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The Ascorbic Acid Metabolism of Fifty College Women in the North Texas State Teachers College
Date: 1943
Creator: Harshbarger, Marjorie
Description: A study of the ascorbic acid metabolism of a group of fifty college women in the North Texas State Teachers College between the months of April and July, 1943.
Contributing Partner: UNT Libraries
Chemical Analysis of the Bottom Deposits of Artificial Lakes with Special Emphasis on Lake Dallas
Date: 1940
Creator: Patrick, Paul V.
Description: This study is for the purpose of determining the chemical content of typical artificial reservoir bottom deposits.
Contributing Partner: UNT Libraries
A Chemical, Physical, and Biological Investigation of the Total Suspended and Dissolved Substances in Lake Dallas with Emphasis on Sanitation
Date: 1942
Creator: Eads, Ewin A.
Description: The purpose of this investigation is to determine the suspended organic matter and the total phosphorus in the waters of Lake Dallas and to evaluate these findings. Since organic matter floating in lakes is largely composed of minute plants, animals, and detritus derived from animals and plants, the fertilizing effect of phosphorus must be considered as an integral part of this problem.
Contributing Partner: UNT Libraries
A Comparison of the Achievements of Science and Non-Science Majors Enrolled in General Chemistry at North Texas State College
Date: 1951
Creator: Brogdon, Billie R.
Description: It is the specific purpose of this investigation to determine the difference, if any, in the amount of practical, everyday chemistry learned by the science majors as opposed to the non-science majors enrolled in general chemistry at the North Texas State College during the school year 1950-1951.
Contributing Partner: UNT Libraries
Manufacturer [Sic] of Densified-Refuse Derived Fuel (d-RDF) Pellets and Methods for the Determination of d-RDF Pellet Densities
Date: December 1986
Creator: Attili, Bassam Saleem
Description: There are 150 million tons of Municipal Solid Waste (MSW) annually produced in the United States, which is approximately equivalent to 150 million barrels of oil. MSW production is inexhaustible, and is increasing on an annual per capita basis of approximately three per cent. After controlling the moisture and adding a binder, the combustible portion of MSW was converted to pellets. The objects of this project were to 1) evaluate the binder, 2) prepare the pellets, and 3) evaluate the pellets with regard to density. The manufacture of pellets was conducted at the Naval Air Station, Jacksonville, Florida. The evaluation of the binders and the pellets was done at North Texas State University (NTSU). There were three procedures for measuring the density. The first, using water displacement, was from the American Society for Testing and Material (ASTM). The second, using wax coating, was also from ASTM. The third, using sharply-cut cylindrical pellets, was developed at NTSU.
Contributing Partner: UNT Libraries
A Mineral Analysis of the Henrietta Water Supply
Date: 1941
Creator: Selvidge, R. F.
Description: The water which supplies the city of Henrietta, Clay County, Texas, is obtained from the Little Wichita River. A concrete dam was built across the river at a point about a mile and a half north of town.
Contributing Partner: UNT Libraries
Quantitative Chemical Analysis of the Soils of Erath County, Texas
Date: June 1938
Creator: Barnes, Benjamin F.
Description: A chemical analysis of representative samples of Windthorst sand, Denton sand, and Denton clay has been made, and this analysis shows that their composition has a strict correlation with respect to their geological origins. The analyses of the different soils have shown the Windthorst sand to be highly deficient in all of the essential elements, whereas the Denton sand is deficient in only one; namely, phosphorus. The analysis of the Denton clay showed it to be highly fertile. From the consideration of the pH and the lime content, it has been determined to some extent what crops will grow in each of the soils.
Contributing Partner: UNT Libraries
The Storage of Organic Matter in Bottom Deposits of Lake Dallas
Date: 1941
Creator: Williams, Cyrus Paul
Description: The purpose of this investigation is to find which season of the year organic matter increases most in the bottom deposits of Lake Dallas, the reason for the increase, and the amount of organic matter increase from year to year. It is hoped that this study will be beneficial in understanding the conditions in artificial reservoirs.
Contributing Partner: UNT Libraries


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The Hammer and KCRW 89.9FM present Summer of Soul, four free nights of live music that shine a light on the timeless power of soul music with a diverse line-up of talented musical acts in the Hammer's courtyard.
