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PubMed2007

Structural characterization of a beta-diketone hydrolase from the cyanobacterium Anabaena sp. PCC 7120 in native and product-bound forms, a coenzyme A-independent member of the crotonase suprafamily.

The gene alr4455 from the well-studied cyanobacterium Anabaena sp. PCC 7120 encodes a crotonase orthologue that displays beta-diketone hydrolase activity. Anabaena beta-diketone hydrolase (ABDH), in common with 6-oxocamphor hydrolase (OCH) from Rhodococcus sp. NCIMB 9784, catalyzes the desymmetrization of bicyclo[2.2.2]octane-2,6-dione to yield [(S)-3-oxocyclohexyl]acetic acid, a reaction unusual among the crotonase superfamily as the substrate is not an acyl-CoA thioester. The structure of ABDH has been determined to a resolution of 1.5 A in both native and ligand-bound forms. ABDH forms a hexamer similar to OCH and features one active site per enzyme monomer. The arrangement of side chains in the active site indicates that while the catalytic chemistry may be conserved in OCH orthologues, the structural determinants of substrate specificity are different. In the active site of ligand-bound forms that had been cocrystallized with the bicyclic diketone substrate bicyclo[2.2.2]octane-2,6-dione was found the product of the asymmetric enzymatic retro-Claisen reaction [(S)-3-oxocyclohexyl]acetic acid. The structures of ABDH in both native and ligand-bound forms reveal further details about structural variation and modes of coenzyme A-independent activity within the crotonases and provide further evidence of a wider suprafamily of enzymes that have recruited the crotonase fold for the catalysis of reactions other than those regularly attributed to canonical superfamily members.

Amino Acid Sequence↗
PubMed1996

Oxidation of phenols, anilines, and benzenethiols by fungal laccases: correlation between activity and redox potentials as well as halide inhibition.

A comparative study has been performed with several fungal laccases for the oxidation of a series of phenols, anilines, and benzenethiols and for the inhibition by halides. The observed K(m) and kcat were correlated to the structure of substrate. The change in log (kcat/K(m)) was found to be proportional to the one-electron redox potential difference between laccase's type 1 copper site and substrate. This correlation indicated that the first electron transfer from substrate to laccase was governed by the "outersphere" mechanism. Compared to the electronic factor, the steric effect of small o-substituents (such as methyl and methoxy groups) was found to be unimportant. The depth of the laccase's type 1 copper site was estimated as approximately 10 A by comparing the steric effect among five 2-methoxyphenols whose 4-substituents ranged from 0.1 to 14 kDa in mass. The observed inhibition potency order of F- > Cl- > Br- was attributed to limited accessibility of laccase's type 2/type 3 trinuclear copper cluster site. Although the enzymes studied have homologous primary sequences and predicted similar backbone structures, the difference exhibited by each enzyme (in interacting with individual substrate or inhibitor) suggested the structural variation in their functional domains.

Aniline Compounds↗
PubMed1999

Structural basis of electron transfer modulation in the purple CuA center.

The X-ray structure of an engineered purple CuA center in azurin from Pseudomonas aeruginosa has been determined and refined at 1.65 A resolution. Two independent purple CuA azurin molecules are in the asymmetric unit of a new P21 crystal, and they have nearly identical conformations (rmsd of 0.27 A for backbone atoms). The purple CuA azurin was produced by the loop-engineering strategy, and the resulting overall structure is unperturbed. The insertion of a slightly larger Cu-binding loop into azurin causes the two structural domains of azurin to move away from each other. The high-resolution structure reveals the detailed environment of the delocalized mixed-valence [Cu(1.5).Cu(1.5)] binuclear purple CuA center, which serves as a useful reference model for other native proteins, and provides a firm basis for understanding results from spectroscopic and functional studies of this class of copper center in biology. The two independent Cu-Cu distances of 2.42 and 2.35 A (with respective concomitant adjustments of ligand-Cu distances) are consistent with that (2.39 A) obtained from X-ray absorption spectroscopy with the same molecule, and are among the shortest Cu-Cu bonds observed to date in proteins or inorganic complexes. A comparison of the purple CuA azurin structure with those of other CuA centers reveals an important relationship between the angular position of the two His imidazole rings with respect to the Cu2S2(Cys) core plane and the distance between the Cu and the axial ligand. This relationship strongly suggests that the fine structural variation of different CuA centers can be correlated with the angular positions of the two histidine rings because, from these positions, one can predict the relative axial ligand interactions, which are responsible for modulating the Cu-Cu distance and the electron transfer properties of the CuA centers.

