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At least 253 records · Page 14Linked to original sources
PubMed2006

Intermolecular insertion of an N,N-heterocyclic carbene into a nonacidic C-H bond: Kinetics, mechanism and catalysis by (K-HMDS)2 (HMDS = Hexamethyldisilazide).

The reaction of 2-[13C]-1-ethyl-3-isopropyl-3,4,5,6-tetrahydropyrimidin-1-ium hexafluorophosphate ([13C1]-1-PF6) with a slight excess (1.03 equiv) of dimeric potassium hexamethyldisilazide ("(K-HMDS)2") in toluene generates 2-[13C]-3-ethyl-1-isopropyl-3,4,5,6-tetrahydropyrimid-2-ylidene ([13C1]-2). The hindered meta-stable N,N-heterocyclic carbene [13C1]-2 thus generated undergoes a slow but quantitative reaction with toluene (the solvent) to generate the aminal 2-[13C]-2-benzyl-3-ethyl-1-isopropylhexahydropyrimidine ([13C1]-14) through formal C-H insertion of C2 (the "carbene carbon") at the toluene methyl group. Despite a significant pKa mismatch (Delta pKa 1+ and toluene estimated to be ca. 16 in DMSO) the reaction shows all the characteristics of a deprotonation mechanism, the reaction rate being strongly dependent on the toluene para substituent (rho = 4.8(+/-0.3)), and displaying substantial and rate-limiting primary (k(H)/k(D) = 4.2(+/-0.6)) and secondary (k(H)/k(D) = 1.18(+/-0.08)) kinetic isotope effects on the deuteration of the toluene methyl group. The reaction is catalysed by K-HMDS, but proceeds without cross over between toluene methyl protons and does not involve an HMDS anion acting as base to generate a benzyl anion. Detailed analysis of the reaction kinetics/kinetic isotope effects demonstrates that a pseudo-first-order decay in 2 arises from a first-order dependence on 2, a first-order dependence on toluene (in large excess) and, in the catalytic manifold, a complex noninteger dependence on the K-HMDS dimer. The rate is not satisfactorily predicted by equations based on the Brønsted salt-effect catalysis law. However, the rate can be satisfactorily predicted by a mole-fraction-weighted net rate constant: -d[2]/dt = ({x2 k(uncat)} + {(1-x2) k(cat)})[2]1[toluene]1, in which x2 is determined by a standard bimolecular complexation equilibrium term. The association constant (Ka) for rapid equilibrium-complexation of 2 with (K-HMDS)2 to form [2(K-HMDS)2] is extracted by nonlinear regression of the 13C NMR shift of C2 in [13C1]-2 versus [(K-HMDS)2] yielding: Ka = 62(+/-7) M(-1); delta(C(2)) in 2=237.0 ppm; delta(C(2)) in [2(K-HMDS)2] = 226.8 ppm. It is thus concluded that there is discrete, albeit inefficient, molecular catalysis through the 1:1 carbene/(K-HMDS)2 complex [2(K-HMDS)2], which is found to react with toluene more rapidly than free 2 by a factor of 3.4 (=k(cat)/k(uncat)). The greater reactivity of the complex [2(K-HMDS)2] over the free carbene (2) may arise from local Brønsted salt-effect catalysis by the (K-HMDS)2 liberated in the solvent cage upon reaction with toluene.

Journal Article↗
PubMed1991

Ribosomal RNA identity elements for ricin A-chain recognition and catalysis.

