Substrate activation catalysis

Dual activation of nucleophile and epoxide has emerged as an important mechanistic principle in asymmetric catalysis [110], and it appears to be particularly important in epoxide ARO reactions. Future work in this area is likely to build on the concept of dual substrate activation in interesting and exciting new ways. 

Some enzymes require cofactors to activate catalysis. Typical cofactors are metal atoms, ammonia, and small organic molecules that associate with the enzyme and help to structure the catalytic site. To conduct an enz5anatic reaction, the necessary cofactors must be suppUed along with the substrate and the enzyme. In cell metabolism, a variety of these cofactors act in conjunction with inhibitors to control the metabolic rate. 

Woolridge, E. M. Rokita, S. E. 6-(Difluoromethyl)tryptophan as a probe for substrate activation during the catalysis of tryptophanase. Biochemistry 1991, 30, 1852-1857. 

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

Chiral base catalysis was classified into five sections and reviewed. Although the reactions described herein are promoted by Bronsted or Lewis bases, the Lewis acidic characteristics of metals play important roles in both substrate activation and enantioselection. Compared with chiral Lewis acid-catalyzed reactions,... 

Unconsumed substrates are treated as substrates or essential activators in deriving rate equations and studying detailed mechanisms. Nonetheless, one must indicate whether an unconsumed substrate (U) remains bound to the enzyme or not (in this case, U also becomes an unaltered product) in the reaction scheme. In practice, unconsumed substrates are likely to be involved in all the typical multisubstrate kinetic mechanisms Only one case is illustrated here, namely that the unconsumed substrate Su activates catalysis when bound in a rapid-equilibrium ordered mechanism ... 

Many metal ions can act as electron sinks, which allows them to participate in catalysis by electron withdrawal from the substrate, activating it toward reaction. 

Schematic representation of the structure of a TIM monomer. Helices and strands are labeled as H and B, respectively. The view is along the axis of the (3 barrel, into the active site. Key catalytic residues Lysl3, His95, and Glul67 are shown along with the helix that binds the substrate phosphate and the flexible loop that covers the substrate during catalysis. Black dots indicate residues in contact with the second monomer of the enzyme. (From Ref.24. Copyright 1991 by Harcourt Brace.)...

In electrophilic catalysis, the metal ion acts as a Lewis acid. An example from organic chemistry is the formation of an acylium ion from aluminum chloride and an acid chloride in Friedel-Crafts acylation reactions (Figure 2). In this case substrate activation results in cleavage of the C—Cl bond. In most cases, however, substrate activation by Lewis acids involves electron redistribution without bond breaking (Figure 3). 

N — M more electrophilic than RC Figure 3 Substrate activation in electrophilic catalysis. — N... 

Homolytic catalysis is observed with both organometallic and coordination complexes. It is involved in a wide variety of metal-mediated transformations, often in competition with electrophilic or nucleophilic catalysis [11], For example, many metal-catalyzed oxidations involve substrate activation by homolytic catalysis (Eq. 5) [12], Similarly, oxidative additions (Eq. 6) and dioxygen activation (Eq. 7) can proceed via two-step homolytic mechanisms. 

An inhibitor is any agent that interferes with the activity of an enzyme. Inhibitors may affect the binding of enzyme to substrate, or catalysis (via modification of the enzyme s active site), or both. Researchers use enzyme inhibitors to define metabolic pathways and to understand enzyme reaction mechanisms. Many drugs are designed as inhibitors of target enzymes. Inhibition is also a natural phenomenon. Cells regulate metabolic pathways by specific inhibition of key enzymes. 

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

Metalloporphyrins catalyze the autoxidation of olefins, and with cyclohexene at least, the reaction to ketone, alcohol, and epoxide products goes via a hydroperoxide intermediate (129,130). Porphyrins of Fe(II) and Co(II), the known 02 carriers, can be used, but those of Co(III) seem most effective and no induction periods are observed then (130). ESR data suggest an intermediate cation radical of cyclohexene formed via interaction of the olefin with the Co(III) porphyrin this then implies possible catalysis via olefin activation rather than 02 activation. A Mn(II) porphyrin has been shown to complex with tetracyanoethylene with charge transfer to the substrate (131), and we have shown that a Ru(II) porphyrin complexes with ethylene (8). Metalloporphyrins remain as attractive catalysts via such substrate activation, and epoxidation of squalene with no concomitant allylic oxidation has been noted and is thought to proceed via such a mechanism (130). Phthalocyanine complexes also have been used to catalyze autoxidation reactions (69). 

---