Azurin↗
PubMed1999

Structure of a triple helical DNA with a triplex-duplex junction.

Extended purine sequences on a DNA strand can lead to the formation of triplex DNA in which the third strand runs parallel to the purine strand. Triplex DNA structures have been proposed to play a role in gene expression and recombination and also have potential application as antisense inhibitors of gene expression. Triplex structures have been studied in solution by NMR, but have hitherto resisted attempts at crystallization. Here, we report a novel design of DNA sequences, which allows the first crystallographic study of DNA segment containing triplexes and its junction with a duplex. In the 1.8 A resolution structure, the sugar-phosphate backbone of the third strand is parallel to the purine-rich strand. The bases of the third strand associate with the Watson and Crick duplex via Hoogsteen-type interactions, resulting in three consecutive C(+).GC, BU.ABU (BU = 5-bromouracil), and C(+).GC triplets. The overall conformation of the DNA triplex has some similarity to the B-form, but is distinct from both A- and B-forms. There are large changes in the phosphate backbone torsion angles (particularly gamma) of the purine strand, probably due to the electrostatic interactions between the phosphate groups and the protonated cytosine. These changes narrow the minor groove width of the purine-Hoogsteen strands and may represent sequence-specific structural variations of the DNA triplex.

Base Pairing↗
PubMed2000

Bacterial poly(3-hydroxybutyrate): an optical microscopy and microfocus X-ray diffraction study.

Two-dimensional spatially resolved microfocus X-ray diffraction has been used to investigate spherulites of pure bacterial poly(3-hydroxybutyrate) (PHB) and of a blend of natural and synthetic atactic PHB (a-PHB) crystallized at a relatively high temperature (Tc = 140 degrees C). Both samples investigated contained practically two-dimensional spherulites, characterized by wide extinction bands (band spacing > 80 microns). The X-ray diffraction patterns confirmed that the unit cell alpha-axis is oriented along the spherulite radius in PHB and that the same is true for the a-PHB containing blend. Comparison of the matrix of diffraction patterns with the polarized optical micrograph of the scanned sample area indicated a very clear correlation between pattern changes and banding, yielding a straightforward picture of the structural variations within the spherulite.

Bacteria↗
PubMedDate not supplied

Electronic van der Waals surface property descriptors and genetic algorithms for developing structure-activity correlations in olfactory databases.

A methodology to facilitate the intelligent design of new odorants (e.g., musks) with specialized properties has been developed as part of an ongoing research effort in machine learning. In a traditional framework, the introduction of a new odorant is a lengthy, costly, and laborious discovery, development, and testing process. We propose to streamline this process utilizing large existing olfactory databases available through the open scientific literature as input for a new structure/activity correlation methodology. The first step in this process is to characterize each molecule in the database by an appropriate set of descriptors. To accomplish this task, an enhanced version of Breneman's Transferable Atom Equivalent (TAE) descriptor methodology will be used to create a large set of electron density derived shape/property hybrid (PEST), wavelet coefficient (WCD), and TAE histogram descriptors. We have chosen these molecular property descriptors to represent the problem because they have been shown to contain pertinent shape and electronic properties of the molecule and correlate with key modes of intermolecular interactions. Traditional QSAR methodologies, which employ fragment based descriptors, have been shown to be effective for QSAR development within homologous sets of molecules but are less effective when applied to data sets containing a great deal of structural variation. In contrast to previous attempts at SAR, our use of shape-aware electron density based molecular property descriptors has removed many of the limitations brought about by the use of descriptors based on substructure fragments, molecular surface properties, or other whole molecule descriptors. Another reason for the mixed success of past QSAR efforts can be traced to the nature of the underlying modeling problem, which is often quite complex. To meet these challenges, a genetic algorithm for pattern recognition analysis has been developed that selects descriptors which create class separation in a plot of the two largest principal components of the data while simultaneously searching for features that increase clustering of the data.

