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At least 685 records · Page 38Linked to original sources
PubMed2000

The crystal structure of bacillus cereus phosphonoacetaldehyde hydrolase: insight into catalysis of phosphorus bond cleavage and catalytic diversification within the HAD enzyme superfamily.

Phosphonoacetaldehyde hydrolase (phosphonatase) catalyzes the hydrolysis of phosphonoacetaldehyde to acetaldehyde and phosphate using Mg(II) as cofactor. The reaction proceeds via a novel bicovalent catalytic mechanism in which an active-site nucleophile abstracts the phosphoryl group from the Schiff-base intermediate formed from Lys53 and phosphonoacetaldehyde. In this study, the X-ray crystal structure of the Bacillus cereus phosphonatase homodimer complexed with the phosphate (product) analogue tungstate (K(i) = 50 microM) and the Mg(II) cofactor was determined to 3.0 A resolution with an R(cryst) = 0.248 and R(free) = 0.284. Each monomer is made up of an alpha/beta core domain consisting of a centrally located six-stranded parallel beta-sheet surrounded by six alpha-helices. Two flexible, solvated linkers connect to a small cap domain (residues 21-99) that consists of an antiparallel, five-helix bundle. The subunit-subunit interface, formed by the symmetrical packing of the two alpha8 helices from the respective core domains, is stabilized through the hydrophobic effect derived from the desolvation of paired Met171, Trp164, Tyr162, Tyr167, and Tyr176 side chains. The active site is located at the domain-domain interface of each subunit. The Schiff base forming Lys53 is positioned on the cap domain while tungstate and Mg(II) are bound to the core domain. Mg(II) ligands include two oxygens of the tungstate ligand, one oxygen of the carboxylates of Asp12 and Asp186, the backbone carbonyl oxygen of Ala14, and a water that forms a hydrogen bond with the carboxylate of Asp190 and Thr187. The guanidinium group of Arg160 binds tungstate and the proposed nucleophile Asp12, which is suitably positioned for in-line attack at the tungsten atom. The side chains of the core domain residue Tyr128 and the cap domain residues Cys22 and Lys53 are located nearby. The identity of Asp12 as the active-site nucleophile was further evidenced by the observed removal of catalytic activity resulting from Asp12Ala substitution. The similarity of backbone folds observed in phosphonatase and the 2-haloacid dehalogenase of the HAD enzyme superfamily indicated common ancestry. Superposition of the two structures revealed a conserved active-site scaffold having distinct catalytic stations. Analysis of the usage of polar amino acid residues at these stations by the dehalogenases, phosphonatases, phosphatases, and phosphomutases of the HAD superfamily suggests possible ways in which the active site of an ancient enzyme ancestor might have been diversified for catalysis of C-X, P-C, and P-O bond cleavage reactions.

Amino Acid Sequence↗
PubMed2005

HAD superfamily phosphotransferase substrate diversification: structure and function analysis of HAD subclass IIB sugar phosphatase BT4131.

The BT4131 gene from the bacterium Bacteroides thetaiotaomicron VPI-5482 has been cloned and overexpressed in Escherichia coli. The protein, a member of the haloalkanoate dehalogenase superfamily (subfamily IIB), was purified to homogeneity, and its X-ray crystal structure was determined to1.9 A resolution using the molecular replacement phasing method. BT4131 was shown by an extensive substrate screen to be a broad-range sugar phosphate phosphatase. On the basis of substrate specificity and gene context, the physiological function of BT4131 in chitin metabolism has been tentatively assigned. Comparison of the BT4131 structure alpha/beta cap domain structure with those of other type IIB enzymes (phosphoglycolate phosphatase, trehalose-6-phosphate phosphatase, and proteins of unknown function known as PDB entries , , and ) identified two conserved loops (BT4131 residues 172-182 and 118-130) in the alphabetabeta(alphabetaalphabeta)alphabetabeta type caps and one conserved loop in the alphabetabetaalphabetabeta type caps, which contribute residues for contact with the substrate leaving group. In BT4131, the two loops contribute one polar and two nonpolar residues to encase the displaced sugar. This finding is consistent with the lax specificity BT4131 has for the ring size and stereochemistry of the sugar phosphate. In contrast, substrate docking showed that the high-specificity phosphoglycolate phosphatase (PDB entry ) uses a single substrate specificity loop to position three polar residues for interaction with the glycolate leaving group. We show how active site "solvent cages" derived from analysis of the structures of the type IIB HAD phosphatases could be used in conjunction with the identity of the residues stationed along the cap domain substrate specificity loops, as a means of substrate identification.