Ricin is a cytotoxic protein that inactivates ribosomes by hydrolyzing the N-glycosidic bond between the base and the ribose at position A4324 in eukaryotic 28 S rRNA. The requirements for the recognition by ricin A-chain of this nucleotide and for the catalysis of cleavage were examined using a synthetic oligoribonucleotide that reproduces the sequence and the secondary structure of the RNA domain (a helical stem, a bulged nucleotide, and a 17-member single-stranded loop). The wild-type RNA (35mer) and a number of mutants were transcribed in vitro from synthetic DNA templates with phage T7 RNA polymerase. With the wild-type oligoribonucleotide the ricin A-chain catalyzed reaction has a Km of 13.55 microM and a Kcat of 0.023 min-1. Recognition and catalysis by ricin A-chain has an absolute requirement for A at the position that corresponds to 4324. The helical stem is also essential; however, the number of base-pairs can be reduced from the seven found in 28 S rRNA to three without loss of identity. The nature of these base-pairs can affect catalysis. A change of the second set from one canonical (G.C) to another (U.A) reduces sensitivity to ricin A-chain; whereas, a change of the third pair (U.A----G.C) produces supersensitivity. The bulged nucleotide does not contribute to identification. Hydrolysis is affected by altering the nucleotides in the universal sequence surrounding A4324 or by changing the position in the loop of the tetranucleotide GA(ricin)GA: all of these mutants have a null phenotype. If ribosomes are treated first with alpha-sarcin to cleave the phosphodiester bond at G4325 ricin can still catalyze depurination at A4324. This implies that cleavage by alpha-sarcin at the center of what has been presumed to be a 17 nucleotide single-stranded loop in 28 S rRNA produces ends that are constrained in some way. On the other hand, hydrolysis by alpha-sarcin of the corresponding position in the synthetic oligoribonucleotide prevents recognition by ricin A-chain. The results suggest that the loop has a complex structure, affected by ribosomal proteins, and this bears on the function in protein synthesis of the alpha-sarcin/ricin rRNA domain.

Adenosine↗
PubMed1996

Ribonuclease A mutant His119 Asn: the role of histidine in catalysis.

Bovine pancreatic ribonuclease A (RNase A) has been widely used as a convenient model for structural and functional studies. The enzyme catalyzes cleavage of phosphodiester bonds in RNA and related substrates. Three amino acid residues located at the active site of RNase A (His12, His119, and Lys41) are known to be involved in catalysis. Mutation of His119 to asparagine was generated to study the role of His119 in RNase A catalysis. The mutant enzyme has been isolated and characterized. The mutation significantly decreases the rate of the transesterification reaction and has no effect on substrate affinity of the enzyme. An analysis of the enzymatic properties of H119N RNase A suggests that the imidazole ring of His119 of the wild-type enzyme must be protonated in an enzyme-substrate productive complex. Thus our results indicate that a contribution of protonated His119 into the catalysis is not restricted to protonation of oxygen atom of the substrate leaving group and that His119 participates directly in a transition state stabilization via hydrogen bonding.

Asparagine↗
PubMed1999

Hydrogen bonding in enzymatic catalysis: analysis of energetic contributions.

Enzymes can provide catalysis by increasing the strengthening of hydrogen bonds to groups undergoing charge rearrangement in the course of reaction relative to the strengthening of the hydrogen bonds in the corresponding solution reactions. This can be accomplished by using hydrogen bond donors and acceptors that are stronger than water and by lowering the effective dielectric relative to that in aqueous solution. We suggest that these electrostatic effects are of general significance in enzymatic catalysis. The effective dielectric is lowered by the overall "rigidity" of the folded enzyme, which facilitates the formation of active site interactions, and by the fixation of active site functional groups within the enzyme x substrate complex. This underscores the fundamental interconnection of catalytic mechanisms in enzymatic catalysis.

Binding Sites↗
PubMed2002

Does P450-type catalysis proceed through a peroxo-iron intermediate? A review of studies with microperoxidase.

