Peptide model complexes, catalysis

Recently, the crystal structure of S-protein complexed with the model peptide has been solved to moderate resolution (3 A) (Taylor et al., 1985). Most of the structural features envisioned in the design of the model peptide were indeed observed in the structure of the complex. The peptide is in a helical conformation, the histidine is held in a reasonable orientation for catalysis, and the complex is stabilized by nonbonded interactions between the hydrophobic cleft of S-protein and the side chains of Phe-8 and Met-13 of the peptide. There were also a number of subtle differences between the structures of the native and the model S-protein S-peptide complexes. Most notably, the N terminus of the peptide has undergone a major reorientation that prevents Glu-2 from forming a hydrogen bond with Arg-10. Further, the 8-nitrogen of the active-site... 

One particularly important example is also an exception to the rule that catalysis in terran life is carried out by protein enzymes. This is the ribosome, the molecular machine that synthesizes proteins using the information provided by a messenger RNA. It is an ancient machine and a key component of every known form of life on Earth. The ribosome is a large complex of at least three RNA molecules and more than 50 proteins. The structure of the large subunit of the ribosome was solved in 2000,8 followed closely by the structure of the entire ribosome.9 Consistent with the RNA world model, RNA was present at the site in the ribosome where the peptide bond is synthesized.10 The active site is composed entirely of RNA. Nearly all catalytic functions in living organisms have been taken over by proteins, which are inherently more suited for catalysis than RNAs. However, at the heart of this centrally important and ancient molecular machine, catalysis is still being executed by the RNA. 

CsA and equivalent rotamase catalytic activity, indicating that the cysteines play no essential role in binding or catalysis (161). In the case of FKBP, NMR studies of [8,9-[ C]FK-506 bound to recombinant FKBP, wherein the likely mechanism of inhibition also is nonco-valent, suggesting that the a-ketoamide of FK-506 serves as an effective surrogate for the twisted amide of a bound peptide substrate (162). Numerous further NMR, X-ray crystallographic and computational modeling studies have been carried out on both CsA/CyP and FK-506/FKBP complexes to attempt to fully determine a structural basis for activity (163, 164). 

The cobalt(III)-promoted hydrolysis of amino acid esters and peptides and the application of cobalt(III) complexes to the synthesis of small peptides has been reviewed. The ability of a metal ion to cooperate with various inter- and intramolecular acids and bases and promote amide hydrolysis has been investigated. The cobalt complexes (5-10) were prepared as potential substrates for amide hydrolysis. Phenolic and carboxylic functional groups were placed within the vicinity of cobalt(III) chelated amides, to provide models for zinc-containing peptidases such as carboxypeplidase A. The incorporation of a phenol group as in (5) and (6) enhanced the rate of base hydrolysis of the amide function by a factor of 10 -fold above that due to the metal alone. Intramolecular catalysis by the carboxyl group in the complexes (5) and (8) was not observed. The results are interpreted in terms of a bifunctional mechanism for tetrahedral intermediate breakdown by phenol. 

The above studies established (1) that broad peptide sequence space can furnish catalysts that are effective across both a wide array of substrates and for several chemical transformations and (2) that nucleophilic peptide catalysis was effective at modulating barriers to reaction in the context of enantioselective reactions and site-selective reactions such that inherent preferences could be enhanced, e.g., inositols (Fig. 2c), or inverted (Fig. 2c) in a catalyst-controlled manner. At this time it became clear that the stage was set to explore beyond model systems and to begin treating large, complex natural products as substrates themselves. 

We recently reported a novel enzyme model for the synthesis of peptides by using the multi-functionalized chiral 18-crown-6 derivatives [3]. The new hosts have achieved the assembly of plural guests by covalent bonds formed through non-covalent complexes between the host and the guest, and then enhanced the bond formation between the bound guests. This enzyme model has mimicked the general concept of enzyme catalysis, in which the reactive enzyme-substrate covalent intermediate (E/v aSi) is formed from the noncovalent complex (E Si), and then reacts with the second substrate (S2) to give the product (Sj—S2) as shown in Equation (1) [4]. 

Lewis acid catalysis of the hydrolysis of peptide bonds by metal ions and complexes has been investigated S with regard to the hydrolytic stability of proteins. An amide linkage in a protein has a half-life of about seven years at neutral pH and 25 C. In model systems, the hydrolysis rate can be increased by ca. 10 through coordination of the amide carbonyl group to a cationic metal complex. The coordination to cobaltflll) and subsequent Lewis acid assisted hydrolysis of the amide group in the simple amide, 4-formylmorpholine is illustrated in Scheme 1.19 55... 

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