Biomimetic catalysis of SN2 reactions through cation-.pi. interactions. The role of polarizability in catalysis

McCurdy, A. K.; Jimenez, Leslie S.; Stauffer, David A.; Dougherty, Dennis A.

doi:10.1021/ja00052a031

Cited by 150 publications

(101 citation statements)

References 6 publications

(14 reference statements)

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“…8b) (56). This postulate is substantiated by evidence that the stabilization of the cationic transition state through cation-interactions accelerates catalysis of biomimetic methylation reactions (58,59). Moreover, this is consistent with the proposed interaction of the AdoMet molecule with the conserved motif IV region, which is rich in aromatic residues (Fig.…”

Section: Discussionsupporting

confidence: 77%

Mapping and Molecular Modeling ofS-Adenosyl-l-methionine Binding Sites inN-Methyltransferase Domains of the Multifunctional Polypeptide Cyclosporin Synthetase

Velkov

Lawen

2003

Journal of Biological Chemistry

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We employed a highly specific photoaffinity labeling procedure, using 14 The modified sequence regions correspond to the motif II consensus sequence element, which is involved in directly complexing the adenine and ribose components of AdoMet. We conclude that the AdoMet binding to nonribosomal peptide synthetase N-methyltransferase domains obeys the consensus cofactor interactions seen among most structurally characterized low molecular weight AdoMet-dependent methyltransferases.

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Section: Discussionsupporting

confidence: 77%

Mapping and Molecular Modeling ofS-Adenosyl-l-methionine Binding Sites inN-Methyltransferase Domains of the Multifunctional Polypeptide Cyclosporin Synthetase

Velkov

Lawen

2003

Journal of Biological Chemistry

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“…The developing positive charge on sulfur in the TS* may be stabilized by the electron-rich aromatic ring of TyrL32 via a putative cation-pi interaction. Such interactions have been invoked to explain cyclophane-catalyzed SN2 reactions, acetylcholine recognition, and the ion selectivity of channel proteins (26,28,29). The close van der Waals contact between TyrL32 and the benzylic carbon of the hapten may also explain the high rate of acceleration for p-nitrothioanisole oxidation (7).…”

Section: Resultsmentioning

confidence: 99%

Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution.

Hsieh‐Wilson

Schultz

Stevens

1996

Proc. Natl. Acad. Sci. U.S.A.

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The x-ray crystal structures of the sulfide oxidase antibody 28B4 and of antibody 28B4 complexed with hapten have been solved at 2.2-A and 1.9-A resolution, respec-tively. To our knowledge, these structures are the highest resolution catalytic antibody structures to date and provide insight into the molecular mechanism of this antibodycatalyzed monooxygenation reaction. Specifically, the data suggest that entropic restriction plays a fundamental role in catalysis through the precise alignment of the thioether substrate and oxidant. The antibody active site also stabilizes developing charge on both sulfur and periodate in the transition state via cation-pi and electrostatic interactions, respectively. In addition to demonstrating that the active site of antibody 28B4 does indeed reflect the mechanistic information programmed in the aminophosphonic acid hapten, these high-resolution structures provide a basis for enhancing turnover rates through mutagenesis and improved hapten design.Antibodies have been shown to catalyze a wide variety of reactions with exquisite control over the reaction pathway (1). However, the further improvement of antibody catalysis depends on high-resolution structural data. The few reported crystal structures of catalytic antibodies have focused, with one exception, on esterolytic reactions (2-6). We now report the three-dimensional structure of an antibody (28B4) that catalyzes the monooxygenation of thioethers. An examination of the structural data may provide insight into enhancing the catalytic efficiencies of antibodies as well as elucidate the mechanisms and evolution of enzymatic catalysis.Antibody 28B4 catalyzes the periodate-dependent oxidation ( Fig. 1) of sulfide 1 to the corresponding sulfoxide 2 (7). Similar oxygen transfer reactions are performed by naturally occurring monooxygenase enzymes for the biosynthesis of steroids and neurotransmitters, the degradation of endogenous substances, and the detoxification of xenobiotics (8, 9). This reaction was initially examined to extend antibody catalysis to this important class of redox reactions and (ii) to expand the range of "cofactors" used in biological catalysis. The combination of highly abundant and versatile chemical reagents such as metal hydrides and Lewis acids together with antibody catalysis might lead to a number of advantages over natural enzymes, such as eliminating the need for expensive cofactor recycling in large-scale enzymatic synthesis (10).The periodate-dependent oxygenation of thioethers can occur either via sulfur attack on the periodate oxygen in a concerted, SN2-like transition state (TS*) or by initial addition to the iodine center followed by oxygen transfer (Fig. 1) Eight antibodies were found to catalyze the oxidation of substrate 1 and related sulfides with a range of turnover numbers and stereoselectivities. Antibody 28B4, which was among the most efficient, binds hapten 3 with high affinity (Kd= 52 nM) and catalyzes the periodate-dependent oxidation of sulfide 1 with a kcat value of 8.2 s-1...