Recent stopped-flow kinetics demonstrated the existence of an intermediate before the occurrence of the final product of the reaction of both iron-containing microperoxidase-8 (Fe(III)MP-8) and manganese-containing microperoxidase-8 (Mn(III)MP-8) with H(2)O(2). The intermediate was assigned to be (hydro)peroxo-iron. With both mini-catalysts the final state obtained after 30-40 ms showed a resemblance to PorM(IV)MP-8[double bond]O(R(+)*); (R(+)*) is a radical located at the peptide. Quantum mechanical calculations indicate that hydroperoxo-iron is inactive as a catalytic intermediate in cytochrome P450 (P450)-type catalysis. Instead, the calculations suggest that peroxo-iron acts as the catalytic intermediate in P450-type catalysis. In addition, the calculations demonstrate that, although less likely, the possibility that oxenoid-iron acts as a catalytic intermediate in P450 catalysis cannot be fully excluded. An interesting aspect of the reactions catalysed by MP-8 is the possibility that, in view of the reversibility of the reactions between (hydro)peroxo-iron and oxenoid-iron, H(2)O plays a decisive role, at least in some cytochromes P450, in the removal of halogens, avoiding the production of compounds hazardous to the organism.

Cytochrome P-450 Enzyme System↗
PubMed1998

Crystallography and mutagenesis of transketolase: mechanistic implications for enzymatic thiamin catalysis.

The ThDP dependent enzyme transketolase is a convenient model system to study enzymatic thiamin catalysis. Crystallographic studies of the enzyme have identified the ThDP binding fold, the V-conformation of ThDP as the relevant conformation in enzymatic catalysis and details of enzyme-substrate interactions. Based on this structural information, the function of various active site residues in substrate binding and catalysis has been probed by site-directed mutagenesis.

Apoenzymes↗
PubMed2003

The mechanism of methanol to hydrocarbon catalysis.

The process of converting methanol to hydrocarbons on the aluminosilicate zeolite HZSM-5 was originally developed as a route from natural gas to synthetic gasoline. Using other microporous catalysts that are selective for light olefins, methanol-to-olefin (MTO) catalysis may soon become central to the conversion of natural gas to polyolefins. The mechanism of methanol conversion proved to be an intellectually challenging problem; 25 years of fundamental study produced at least 20 distinct mechanisms, but most did not account for either the primary products or a kinetic induction period. Recent experimental and theoretical work has firmly established that methanol and dimethyl ether react on cyclic organic species contained in the cages or channels of the inorganic host. These organic reaction centers act as scaffolds for the assembly of light olefins so as to avoid the high high-energy intermediates required by all "direct" mechanisms. The rate of formation of the initial reaction centers, and hence the duration of the kinetic induction period, can be governed by impurity species. Secondary reactions of primary olefin products strongly reflect the topology and acid strength of the microporous catalyst. Reaction centers form continuously through some secondary pathways, and they age into polycyclic aromatic hydrocarbons, eventually deactivating the catalyst. It proves useful to consider each cage (or channel) with its included organic and inorganic species as a supramolecule that can react to form various species. This view allows us to identify structure-activity and structure selectivity relationships and to modify the catalyst with degrees of freedom that are more reminiscent of homogeneous catalysis than heterogeneous catalysis.

Journal Article↗
PubMed2004

Enamine catalysis is a powerful strategy for the catalytic generation and use of carbanion equivalents.

The chemistry of preformed enamines, especially their use as enolate equivalents, has been a well-investigated area of research since the early 1950s. However, enamine catalysis, the catalysis of carbonyl transformations via enamine intermediates by using primary and secondary amines as catalysts, has only been fully appreciated as a powerful strategy for asymmetric synthesis since the beginning of this century. Contributions from this laboratory to the revitalized interest in asymmetric enamine catalysis are summarized in this Account.

Journal Article↗
PubMed1987

Positional oxygen isotope exchange as a probe for the mechanism of catalysis by Escherichia coli succinyl coenzyme A synthetase.