Journal Article↗
PubMed2001

Solvent effects on uranium(VI) fluoride and hydroxide complexes studied by EXAFS and quantum chemistry.

The structures of the complexes UO(2)F(n)(H(2)O)(5-n)(2-n), n = 3-5, have been studied by EXAFS. All have pentagonal bipyramid geometry with U-F of and U-H(2)O distances equal to 2.26 and 2.48 A, respectively. On the other hand the complex UO(2)(OH)(4)(2-) has a square bipyramid geometry both in the solid state and in solution. The structures of hydroxide and fluoride complexes have also been investigated with wave function based and DFT methods in order to explore the possible reasons for the observed structural differences. These studies include models that describe the solvent by using a discrete second coordination sphere, a model with a spherical, or shape-adapted cavity in a conductor-like polarizable continuum medium (CPCM), or a combination of the two. Solvent effects were shown to give the main contribution to the observed structure variations between the uranium(VI) tetrahydroxide and the tetrafluoride complexes. Without a solvent model both UO(2)(OH)(4)(H(2)O)(2-) and UO(2)F(4)(H(2)O)(2-) have the same square bipyramid geometry, with the water molecule located at a distance of more than 4 A from uranium and with a charge distribution that is very near identical in the two complexes. Of the models tested, only the CPCM ones are able to describe the experimentally observed square and pentagonal bipyramid geometry in the tetrahydroxide and tetrafluoride complexes. The geometry and the relative energy of different isomers of UO(2)F(3)(H(2)O)(2-) are very similar, indicating that they are present in comparable amounts in solution. All calculated bond distances are in good agreement with the experimental observations, provided that a proper model of the solvent is used.

Journal Article↗
PubMed2002

New metalloligands [M(SC[O]Ph)(4)](-): synthesis and characterization of polymeric [A(MeCN)(x)[M(SC[O]Ph)(4)]] compounds (A = Li, Na and K; M = Ga and In; x = 0-2).

Exploiting the ability of the [M(SC[O]Ph)(4)](-) anion to behave like an anionic metalloligand, we have synthesized [Li[Ga(SC[O]Ph)(4)]] (1), [Li[In(SC[O]Ph)(4)]] (2), [Na[Ga(SC[O]Ph)(4)]] (3), [Na(MeCN)[In(SC[O]Ph)(4)]] (4), [K[Ga(SC[O]Ph)(4)]] (5), and [K(MeCN)(2)[In(SC[O]Ph)(4)]] (6) by reacting MX(3) and PhC[O]S(-)A(+) (M = Ga(III) and In(III); X = Cl(-) and NO(3)(-); and A = Li(I), Na(I), and K(I)) in the molar ratio 1:4. The structures of 2, 4, and 6 determined by X-ray crystallography indicate that they have a one-dimensional coordination polymeric structure, and structural variations may be attributed to the change in the alkali metal ion from Li(I) to Na(I) to K(I). Crystal data for 2 x 0.5MeCN x 0.25H(2)O: monoclinic space group C2/c, a = 24.5766(8) A, b = 13.2758(5) A, c = 19.9983(8) A, beta = 108.426(1) degrees, Z = 8, and V = 6190.4(4) A(3). Crystal data for 4: monoclinic space group P2(1)/c, a = 10.5774(7) A, b = 21.9723(15) A, c = 14.4196(10) A, beta = 110.121(1) degrees, Z = 4, and V = 3146.7(4) A(3). Crystal data for 6: monoclinic space group P2(1)/c, a = 12.307(3) A, b = 13.672(3) A, c = 20.575(4) A, beta = 92.356(4) degrees, Z = 4, and V = 3458.8(12) A(3). The thermal decomposition of these compounds indicated the formation of the corresponding AMS(2) materials.

Journal Article↗
PubMed2002

Intra- and intermolecular second-sphere coordination chemistry: formation of capsules, half-capsules, and extended structures with hexaaquo- and hexaamminemetal ions.