A happy hour with cash bar starts at 6:30 p.m. KCRW DJ sets start at 7:30 p.m., and live music starts at 8:15 p.m. The museum's gallery hours will be extended to 9 p.m. so guests can enjoy the Hammer exhibitions.
Location: Courtyard
Ticketing: This drop-in program is not ticketed.
Parking: Under the museum, $6 flat rate after 6 p.m. Cash only.
All Hammer public programs are free and made possible by a major gift from the Dream Fund at UCLA.
Generous support is also provided by Susan Bay Nimoy and Leonard Nimoy, Good Works Foundation and Laura Donnelley, an anonymous donor, and all Hammer members.
The Hammer's digital presentation of its public programs is made possible by the Billy and Audrey L. Wilder Foundation.

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Body with Hypnosis is a bunch of highly trained professionals that are dedicated to conforming to the highest standards in our profession; and are dedicated to helping our clients get results through hypnotherapy. Separate multiple addresses with commas.
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Ligand Binding and Substrate Discrimination by UDP-Galactopyranose Mutase
Gruber, Todd D.
Borrok, M. Jack
Westler, William M.
Forest, Katrina T.
Kiessling, Laura L.
Journal of molecular biology
Galactofuranose (Galf) residues are present in the cell wall glycoconjugates of numerous pathogenic microbes. UDP-galactofuranose (UDP-Galf), the biosynthetic precursor of Galf-containing glycoconjugates, is produced from UDP-galactopyranose (UDP-Galp) by the flavoenzyme UDP-galactopyranose mutase (UGM). The gene encoding UGM (glf) is essential for the viability of pathogens, including Mycobacterium tuberculosis, and this finding underscores the need to understand how UGM functions. Considerable effort has been devoted to elucidating the catalytic mechanism of UGM, but progress has been hindered by a lack of structural data for an enzyme-substrate complex. Such data could reveal not only the substrate binding interactions but how UGM can act preferentially on two very different substrates, UDP-Galp and UDP-Galf, yet avoid other structurally related UDP-sugars present in the cell. Herein, we describe the first structure of a UGM-ligand complex, which provides insight into the catalytic mechanism and the molecular basis for substrate selectivity. The structure of UGM from Klebsiella pneumoniae bound to the substrate analog UDP-glucose (UDP-Glc) was solved by X-ray crystallographic methods and refined to 2.5 Å resolution. The ligand is proximal to the cofactor, a finding that is consistent with a proposed mechanism in which the reduced flavin engages in covalent catalysis. Despite this proximity, the glucose ring of the substrate analog is positioned such that it disfavors covalent catalysis. This orientation is consistent with data indicating that UDP-Glc is not a substrate for UGM. The relative binding orientations of UDP-Galp and UDP-Glc were compared using saturation transfer difference-NMR. The results indicate that the uridine moiety occupies a similar location in both ligand complexes, and this relevant binding mode is defined by our structural data. In contrast, the orientations of the glucose and galactose sugar moieties differ. To understand the consequences of these differences, we derived a model for the productive UGM-substrate complex that highlights interactions that can contribute to catalysis and substrate discrimination.
UDP-galactopyranose mutase; Glf; cell wall biosynthesis; mycobacteria; galactofuranose
Related Articles
Comparison of Dynamics of Wildtype and V94M Human UDP-Galactose 4-Epimerase – A computational perspective on severe Epimerase-deficiency Galactosemia
Timson, David J.
Lindert, Steffen
UDP-galactose 4′-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr-157) and the enzyme-bound NAD+ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (kcat), with less substantial effects on Km. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N-acetylgalactosemine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia.
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Identification, subcellular localization, biochemical properties, and high-resolution crystal structure of Trypanosoma brucei UDP-glucose pyrophosphorylase
Mariño, Karina
Güther, Maria Lucia Sampaio
Wernimont, Amy K
Amani, Mernhaz
Hui, Raymond
Ferguson, Michael AJ
The protozoan parasite Trypanosoma brucei is the causative agent of the cattle disease Nagana and human African sleeping sickness. Glycoproteins play key roles in the parasite's survival and infectivity, and the de novo biosyntheses of the sugar nucleotides UDP-galactose (UDP-Gal), UDP-N-acetylglucosamine, and GDP-fucose have been shown to be essential for their growth. The only route to UDP-Gal in T. brucei is through the epimerization of UDP-glucose (UDP-Glc) by UDP-Glc 4′-epimerase. UDP-Glc is also the glucosyl donor for the unfolded glycoprotein glucosyltransferase (UGGT) involved in glycoprotein quality control in the endoplasmic reticulum and is the presumed donor for the synthesis of base J (β-d-glucosylhydroxymethyluracil), a rare deoxynucleotide found in telomere-proximal DNA in the bloodstream form of T. brucei. Considering that UDP-Glc plays such a central role in carbohydrate metabolism, we decided to characterize UDP-Glc biosynthesis in T. brucei. We identified and characterized the parasite UDP-glucose pyrophosphorylase (TbUGP), responsible for the formation of UDP-Glc from glucose-1-phosphate and UTP, and localized the enzyme to the peroxisome-like glycosome organelles of the parasite. Recombinant TbUGP was shown to be enzymatically active and specific for glucose-1-phosphate. The high-resolution crystal structure was also solved, providing a framework for the design of potential inhibitors against the parasite enzyme.