Succinyl-CoA synthetase of Escherichia coli has an alpha 2 beta 2 subunit structure. The enzyme shows strict half-sites reactivity with respect to the phosphorylation of a histidine residue in the alpha subunit that represents a step in catalysis. Several lines of evidence indicate that this behavior may result from cooperative interactions between alternatingly functional active sites, so that subsequent steps in catalysis at one site may be promoted by phosphoryl transfer to the site on the neighboring half of the molecule. This study is directed toward learning more about the nature of these cooperative interactions. Here we have used positional isotope exchange (i.e., exchange of 18O between the beta, gamma bridge and the beta nonbridge position of ATP) as a test for transient bisphosphorylation. Succinyl-CoA synthetase was ATP) as a test for transient bisphosphorylation. Succinyl-CoA synthetase was prepared in which one of the two active sites was thiophosphorylated; this species thus has one of its two active-site histidine residues occupied and unavailable for further reaction with ATP. Treatment of this monothiophosphorylated enzyme with [beta, gamma-18O]ATP resulted in no significant scrambling of isotope into the nonbridge position, clearly indicating that the enzyme does not undergo even transient bisphosphorylation. We interpret the results in terms of a model of catalysis in which phosphoryl transfer to the second site occurs in concerted fashion with transfer from the first.

Adenosine Triphosphate↗
PubMed2003

Solvent protection of the hammerhead ribozyme in the ground state: evidence for a cation-assisted conformational change leading to catalysis.

Tertiary folding of the hammerhead ribozyme has been analyzed by hydroxyl radical footprinting. Three hammerhead constructs with distinct noncore sequences, connectivities, and catalytic properties show identical protection patterns, in which conserved core residues (G5, A6, U7, G8, and A9) and the cleavage site (C17, G1.1, and U1.2) become reproducibly protected from nucleolytic attack by radicals. Metal ion titrations show that all protections appear together, suggesting a single folding event to a common tertiary structure, rather than an ensemble of different folds. The apparent binding constants for folding and catalysis by Mg(2+) are lower than those for Li(+) by 3 orders of magnitude, but in each case the protected sites are identical. For both Mg(2+) and Li(+), the ribozyme folds into the protected tertiary structure at significantly lower cation concentrations than those required for cleavage. The sites of protection include all of the sites of reduced solvent accessibility calculated from two different crystal structures, including both core and noncore nucleotides. In addition, experimentally observed protected sites include additional sequences adjacent to those predicted by the crystal structures, suggesting that the solution structure may be folded into a more compact shape. A 2'-deoxy substitution at G5 abolishes all protection, indicating that the 2'-OH is essential for folding. Together, these results support a model in which low concentrations of metal ions fold the ribozyme into a stable ground state tertiary structure that is similar to the crystallographic structures, and higher concentrations of metal ions support a transient conformational change into the transition state for catalysis. These data do not themselves address the issue as to whether a large- or small-scale conformational change is required for catalysis.

Magnesium↗
PubMed2005

Is the critical role of loop 3 of Escherichia coli 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase in catalysis due to loop-3 residues arginine-84 and tryptophan-89? Site-directed mutagenesis, biochemical, and crystallographic studies.

Deletion mutagenesis, biochemical, and X-ray crystallographic studies have shown that loop 3 of Escherichia coli 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is required for the assembly of the active center, plays an important role in the stabilization of the ternary complex of HPPK with MgATP and 6-hydroxymethyl-7,8-dihydropterin (HP), and is essential for catalysis. Whether the critical functional importance of loop 3 is due to the interactions between residues R84 and W89 and the two substrates has been addressed by site-directed mutagenesis, biochemical, and X-ray crystallographic studies. Substitution of R84 with alanine causes little changes in the dissociation constants and kinetic constants of the HPPK-catalyzed reaction, indicating that R84 is not important for either substrate binding or catalysis. Substitution of W89 with alanine increases the K(d) for the binding of MgATP by a factor of 3, whereas the K(d) for HP increases by a factor of 6, which is due to the increase in the dissociation rate constant. The W89A mutation decreases the rate constant for the chemical step of the forward reaction by a factor of 15 and the rate constant for the chemical step of the reverse reaction by a factor of 25. The biochemical results of the W89A mutation indicate that W89 contributes somewhat to the binding of HP and more significantly to the chemical step. The crystal structures of W89A show that W89A has different conformations in loops 2 and 3, but the critical catalytic residues are positioned for catalysis. When these results are taken together, they suggest that the critical functional importance of loop 3 is not due to the interactions of the R84 guanidinium group or the W89 indole ring with the substrates.