In the design of novel extended solids, particularly those based on weaker interactions, reliable "synthons" are a valuable commodity. This work concerns the hydrogen-bonded assemblies which result from the second-sphere coordination interactions between a highly preorganized trisulfonate ligand and hexaaquo metal ions. Significantly, supramolecular structural variation, which may be rationalized on the basis of the features of the molecular building blocks, is observed. The results are formation of second-sphere capsules with trivalent ions (Fe(3+), Cr(3+), Al(3+)), and half-capsules with divalent ions (Mg(2+), Zn(2+)). The divalent systems further assemble into extensively hydrogen-bonded hexagonal nets. Effects of geometrical variation of the building blocks are also observed when a Jahn-Teller-distorted divalent ion (Cu(2+)) is substituted for the perfectly octahedral species. The second-sphere effects on the stabilization of the primary coordination sphere are illustrated by TGA experiments. In these assemblies, the potential of a new supramolecular synthon is illustrated, that being the complementary cis-aquo sulfonate interaction. These complexes illustrate the general utility of second-sphere effects, both as an assembly tool and to stabilize metal complexes in the solid state. Finally, as a comparison, a hydrogen-bonded assembly with a hexaammine complex of a trivalent metal (Co(3+)) is presented, which forms an extended network with a completely altered hydrogen bonding array.

Journal Article↗
PubMed2005

Effect of the semirigid capping ligand on the structure formation of cyano-bridged bimetallic assemblies: syntheses, crystal structures, and magnetic properties.

The syntheses, crystal structures, and magnetic properties of three novel cyano-bridged bimetallic assemblies, [Ni(bpm)(2)](3)[Co(CN)(6)](2)x3.5H(2)O (1), [Co(bpm)(2)][Fe(CN)(5)NO]x2H(2)O (2), and [Co(bpm)(2)][Ni(CN)(4)] (3) (bpm = bis(1-pyrazolyl)methane), are reported. Complex 1 crystallizes in the tetragonal space group P4(3)2(1)2 with a = 12.800(5) A, b = 12.800(5) A, c = 42.80(3) A, V = 7012(6) A(3), and Z = 8. Complex 2 crystallizes in the chiral trigonal space group P3(2)21 with a = 11.9961(19) A, b = 11.9961(19) A, c = 16.062(5) A, gamma = 120 degrees , V = 2001.7(8) A(3), and Z = 3. Complex 1 is a trigonal bipyramidal complex in which three [Ni(bpm)(2)](2+) units are situated in the equatorial plane and are connected to the two apical [Co(CN)(6)](3)(-) units via three N ends of the cyanide groups. Complex 2 possesses a triangular left-handed helical chain structure composed of [Co(bpm)(2)](2+) linked by [Fe(CN)(5)NO](2)(-); the shortest intramolecular Co...Fe distance is 5.162 A. To the best of our knowledge, this is the first observation of a heteronuclear helical chain structure based on pentacyanonitrosylferrate(II). The structure of complex 3 is roughly determined by X-ray crystallograhy analysis to be a 1D zigzag chain. These structure variations, from a discrete cluster to a 1D helical chain and a 1D zigzag chain, rely on the semirigidity of the capping ligand bpm. Magnetic susceptibility measurements indicate that complex 1 has an intramolecular ferromagnetic interaction (J = 4.06 cm(-)(1)) between the nickel(II) ions; this is further confirmed by the magnetization measurements. In complexes 2 and 3, the cobalt(II) ions are located in a moderately strong field.

Journal Article↗
PubMed1998

Heterobimetallic (Imido)antimony/Lithium Cages Containing [Sb(NR)(3)](3-) Trianions.

The reactions of [Sb(NMe(2))(3)] with the primary (amido)lithiums [PhCH(2)CH(2)N(H)Li](n)(), [CyN(H)Li](n)() (Cy = C(6)H(11)), [2,4-dmpN(H)Li](n)() [2,4-dmp = 2,4-(MeO)(2)C(6)H(3)], and [(t)()BuN(H)HLi](n)() give the heterobimetallic cage complexes [{Sb(NCH(2)CH(2)Ph)(3)}(2)Li(6).2THF] (1), [{Sb(NCy)(3)}(2)Li(6).2HNMe(2)].2C(6)H(5)CH(3) (2), [Sb{N(2,4-dmp)}(3)](2)Li(6).2THF.2C(6)H(5)CH(3) (3), and [{Sb(NBu(t)())(3)}(2)Li(6)] (4), respectively. The low-temperature X-ray structures of 1-4 show that they are composed of 14-membered polyhedral cages constructed from the association of two [Sb(NR)(3)](3)(-) trianions with six Li(+) cations. Crystal data; 2, triclinic, P&onemacr;, a = 12.775(6) Å, b = 13.191(9) Å, c = 11.015(5) Å, alpha = 111.55(4) degrees, beta = 95.39(4) degrees, gamma = 115.26(4) degrees; 3, triclinic P&onemacr;, a = 10.435(4) Å, b = 12.654(5) Å, c = 14.278(6) Å, alpha = 75.31(4) degrees, beta = 79.33(4) degrees, gamma = 84.33(4) degrees; 4, monoclinic P2(1)/c, a = 9.994(1) Å, b = 17.421(2) Å, c = 10.680(2) Å, beta = 111.33(1) degrees (the structure of 1 being reported previously). Lewis base solvation of the N(6)Li(6) substructures of 1-3 results in distortion and deformation of the Li frameworks. The structural variations in the cores of 1-4 indicate that the bonding in these species is dominated by the valence and bonding demands of the p block metal centers.