Amino Acid Sequence↗
PubMed2005

Diversification of hydrothermal reaction products induced by naphthalene molecules.

Hydrothermal reactions in the system of Ni(II), 1,3,5-benzenetricarboxylic acid (btcH3), and 4,4'-bipyridine (bpy) with or without naphthalene produced three new coordination polymers, [Ni2(bpy)3(btcH)2.(H2O)].(H2O) (2), [Ni2(bpy)2(btcH)2].(C10H8)3 (3), and Ni(bpy)(btcH2)2 (4), in addition to previously reported [Ni2(bpy)2(btcH)2].(C10H8)(0.75).H2O (1). Polymer 2 is the only product when naphthalene is absent in the reaction, and it is composed of 2D layers of coordination polymers with guest water molecules between them. When naphthalene is added to the system, compounds 1, 3, or 4 are formed depending on composition. Compound 3 has a 3D framework structure with naphthalene guests, and 4 has a 1D chainlike structure with no guest. Details of the synthesis condition and crystal structures of each compound are discussed. Crystallographic data: 2, C2/c, a = 22.500(3) A, b = 20.053(3) A, c = 19.625(3) A, beta = 99.314(3) degrees ; 3, P2(1)/c, a = 11.248(2) A, b = 16.801(4) A, c = 14.945(3) A, beta = 103.732(4) degrees ; 4, C2/c, a = 10.692(2) A, b = 11.114(3) A, c = 21.962(5) A, beta = 106.268(11) degrees.

Journal Article↗
PubMed2006

Modulated preparation and structural diversification of ZnII and CdII metal-organic frameworks with a versatile building block 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol.

Four novel Zn(II) and Cd(II) metal-organic coordination polymers with a versatile building block 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol (Hpyt) have been prepared under different conditions. [Zn3(pyt)4(OH)2]n (1) and [Cd(pyt)(HCOO)]n (3) were obtained through a solvothermal method, whereas {[Zn(pyt)2(H2O)(2)].(DMF)2}n (2) and {[Cd(pyt)2].CHCl3}n (4) were isolated under general conditions. X-ray single-crystal diffraction indicates that the anionic ligand pyt adopts a thioamide isomer in 1, 2, and 4, but a thiolate form in 3. Four types of binding modes involving monodentate (eta-N(oxa)), bidentate (mu-N(py),N(oxa), or mu-N(py),S,S) and tridentate (mu-N(py),N(oxa),S) are observed. The discrepancy of the synthetic routes and metal-coordination preferences facilitates the production of the final crystalline materials with distinct network structures, including a 1D zigzag array of 1 with dangling arms, a common 2D (4,4) coordination layer of 2, a decorated 3D alpha-Po network of 3, and an unprecedented (3,6)-connected 3D framework of 4 with a (4(2).6)2(4(2).6(2).8(7).10(2)) topology. Notably, the hydrolysis of DMF solvates leads to the formation of formate ions, being a component in the structure of 3. Complexes 2 and 4 show 1D channels in which the solvates are accommodated, and even after the exclusion of these guests, the porous host frameworks are still retained. Thermal stability and gas adsorption properties have also been studied.

Journal Article↗
PubMed2006

Natural product diversification using a non-natural cofactor analogue of S-adenosyl-L-methionine.

Adenosine analogues bearing either 5'-aziridine or 5'-N-mustard electrophiles are methyltransferase-dependent DNA alkylating agents. We present here a novel synthetic cofactor bearing a pendant 5'-amino acid N-mustard. Unlike previously studied synthetic cofactors, this material is very efficiently used by the natural product biosynthetic enzyme rebeccamycin methyltransferase (RebM) to generate a number of new rebeccamycin analogues. These data promote the notion that natural product methyltransferases can be used with non-natural cofactors to enhance the molecular diversity of natural product analogues for drug discovery. To our knowledge, this is the first documentation of a biological methyltransferase, other than DNA methyltransferases, that can exploit such synthetic cofactors.

Alkylation↗
PubMed2005

Neoglycorandomization and chemoenzymatic glycorandomization: two complementary tools for natural product diversification.

In an effort to explore the contribution of the sugar constituents of pharmaceutically relevant glycosylated natural products, chemists have developed glycosylation methods that are amenable to the generation of libraries of analogues with a broad array of glycosidic attachments. Recently, two complementary glycorandomization strategies have been described, namely, neoglycorandomization, a chemical approach based on a one-step sugar ligation reaction that does not require any prior sugar protection or activation, and chemoenzymatic glycorandomization, a biocatalytic approach that relies on the substrate promiscuity of enzymes to activate and attach sugars to natural products. Since both methods require reducing sugars, this review first highlights recent advances in monosaccharide generation and then follows with an overview of recent progress in the development of neoglycorandomization and chemoenzymatic glycorandomization.