Amino Acid Sequence↗
PubMed1996

4-Oxalocrotonate tautomerase: pH dependence of catalysis and pKa values of active site residues.

The pH-rate profiles for the kinetic parameters of 4-oxalocrotonate tautomerase (4-OT) have been measured using 2-hydroxy-2,4-hexadiendioate (2a) and 2-hydroxy-2,4-pentadienoate (2b) as substrates. The pH dependences of log (kcat/Km) and of log kcat for the slow, nonsticky substrate 2b, which lacks a 6-carboxyl group, were bell-shaped with limiting slopes of unity on both sides of the pH optimum. For 2b, pKa values of 6.2 +/- 0.3 and 9.0 +/- 0.3 for the free enzyme (pKE) and 7.7 +/- 0.3 and 8.5 +/- 0.3 for the ES complex (pKES) were obtained. The pKE of 6.2 +/- 0.3 for 2b represents a true pKa for a basic group on the enzyme and is most likely Pro-1 on the basis of inhibition studies with the substrate-based affinity label 3-bromopyruvate (3-BP) [Stivers et al. (1996) Biochemistry 35, 803-813]. Accordingly, 15N NMR titration of the uniformly 15N-labeled enzyme showed that the pKa of the amino group of Pro-1 is 6.4 +/- 0.2, in reasonable agreement with those found by the effect of pH on kcat/Km for 2b (6.2 +/- 0.3) and on kinact/K1 for 3-BP (6.7 +/- 0.3), but three units lower than the pKa of the model compound proline amide (pKa = 9.4 +/- 0.2). The pKa values for the two histidine residues of 4-OT, which were measured by 1H NMR (His-6, pKa < or = 5; His-49, pKa = 5.2 +/- 0.2), are at least one pK unit lower than the pKE, excluding these residues as candidates for the general base. A plot of log (kcat/Km) vs pH for the 10(4)-fold more reactive, but sticky substrate 2a [(kcat/Km)max = 3.9 x 10(6) M-1 s-1] shows a limiting slope of two on the ascending limb indicating the ionization of two essential groups on the free enzyme and/or substrate. One of these groups, with a pKa value of 5.4, is reasonably assigned to the 6-carboxylate moiety of 2a (pKaCOOH = 5.4). This assignment is supported by the slope of unity for the ascending limb of log (kcat/Km) versus pH for 2b which lacks this group. Thus a negative charge at the 6-position is important for substrate binding and catalysis. The other group (pKa2 = 5.2) most likely represents a perturbed pKa for the general base Pro-1 (pKatrue = 6.4). The descending limb of log kcat/Km vs pH for 2a has a slope of unity and was fit to a single pKa3 = 10.3 +/- 0.2. The pH dependence of kcat for 2a gives pKa values for the ES complex (pKES) of 6.5 and 9.6. On the basis of these results, an isomerization mechanism involving general-base catalysis by a low pKa proline-1 and electrophilic catalysis by an as yet unidentified enzymic general-acid (pKa = 9.0) is proposed.

Binding Sites↗
PubMed2003

The Rh4(CO)12-catalyzed hydroformylation of 3,3-dimethylbut-1-ene promoted with HMn(CO)5. Bimetallic catalytic binuclear elimination as an origin for synergism in homogeneous catalysis.