Journal Article↗
PubMed1998

Metal-Metal Bonding in Pentanuclear Bow-Tie Metal Sulfido Clusters. Synthetic and Structural Studies on the Cationic Pentanuclear Clusters [(CpIr)(2)(&mgr;(3)-S)(2)M(&mgr;(3)-S)(2)(IrCp)(2)](n)()(+) (M = Fe, Co, Ni; n = 1, 2).

Reactions of [CpMCl(&mgr;(2)-SH)(2)MCpCl] (1, M = Ir; 2, M = Rh; Cp = eta(5)-C(5)Me(5)) with excess FeCl(2).4H(2)O in THF gave the paramagnetic trinuclear clusters [(CpM)(2)(&mgr;(3)-S)(2)FeCl(2)] (3, M = Ir; 4, M = Rh), which were further converted into the dicationic 78e(-) pentanuclear bow-tie cluster [(CpIr)(2)(&mgr;(3)-S)(2)Fe(&mgr;(3)-S)(2)(IrCp)(2)](2+) (5) by treatment with NaBPh(4). When complex 1 was allowed to react with CoCl(2) and NiCl(2).6H(2)O or Ni(cod)(2) (cod = cyclooctadiene), the related pentanuclear 79e(-) and 80e(-) bow-tie clusters [(CpIr)(2)(&mgr;(3)-S)(2)M(&mgr;(3)-S)(2)(IrCp)(2)](2+) (6, M = Co; 7, M = Ni) were obtained directly, respectively. Cyclic voltammograms of 5[BPh(4)](2), 6[BPh(4)](2), and 7[BPh(4)](2) showed two reversible reduction waves at -0.25 to -0.43 V and -1.04 to -1.34 V. In both redox couples, the redox potential was in the order Fe < Co < Ni. One-electron reduction of clusters 5[BPh(4)](2), 6[BPh(4)](2), and 7[BPh(4)](2) with Co(eta(5)-C(5)H(5))(2) gave the corresponding monocationic pentanuclear 79-81e(-) bow-tie clusters [(CpIr)(2)(&mgr;(3)-S)(2)M(&mgr;(3)-S)(2)(IrCp)(2)](+) (8, M = Fe; 9, M = Co; 10, M = Ni). The molecular structures of 3, 4, 5[BPh(4)](2).CH(2)Cl(2), 6[CoCl(3)(NCMe)](2), 7[NiCl(4)].CH(2)Cl(2), 8[BPh(4)], 9[BPh(4)], and 10[BPh(4)] were unambiguously determined by X-ray diffraction study. The structures of the pentanuclear bow-tie cluster cores remarkably changed stepwise as the core electrons increased from 78 to 81. Two of the M-Ir (M = Fe, Co) bonds in the 79e(-) clusters 6 and 8 show significant elongation in comparison with the Fe-Ir bonds in the 78e(-) cluster 5. Two different types of the bow-tie structures were observed for the 80e(-) clusters 7 and 9. Cluster 7 has a Z-shaped metal core with only two Ni-Ir bonds, while in cluster 9, the six metal-metal bonds in the bow-tie structure are retained with slight elongation of the Co-Ir bonds in comparison with the corresponding dication 6. The 81e(-) cluster 10 has two normal Ni-Ir bonds and one long Ni-Ir bonding interaction with the fourth nonbonding Ni-Ir contact. This structural variation is interpreted in terms of the total electron counts and molecular orbital calculations of the clusters.

