalysed by 4-phospho-3,4-dihydroxy-2-butanone synthetase. The enzyme catalyses the formation of the eponymous intermediate in secondary metabolism from ribulose 5-phosphate. Labelling studies indicated that C1-C3 of the substrate became C1-C3 of the product, that H3 of the substrate derived from solvent and that C4 was lost as formate. X-ray crystal structures of the native enzyme and a partly active mutant in complex with the substrate are available. The active site of the enzyme from Met ha-nococcus jannaschii contains two metals, which can be any divalent cations of the approximate radius of Mg " or Mn ", the two usually observed. Their disposition is very reminiscent of those in the hydride transfer aldose-ketose isomerases, but also to ribulose-5-phosphate carboxylase, which works by an enolisation mechanism, so the enolisation route suggested by Steinbacher et al. is repeated in Figure 6.14, as is the Bilik-type alkyl group shift, for which an equivalent reverse aldol-aldol mechanism cannot be written. 

During the last few years, more efficient reagents for transforming alkynes into allenes have been developed and even an enzyme catalysed reaction has been investigated The main mechanistic development has been the solution to the problem of whether rearrangements of an alkyne into an allene (and vice versa) involve an intermediate carbanion, or if the reaction can occur via a concerted mechanism in which a proton is donated from the solvent synchronously with the abstraction of a proton from the substrate by a base. 

There are two ways in which the cosynthetase enzyme could turn the fourth PBG unit around. Battersby believes an enzyme-bound spiro-intermediate is formed, which goes on to form uro gen 111. ° An alternative proposal, by Ian Scott at Texas A M University, is that the cleaved hydroxybilane intermediate self-assembles to form a lactone via the acetic acid side chain at position 17 in ring D. Although support for this view comes from the observation that synthetic bilanes without this side chain will not undergo enzyme-catalysed rearrangement to the type III isomer, the weight of experimental evidence seems to support Battersby s spiro-... 

The participation of enzymes in Diels-Alder reactions (Fig. 5.157) was postulated for more than 100 natural products. [381,383] However, the structure of Diels-Alderases, and therefore the mechanism of the biocatalysed [4 -i- 2]Other enzyme-catalysed electrocyclic reactions, like the Cope rearrangement of chorismic acid into prephenic acid by chorismate-mutase, were aiready known for a while and are well investigated. 

The isomerases catalyse intramolecular rearrangement in optical and positional isomers. Typical of this class are the epimerases, such as uridine diphosphate glucose 4-epimerase. This enzyme catalyses the change of configiu tion at the fourth carbon atom of glucose, and galactose is produced (see Chapter 9). The group includes ... 

Also found in P. eyelopium cultures are viridicatin (7.48) and vir-idicatol (7.49). They are enzymically derived from cyclopenin (7.46) and cyclopenol (7.47), respectively, and the peculiar rearrangement is catalysed in a similar way by base or acid [17, 24]. 

Photolytic deprotection of the ulosonic acid -nitrobenzyl glycoside (49) did not yield the expected enolpyranose but the rearranged 3-dehydroquinic acid (50) the stereospecific label rearrangement implies a chair transition state, and suggests the biosynthetic pathway by this route is not enzyme-catalysed. ... 

Besides the obvious biological interest, chorismate mutase is important for being a rare example of an enzyme that catalyses a pericyclic reaction (the Claisen rearrangement), which also occurs in solution without the enzyme, providing a unique... 

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