kinetoplastids; sugar nucleotide metabolism; Trypanosoma brucei; UDP-glucose; UDP-glucose pyrophosphorylase
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Galactose Starvation in a Bloodstream Form Trypanosoma brucei UDP-Glucose 4′-Epimerase Conditional Null Mutant
Urbaniak, Michael D.
Turnock, Daniel C.
Ferguson, Michael A. J.
Eukaryotic Cell
Galactose metabolism is essential for the survival of Trypanosoma brucei, the etiological agent of African sleeping sickness. T. brucei hexose transporters are unable to transport galactose, which is instead obtained through the epimerization of UDP-glucose to UDP-galactose catalyzed by UDP-glucose 4′-epimerase (galE). Here, we have characterized the phenotype of a bloodstream form T. brucei galE conditional null mutant under nonpermissive conditions that induced galactose starvation. Cellular levels of UDP-galactose dropped rapidly upon induction of galactose starvation, reaching undetectable levels after 72 h. Analysis of extracted glycoproteins by ricin and tomato lectin blotting showed that terminal β-d-galactose was virtually eliminated and poly-N-acetyllactosamine structures were substantially reduced. Mass spectrometric analysis of variant surface glycoprotein confirmed complete loss of galactose from the glycosylphosphatidylinositol anchor. After 96 h, cell division ceased, and electron microscopy revealed that the cells had adopted a morphologically distinct stumpy-like form, concurrent with the appearance of aberrant vesicles close to the flagellar pocket. These data demonstrate that the UDP-glucose 4′-epimerase is essential for the production of UDP-galactose required for galactosylation of glycoproteins and that galactosylation of one or more glycoproteins, most likely in the lysosomal/endosomal system, is essential for the survival of bloodstream form T. brucei.
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UDP-Galactose 4′-Epimerase Activities toward UDP-Gal and UDP-GalNAc Play Different Roles in the Development of Drosophila melanogaster
Daenzer, Jennifer M. I.
Sanders, Rebecca D.
Hang, Darwin
Fridovich-Keil, Judith L.
PLoS Genetics
In both humans and Drosophila melanogaster, UDP-galactose 4′-epimerase (GALE) catalyzes two distinct reactions, interconverting UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc) in the final step of the Leloir pathway of galactose metabolism, and also interconverting UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc). All four of these UDP-sugars serve as vital substrates for glycosylation in metazoans. Partial loss of GALE in humans results in the spectrum disorder epimerase deficiency galactosemia; partial loss of GALE in Drosophila melanogaster also results in galactose-sensitivity, and complete loss in Drosophila is embryonic lethal. However, whether these outcomes in both humans and flies result from loss of one GALE activity, the other, or both has remained unknown. To address this question, we uncoupled the two activities in a Drosophila model, effectively replacing the endogenous dGALE with prokaryotic transgenes, one of which (Escherichia coli GALE) efficiently interconverts only UDP-gal/UDP-glc, and the other of which (Plesiomonas shigelloides wbgU) efficiently interconverts only UDP-galNAc/UDP-glcNAc. Our results demonstrate that both UDP-gal and UDP-galNAc activities of dGALE are required for Drosophila survival, although distinct roles for each activity can be seen in specific windows of developmental time or in response to a galactose challenge. By extension, these data also suggest that both activities might play distinct and essential roles in humans.