Journal Article↗
PubMed2002

The first direct and enantioselective cross-aldol reaction of aldehydes.

The first enantioselective catalytic direct cross-aldol reaction that employs nonequivalent aldehydes has been accomplished using proline as the reaction catalyst. Structural variation in both the aldol donor (R1 = Me, n-Bu, Bn, 91 to >99%) and aldol acceptor (R2 = I-Pr, I-Bu, c-C6H11, Et, Ph, 97-99% ee) are possible while maintaining high reaction efficiency (75-88% yield). Significantly, this new aldol variant allows facile enantioselective access to a broad range of beta-hydroxy aldehydes which are valuable intermediates in polyketide syntheses.

Journal Article↗
PubMed2005

Highly enantioselective phase-transfer-catalyzed alkylation of protected alpha-amino acid amides toward practical asymmetric synthesis of vicinal diamines, alpha-amino ketones, and alpha-amino alcohols.

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.

Alkylation↗
PubMed2006

Self-assembled pi-nanotapes as donor scaffolds for selective and thermally gated fluorescence resonance energy transfer (FRET).

Self-assembled nanotapes of a few tailor-made oligo(p-phenylenevinylene)s (OPVs) have been prepared and used as supramolecular donor scaffold to study the fluorescence resonance energy transfer (FRET) to a suitable acceptor. In nonpolar solvents, FRET occurs with nearly 63-81% efficiency, exclusively from the self-assembled OPVs to entrapped Rhodamine B, resulting in the quenching of the donor emission with concomitant formation of the acceptor emission at 625 nm. The efficiency of FRET is considerably influenced by the ability of the OPVs to form the self-assembled aggregates and hence could be controlled by structural variation of the molecules, and polarity of the solvent. Most importantly, FRET could be controlled by temperature as a result of the thermally reversible self-assembly process. The FRET efficiency was significantly enhanced (ca. 90%) in a xerogel film of the OPV1 which is dispersed with relatively less amount of the acceptor (33 mol %), when compared to that of the aggregates in dodecane gel. FRET is not efficient in polar solvents due to weak self-organization of the chromophores. These results indicate that energy transfer occurs exclusively from the self-assembled donor and not directly from the individual donor molecules. The present study illustrates that the self-assembly of chromophores facilitates temperature and solvent controlled FRET within pi-conjugated nanostructures.

Journal Article↗
PubMed2006

Redox ionic liquid phases: ferrocenated imidazoliums.

This communication reports the synthesis of new intrinsically electroactive N-alkyl imidazolium ionic liquids useful for the investigation of charge transport phenomena in undiluted semisolid redox media. The redox site chosen is ferrocene, but the overall approach should be general for designing imidazolium-based molten salts. The ferrocene is attached to imidazolium with several structural variations, and preliminary voltammetry of a melt is presented.

Journal Article↗
PubMed2007

Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise.

O-GlcNAcase catalyzes the cleavage of beta-O-linked 2-acetamido-2-deoxy-beta-d-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-alpha-d-glucopyranoso[2,1-d]-Delta2'-thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal beta-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise.

Acetylglucosamine↗
PubMed2002

Color and antioxidant properties of cyanidin-based anthocyanin pigments.

A series of cyanidin-based anthocyanin pigments was investigated to determine the effect of structural variation on a number of chemical and physical properties: CIELAB color coordinates, visual detection thresholds, hydration constants (pK(H)), and in vitro antioxidant activities (ORAC). In addition to individual isolated compounds, purified total pigment isolates from blackberry, elderberry, black carrot, red cabbage, and sweet potato were also examined. Acylation with cinnamic acids shifted color tonality (hue angle) to purple, and markedly increased pK(H) and antioxidant activity, but lowered the visual detection threshold. Glycosidic substitution at the 5 position moved tonalities toward purple and decreased pK(H), and tended to lower the ORAC value, but raised the visual detection threshold. Increasing the number of sugar substituents at the 3 position also affected all of these parameters, however, the extent was not predictable. Antioxidant levels of purified anthocyanin extracts were much higher than expected from anthocyanin content indicating synergistic effect of anthocyanin mixtures.

Anthocyanins↗