The bimetallic origins of catalytic synergism were studied using unmodified rhodium and manganese carbonyls as catalyst precursors during the low-temperature hydroformylation of 3,3-dimethylbut-1-ene to 4,4-dimethylpentanal in n-hexane solvent (T approximately 298 K, P(CO) = 1.0-4.0 MPa, P(H2) = 0.5-2.0 MPa). A dramatic increase in the catalytic rate was observed in the experiments conducted when both metals were used simultaneously. Detailed in-situ FTIR measurements indicated the observable presence of only homometallic complexes during catalysis, e.g., RCORh(CO)(4), Rh(4)(CO)(12), Rh(6)(CO)(16), HMn(CO)(5), and Mn(2)(CO)(10). The kinetics of product formation show a distinct linear-bilinear form in observables: k(1)[RCORh(CO)(4)][CO](-1)[H(2)] + k(2)[RCORh(CO)(4)][HMn(CO)(5)][CO](-1.5). The first term represents the classic unicyclic rhodium catalysis, while the second indicates a hydride attack on an acyl species. These spectroscopic and kinetic results strongly suggest that the origin of synergism is the presence of bimetallic catalytic binuclear elimination and not cluster catalysis. This appears to be the first detailed evidence for such a catalytic mechanism, and its implications for selectivity and nonlinear catalytic activity are accordingly discussed.

Journal Article↗
PubMed1999

Mechanisms of Acid Decomposition of Dithiocarbamates. 2. Efficiency of the Intramolecular General Acid Catalysis.

The acid decomposition of ethylenebis(dithiocarbamate) (EbisDTC) and glycinedithiocarboxylate (glyDTC) was studied in water at 25 degrees C in the range of H(o) -5 to pH 5. The acid dissociation constants of all species involved were calculated from LFER and from the pH-rate profiles. According to the pK(a) of the parent amine of the reactive species, both compounds decompose through the dithiocarbamate anion and a zwitterion intermediate. The intermolecular N-protonation rate constant of the carboxylic conjugate acid of glyDTC anion is 12.6 M(-)(1) s(-)(1), slower than the C-N breakdown. This species also cleaves through an intramolecular general acid-catalyzed mechanism where the rate constant for the N-protonation is (7.1 +/- 4.2) x 10(3) s(-)(1) and the efficiency of the proton-transfer step as measured by the effective molarity is (5.6 +/- 3.3) x 10(2) M. The acid decomposition of the dithiocarbamic conjugate acid of EbisDTC anion proceeds through a fast N-protonation and a slower C-N breakdown. The intramolecular general acid catalysis rate constant is (8.2 +/- 2.8) x 10(6) s(-)(1), but the efficiency of this fast proton transfer is only (14.3 +/- 4.9) M. The intramolecular general acid catalysis of the free acid forms of the carboxylic and dithiocarbamic groups is unfavorable for about 4 kcal mol(-)(1) with respect to the protonation of the external hydron, and consequently, no external buffer catalysis is expected to be observed for dithiocarbamates that decompose through a zwitterion intermediate. The difference between the pK(b) of the proton acceptor and the pK(a) of the donor follows the order of the proton efficiency. Estimation of the strength of the hydrogen bonding in the reagent and product supports the assumption that a thermodynamically favorable change of hydrogen bonding from reagent to product increases the efficiency of proton transfer.

Journal Article↗
PubMed2000

Electrostatic and electrophilic catalysis in the reductive cleavage of alkyl aryl ethers. The influence of ion pairing on the regioselectivity

Electrophilic and electrostatic catalysis have been identified as distinct contributions that affect the reactivity of radical anions in the reductive cleavage of alkyl aryl ethers. Two modes of mesolytic scission of these radical anions are possible: homolytic (dealkylation, a thermodynamically favored but kinetically forbidden process) and heterolytic (dealkoxylation). From our studies (alkali metal reductions, electrochemical studies, use of substrates with a preformed positive charge in certain positions of their structure) it can be concluded that the heterolytic scission is very much dependent on the electrophilic assistance by the counterion and it is only observed in contact ionic pairs with unsaturated cations (electrophilic catalysis). On the other hand, the homolytic scission is observed in solvent-separated ionic pairs, and it is especially efficient when the pair has a controlled topology with a tetralkylammonium cation (saturated cation) near the oxygen atom. The effect of the cation has, in this case, electrostatic origin (electrostatic catalysis), probably lowering the barrier of the intramolecular pi-sigma electron transfer process and thus reducing the kinetic control of the reaction in such a way that the thermodynamically more favorable process is produced.