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“…Motif II is unusually rich in aromatic amino acids (Tyr, Trp, and Phe), which are located around a central invariant aspartate residue (27). Aromatic rings are considered to be involved in binding SAM through cation-quadrapole interactions with the positively charged sulfonium moiety of SAM (13,31). The importance of tyrosine in motif II of rat guanidinoacetate methyltransferase (RGAMT) has already been demonstrated (22).…”

mentioning

confidence: 99%

Escherichia coli TehB Requires S -Adenosylmethionine as a Cofactor To Mediate Tellurite Resistance

et al. 2000

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The Escherichia coli chromosomal determinant for tellurite resistance consists of two genes (tehA and tehB) which, when expressed on a multicopy plasmid, confer resistance to K 2 TeO 3 at 128 g/ml, compared to the MIC of 2 g/ml for the wild type. TehB is a cytoplasmic protein which possesses three conserved motifs (I, II, and III) found in S-adenosyl-L-methionine (SAM)-dependent non-nucleic acid methyltransferases. Replacement of the conserved aspartate residue in motif I by asparagine or alanine, or of the conserved phenylalanine in motif II by tyrosine or alanine, decreased resistance to background levels. Our results are consistent with motifs I and II in TehB being involved in SAM binding. Additionally, conformational changes in TehB are observed upon binding of both tellurite and SAM. The hydrodynamic radius of TehB measured by dynamic light scattering showed a ϳ20% decrease upon binding of both tellurite and SAM. These data suggest that TehB utilizes a methyltransferase activity in the detoxification of tellurite.Tellurite (TeO 3 2Ϫ ) resistance, which is found in many microorganisms (37), is carried on plasmids of IncHI, IncHII, and IncP incompatibility groups (3, 36, 39) and/or on chromosomes (9, 10, 29, 33). Tellurite resistance (Te r ) determinants are very diverse, and at least five different determinants have been identified (37). Te r determinants are unrelated, and probably different resistance mechanisms are involved. Except for that encoded by the Pseudomonas syringae tpm gene, Te r mechanisms are not clearly understood. tpm encodes a methyltransferase that catalyzes S-adenosyl-L-methionine (SAM) methylation of 6-mercaptopurine, a substrate for human thiopurine methyltransferase. It was assumed that tellurite is also a substrate for this enzyme (11).The Te r determinant tehAB, an operon located at 32.3 min on the Escherichia coli K-12 chromosome (38), encodes proteins of 330 (TehA) and 197 (TehB) amino acids. TehA is a membrane protein with 10 transmembrane segments, whereas TehB is a soluble protein. The closest homologues of these two genes are found in Haemophilus influenzae (15).A sequence search performed with the BLAST program (National Center for Biotechnology Information), followed by alignment analysis with the Genetics Computer Group software package (University of Wisconsin) (12), demonstrated that TehB displays some amino acid sequence similarity to many SAM-dependent non-nucleic acid methyltransferases. These proteins have three shared motifs, and the TehB proteins show homologies within all regions with comparable sequence interval distances (Fig.

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Biomimetic catalysis of SN2 reactions through cation-.pi. interactions. The role of polarizability in catalysis

Cited by 150 publications

References 6 publications

Mapping and Molecular Modeling ofS-Adenosyl-l-methionine Binding Sites inN-Methyltransferase Domains of the Multifunctional Polypeptide Cyclosporin Synthetase

Mapping and Molecular Modeling ofS-Adenosyl-l-methionine Binding Sites inN-Methyltransferase Domains of the Multifunctional Polypeptide Cyclosporin Synthetase

Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution.

Escherichia coli TehB Requires S -Adenosylmethionine as a Cofactor To Mediate Tellurite Resistance

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