Aldehyde-Lyases↗
PubMed2001

Convenient synthesis and diversification of dehydroalaninyl phosphinic peptide analogues.

[structure: see text]. Dehydroalaninyl phosphinic dipeptide analogues were synthesized, via an efficient tandem Arbuzov addition/allylic rearrangement, in high yields. The susceptibility of the conjugate system to 1,4 nucleophilic additions was investigated. C-Elongation of the dipeptides was performed, and the efficiency of 1,4 addition to the resulting acrylamidic moiety was evaluated. Derivatization of such phosphinic templates is a powerful approach for rapid access to large number of phosphinic pseudopeptides bearing various side chains in the P1' position.

Alanine↗
PubMed2005

Late-stage intermolecular CH activation for lead diversification: a highly chemoselective oxyfunctionalization of the C-9 position of potent bryostatin analogues.

Treatment of highly potent and densely functionalized bryostatin analogue 1 with dimethyldioxirane afforded the C-9 hydroxylated hemiketal 2 via oxyfunctionalization of the C9-CH bond, one of 12 CH bonds geminal to an oxygen substituent in 1. When bryostatin analogue 3 was subjected to identical conditions, oxidation of a C-26 secondary hydroxyl group was found to compete with C-9 hydroxylation. Complete selectivity for C-9 hydroxylation was restored upon acylation of the C-26 secondary alcohol.

Bryostatins↗
PubMed1999

Systematics of the Eucestoda: advances toward a new phylogenetic paradigm, and observations on the early diversification of tapeworms and vertebrates.

Evolutionary relationships of the Eucestoda have received intense but sporadic attention over the past century. Since 1996, the landscape has dramatically changed with respect to our knowledge of the phylogenetic relationships among the tapeworms. The 2nd International Workshop for Tapeworm Systematics (IWTS) held in Lincoln, Nebraska in October of that year provided the catalyst for development of novel hypotheses for inter- and intraordinal phylogeny. The working-group structure of the 2nd IWTS and results of phylogenetic studies are briefly introduced in the present manuscript. Higher-level phylogenies derived from parsimony analysis of independent data bases representing comparative morphology or molecular sequences were largely congruent and supported monophyly for the Eucestoda. The Caryophyllidea are basal; difossate forms such as the Pseudophyllidea are primitive; tetrafossates including the Tetraphyllidea, Proteocephalidea, Nippotaeniidea, Tetrabothriidea and Cyclophyllidea are derived; and hypotheses differed in the placement of the Trypanorhyncha and the Diphyllidea. These studies may provide a foundation for resolution of inter- and intra-ordinal relationships for the tapeworms. Additionally, the first comprehensive phylogenetic hypotheses for the Pseudophyllidea, Diphyllidea, Trypanorhyncha, the paraphyletic Tetraphyllidea + Lecanicephalidea, Proteocephalidea and Cyclophyllidea were developed during and subsequent to the 2nd IWTS. The stage is now set for continued and rapid advances in our understanding of the eucestodes. These studies have also served to re-emphasise the rich genealogical diversity of tapeworms and the temporally deep history for their origin. A co-evolutionary history and radiation of eucestodes may involve deep co-speciation with vertebrate host taxa, accompanied by some level of colonisation and extinction, extending into the Palaeozoic, minimally 350-420 million years ago.

Animals↗
PubMed2004

New karyotypes and some considerations about the chromosomal diversification of Ctenomys minutus (Rodentia: Ctenomyidae) on the coastal plain of the Brazilian state of Rio Grande do Sul.

The dominant mammals occupying the subterranean niche in South America are rodents of the genus Ctenomys, which form a large group of 56 species with chromosome numbers ranging from 2n = 10 to 70. In southern Brazil, Ctenomys minutus is the species with the widest geographic distribution, inhabiting sandy fields and dunes extending from Jaguaruna beach in the state of Santa Catarina to the town of São José do Norte in the state of Rio Grande do Sul. Eleven karyotypes (2n = 42; 2n = 46a; 2n = 46b; 2n = 47a; 2n = 47b; 2n = 48a; 2n = 48b; 2n = 49a; 2n = 49b; 2n = 50a and 2n = 50b) were described for this species and zones of hybridization are also known. A sample of 51 C. minutus specimens was collected from five sampling sites about 20km apart along the coastal plain of Rio Grande do Sul between the municipalities of Tavares (31 degrees 23'S 51 degrees 09'W) and São José do Norte (31 degrees 52'S 51 degrees 54'W). We were able to extend the known geographic distribution of C. minutus by 90 km, from Tavares southwards to São José do Norte. During our study we found five karyotypes (2n = 46b, 47b, 48b, 49b and 50b), four of which (2n = 47b, 48b, 49b and 50b) have not previously been described for this species.

