Stereospecificity prochiral centers

Hill, R. K. Enzymatic Stereospecificity at Prochiral Centers of Amino Acids, in Bio-organic chemistry, Vol. 2, p. 111. (van Tamelen, E. E. ed.). New York Academic Press 1978... 

ATPases. A few pyrophosphotransferases catalyze substitution at Pg. P0 and Pg are prochiral centers and can be made chiral by stereospecific replacement of one or the other diastereotopic oxygen with sulfur or enrichment with lsO or nO. Py is an achiral center which can be made chiral either by replacement of one of the three equivalent oxygens with sulfur and stereospecific enrichment of another with 180 to give a chiral [180]phosphorothioate, or by stereospecific enrichment of one with nO and another with lsO to give a chiral [160, nO, lsO]phosphate. 

The first chiral phosphates to be used for stereochemical analyses were chiral phosphorothioates, which were used to determine the stereochemical courses of ribonuclease, UDP-glucose pyrophosphorylase, adenylate kinase and several other kinases and synthetases. The chiral phosphorothioates either had sulfur in place of an oxygen at an otherwise prochiral center of a phosphodiester or phosphoanhydride or stereospecifically placed sulfur and 180 (or nO) in a terminal phosphoryl group. The syntheses and configurational analyses of the most important of these compounds are outlined in the following. 

This process is stereospecific and has the advantage of giving a quantitative conversion. Although AMP, the usual acceptor substrate for adenylate kinase, is achiral at phosphorus and so not subject to stereospecific phosphorylation, the phosphorus in AMPS is a prochiral center. Adenylate kinase catalyzes the phosphorylation of the pro-R oxygen exclusively to produce the (Sp) configuration. 

The coordination structures of enzyme-bound manganese nucleotides can in favorable cases be determined by analysis of electron paramagnetic resonance (EPR) spectra of Mn(II) coordinated to O-labeled nucleotides. When the nucleotide is stereospecifically labeled with O at one diastereotopic position of a prochiral center, either oxygen can in principle be bound to Mn(II) in the coordination complex in an enzymic site. When the coordination bond is between Mn(II) and O, the EPR signals for Mn(II) are broadened and attenuated, owing to unresolved superhyperfine coupling between the nucleus of 0 and the unpaired electrons of Mn(II) (23). No such effect is possible with 0, which has no nuclear spin. The effect is observable in samples in which all the Mn(Il) is specifically bound in one or two defined complexes of the nucleotide with the enzyme. Thus the complex Mg(Sp)-[a- 0]ADP bound at the active site of ere-... 

Naturally occurring MVA (Fig. 5) is the 3/ isomer (Eberle and Arigoni, 1960) and mevalonate kinase acts only upon this isomer (Lynen and Grassl, 1958 Comforth et al., 1962). In addition, there are three prochiral centers at C-2, C-4, and C-5, and MVA has been synthesized with the methylene groups at these positions stereospecifically labeled with deuterium or tritium (Comforth et al., 1966a,b Donninger and Popjak, 1%6 Blattmann and Retey, 1971 Comforth and Ross, 1970 Scott et al., 1970). This has made it possible to determine the stereochemistry of many reactions in terpenoid biosynthesis (Britton, 1976a). 

By use of ADPpS, the of ADP becomes a prochiral center. In principle, enzymes can distinguish the two diastereotopic oxygens. Therefore, the phosphorylation may be stereospecific (Scheme 3). 

An isotactic stereospecific polymerization arises essentially from the favored complexation of one prochiral face of the a-olefin, followed by a stereospecific process. The stereospecific insertion process and the stereospecific polymerization of racemic a-olefins giving isotactic polymers may be expected to be stereoselective whenever the asymmetric carbon atom is in an a- or /3-position relative to the double bond, and when the interaction between the chirality center of the olefin and the chiral catalytic site is negligible. 

MSA does not contain any chiral carbon centers. Before the aromatization of the six-membered ring occurs, two prochiral carbons (C-2 and C-4 in the six-carbon intermediate) evolve, each of which loses a hydrogen in the process of the dehydratization/aromatization steps. In addition, C-3 of the six-carbon intermediate forms a chiral center when the ketone is reduced to a hydroxyl by a ketoreductase activity (Fig. 5). The chirality of this hydroxyl carbon is unclear since the intermediate has not been isolated. It is also unknown if this carbon retains its chirality in an eight-carbon intermediate or whether the hydroxyl is eliminated by dehydration prior to the third condensation reaction. The stereospecificity at the prochiral C-2 and C-4 carbons in the reaction intermediates was addressed using chemically synthesized (] )- and (S)-[1- C, 2- H]malonate precursors which were enzymatically converted into CoA derivatives via succinyl CoA transferase [127,128]. Thus, the prochiral methylene in malonyl CoA was replaced by chiral, double-labeled (S)- or (J )-[1- C, 2- H]malonyl CoA substrates in the reaction mixture with 6-MSAS. The condensation is expected to occur with inversion of configuration and the intact methylene... 

For stereospecific polymerization of a-olefms such as propene, a chiral active center is needed, giving rise to diastereotopic transition states when combined with the prochiral monomer and thereby different activation energies for the insertion (see Figure 2). Stereospecificity may arise form the chiral /0-carbon atom at the terminal monomer unit of the growing chain - chain end control - or from a chiral catalyst site - enantiomorphic site control . The microstructure of the polymer produced depends on the mechanism of stereocontrol as well as on the metallocene used [42-44]. 

One normally expects antibodies to have a low tolerance to substrate modifications, however an ongoing feature of these aldolase antibodies is their wide scope. They accept a remarkable range of aldol donors and acceptors and perform crossed-, intramolecular- and retro-variants of this reaction, with high yields, rates, and stereospecificities [81,82,83]. Substrate modification experiments have revealed that when acetone is the aldol donor in a ketone-aldehyde crossed aldol reaction, stereoinduction is linked to attack of the sz-face of a prochiral aldehyde with typically >95% ee and when hydroxyacetone is the donor substrate, attack occurs preferentially at the re-face of the aldehyde leading to a diastereomeric a,P-dihydroxy ketones with the two stereogenic centers having an a-syn configuration. This reaction leads to stereospecificities of typically 70 to >99% ee. 

More recent views (17) of the origin of stereospecificity in the synthesis of isotactic polymers connect this origin with the ability of the catalyst-growing polymer chain system, that is, the catalytic center, to discriminate between the two prochiral faces of the a-olefin. The catalytic system must possess one or more chirality centers (Figure 4). 

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