Journal Article↗
PubMed2000

A homochiral metal-organic porous material for enantioselective separation and catalysis

Inorganic zeolites are used for many practical applications that exploit the microporosity intrinsic to their crystal structures. Organic analogues, which are assembled from modular organic building blocks linked through non-covalent interactions, are of interest for similar applications. These range from catalysis, separation and sensor technology to optoelectronics, with enantioselective separation and catalysis being especially important for the chemical and pharmaceutical industries. The modular construction of these analogues allows flexible and rational design, as both the architecture and chemical functionality of the micropores can, in principle, be precisely controlled. Porous organic solids with large voids and high framework stability have been produced, and investigations into the range of accessible pore functionalities have been initiated. For example, catalytically active organic zeolite analogues are known, as are chiral metal-organic open-framework materials. However, the latter are only available as racemic mixtures, or lack the degree of framework stability or void space that is required for practical applications. Here we report the synthesis of a homochiral metal-organic porous material that allows the enantioselective inclusion of metal complexes in its pores and catalyses a transesterification reaction in an enantioselective manner. Our synthesis strategy, which uses enantiopure metal-organic clusters as secondary building blocks, should be readily applicable to chemically modified cluster components and thus provide access to a wide range of porous organic materials suitable for enantioselective separation and catalysis.

Journal Article↗
PubMed2005

Micellar catalysis on the electron transfer reactions of iron(III)-polypyridyl complexes with organic sulfides-importance of hydrophobic interactions.

The oxidation of organic sulfides with iron(III)-polypyridyl complexes [Fe(NN)3]3+ proceeds through an electron transfer mechanism and an increase in the methanol content in the methanol-water mixture favors the reaction. The reaction is catalyzed by both the anionic surfactant, sodium dodecyl sulfate (SDS) and the cationic surfactant, cetyltrimethylammonium bromide (CTAB). The micellar catalysis in the presence of SDS is accounted for in terms of strong binding of the cationic oxidant with the anionic surfactant and the development of positive charge on sulfur center of substrate in the transition state. The micellar catalysis observed on the reaction involving a trication, [Fe(NN)3]3+, in the presence of CTAB indicates the importance of hydrophobic interaction between the micelle and hydrophobic ligand of [Fe(NN)3]3+. The micellar catalysis is explained in terms of a pseudophase ion exchange model.

Journal Article↗
PubMed2000

A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition.

The pH dependence of matrix metalloproteinase (MMP) catalysis is described by a broad bell-shaped curve, indicating the involvement of two unspecified ionizable groups in proteolysis. Stromelysin-1 has a third pK(a) near 6, resulting in a uniquely sharp acidic catalytic optimum, which has recently been attributed to His(224). This suggests the presence of a critical, but unidentified, S1' substructure. Integrating biochemical characterizations of inhibitor-enzyme interactions with active site topography from corresponding crystal structures, we isolated contributions to the pH dependence of catalysis and inhibition of active site residues Glu(202) and His(224). The acidic pK(a) 5.6 is attributed to the Glu(202).zinc.H(2)O complex, consistent with a role for the invariant active site Glu as a general base in MMP catalysis. The His(224)-dependent substructure is identified as a tripeptide (Pro(221)-Leu(222)-Tyr(223)) that forms the substrate cleft lower wall. Substrate binding induces a beta-conformation in this sequence, which extends and anchors the larger beta-sheet of the enzyme. substrate complex and appears to be essential for productive substrate binding. Because the PXY tripeptide is strictly conserved among MMPs, this "beta-anchor" may represent a common motif required for macromolecular substrate hydrolysis. The striking acidic profile of stromelysin-1 defined by the combined ionization of Glu(202) and His(224) allows the design of highly selective inhibitors.

Binding Sites↗