Animals↗
PubMed2004

Diversification of genes encoding mei2 -like RNA binding proteins in plants.

A predominantly plant-based family of genes encoding RNA binding proteins is defined by the presence of a highly conserved RNA binding motif first described in the mei2 gene of the fission yeast Schizosaccharomyces pombe. In silico analyses reveal nine mei2 -like genes in Arabidopsis thaliana and six in Oryza sativa. These predicted genes group into four distinct clades, based on overall sequence similarity and subfamily-specific sequence elements. In situ analysis show that Arabidopsis genes from one of these clades, TEL1 and TEL2, are specifically expressed in central zone of the shoot apical meristem and the quiescent center of the root apical meristem, suggesting that they may somehow function to maintain indeterminacy in these tissues. By contrast, members of two sister clades, AML1 through AML5, are expressed more broadly, a trend that was confirmed by Q-PCR analysis. mei2 -like transcripts with similar sequences showed similar expression patterns, suggesting functional redundancy within the four clades. Phenotypic analyses of lines that contain T-DNA insertions to individual mei2 -like genes reveal no obvious phenotypes, further suggesting redundant activities for these gene products.

Alternative Splicing↗
PubMed2002

Natural selection and the diversification of vertebrate immune effectors.

The molecules of the vertebrate immune system provide some of the best documented examples of natural selection acting at the molecular level. The major histocompatibility complex (MHC) molecules are a family of highly polymorphic loci whose products present peptides to T cells. Four distinct lines of evidence support the hypothesis that the natural selection acts to maintain MHC polymorphism: (1) evidence from the unusual allelic frequency distribution seen at MHC loci; (2) evidence from the pattern of nucleotide substitution at MHC loci, which shows an enhanced rate of nonsynonymous (amino acid-altering) substitution in the codons encoding the peptide-binding region of the molecules; (3) the existence of long-lasting polymorphisms at certain MHC loci; and (4) the fact that introns at MHC loci are homogenized by recombination and subsequent genetic drift. Certain other immune system gene families provide evidence that natural selection has acted to create diversity among family members. Examples include molecules of the specific immune system (such as immunoglobulin V region genes) and molecules of the innate immune system (such as defensins).

Alleles↗
PubMed2005

How subjective grouping of options influences choice and allocation: diversification bias and the phenomenon of partition dependence.

The authors argue that people's tendency to diversify their allocations of money and consumption choices over alternatives gives rise to decisions that vary systematically with the subjective grouping of available options. These subjective groupings are influenced by subtle variations in the presentation of options or elicitation of preferences. Studies 1-4 demonstrate such "partition dependence" in allocations of money to beneficiaries, consumption experiences to future time periods, and choices to a menu of consumption options. Study 5 documents weaker partition dependence among individuals with greater relevant experience discriminating among options, and Study 6 shows that the effect is attenuated among participants with stronger or more accessible intrinsic preferences.

Choice Behavior↗
PubMed2000

Diversification of haematopoietic stem cells to specific lineages.

Diverse types of blood cell (lineages) are produced from rare haematopoietic stem cells that reside in the bone marrow. This process, known as haematopoiesis, provides a valuable model for examining how genetic programs are established and executed in vertebrates, and also how homeostasis of blood formation is altered in leukaemias. So, how does an apparently small group of critical lineage-restricted nuclear regulatory factors specify the diversity of haematopoietic cells? Recent findings not only indicate how this may be achieved but also show the extraordinary plasticity of tissue stem cells in vivo.

Animals↗
PubMed1995

A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks.

Immunoglobulin and T-cell receptor (TCR) molecules are central to the adaptive immune system. Sequence conservation, similarities in domain structure, and usage of similar recombination signal sequences and recombination machinery indicate that there was probably a time during evolution when an ancestral receptor diverged to the modern-day immunoglobulin and TCR. Other molecules that undergo rearrangement have not been described in vertebrates, nor have intermediates been identified that have features of both these gene families. We report here the isolation of a new member of the immunoglobulin superfamily from the nurse shark, Ginglymostoma cirratum, which contains one variable and five constant domains and is found as a dimer in serum.

Amino Acid Sequence↗