Author Summary
In this manuscript we apply a fruit fly model to explore the relative contributions of each of two different activities attributed to a single enzyme—UDP-galactose 4′-epimerase (GALE); partial impairment of human GALE results in the potentially severe metabolic disorder epimerase deficiency galactosemia. One GALE activity involves interconverting UDP-galactose and UDP-glucose in the Leloir pathway of galactose metabolism; the other activity involves interconverting UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. We have previously demonstrated that complete loss of GALE is embryonic lethal in fruit flies, but it was unclear which GALE activity loss was responsible for the outcome. Using genetically modified fruit flies, we were able to remove or give back each GALE activity individually at different times in development and observe the consequences. Our results demonstrate that both GALE activities are essential, although they play different roles at different times in development. These results provide insight into the normal functions of GALE and also have implications for diagnosis and intervention in epimerase deficiency galactosemia.
Related Articles
RATIONAL PROTEOMICS V: STRUCTURE-BASED MUTAGENESIS HAS REVEALED KEY RESIDUES RESPONSIBLE FOR SUBSTRATE RECOGNITION AND CATALYSIS BY THE DEHYDROGENASE AND ISOMERASE ACTIVITIES IN HUMAN 3β-HYDROXYSTEROID DEHYDROGENASE/ISOMERASE TYPE 1
Pletnev, Vladimir Z.
Thomas, James L.
Rhaney, Felicia L.
Holt, Lynley S.
Scaccia, Launa A.
Umland, Timothy C.
Duax, William L.
The Journal of steroid biochemistry and molecular biology
Mammalian 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) is a member of the short chain dehydrogenase/reductase. It is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones. A three dimensional model of a ternary complex of human 3β-HSD type 1 (3β-HSD_1) with an NAD cofactor and androstenedione product has been developed based upon X-ray structures of the ternary complex of E. coli UDP-galactose 4-epimerase (UDPGE) with an NAD cofactor and substrate (PDB_AC: 1NAH) and the ternary complex of human type 1 17β-hydroxysteroid dehydrogenase (17β-HSD_1) with an NADP cofactor and androstenedione (PDB_AC: 1QYX). The dimeric structure of the enzyme was built from two monomer models of 3β-HSD_1 by respective 3D superposition with A and B subunits of the dimeric structure of Streptococcus suis DTDP-D-glucose 4,6-dehydratase (PDB_AC: 1KEP). The 3D model structure of 3β-HSD_1 has been successfully used for the rational design of mutagenic experiments to further elucidate the key substrate binding residues in the active site as well as the basis for dual function of the 3β-HSD_1 enzyme. The structure based mutant enzymes, Asn100Ser, Asn100Ala, Glu126Leu, His232Ala, Ser322Ala and Asn323Leu, have been constructed and functionally characterized. The mutagenic experiments have confirmed the predicted roles of the His232 and Asn323 residues in recognition of the 17-keto group of the substrate and identified Asn100 and Glu126 residues as key residues that participate for the dehydrogenase and isomerization reactions respectively.
3β-hydroxysteroid dehydrogenase; short-chain oxidoreductase; 3D model structure; bioinformatics; rational proteomics; structure based mutagenesis; structure-function relationship
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Structural Insight into the Unique Substrate Binding Mechanism and Flavin Redox State of UDP-galactopyranose Mutase from Aspergillus fumigatus*
van Straaten, Karin E.
Routier, Françoise H.
Sanders, David A. R.
The Journal of Biological Chemistry
Background: UDP-galactopyranose mutase (UGM) is a critical enzyme for the proper formation of the cell wall of pathogenic microbes.
Results: The structure of UGM in complex with substrate reveals novel features of substrate binding.
Conclusion: Oxidation and reduction of the flavin cofactor causes rearrangements in the active site that affect substrate binding.
Significance: These are the first structures of UGM from a eukaryotic pathogen.
UDP-galactopyranose mutase (UGM) is a flavin-containing enzyme that catalyzes the reversible conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). As in prokaryotic UGMs, the flavin needs to be reduced for the enzyme to be active. Here we present the first eukaryotic UGM structures from Aspergillus fumigatus (AfUGM). The structures are of UGM alone, with the substrate UDP-Galp and with the inhibitor UDP. Additionally, we report the structures of AfUGM bound to substrate with oxidized and reduced flavin. These structures provide insight into substrate recognition and structural changes observed upon substrate binding involving the mobile loops and the critical arginine residues Arg-182 and Arg-327. Comparison with prokaryotic UGM reveals that despite low sequence identity with known prokaryotic UGMs the overall fold is largely conserved. Structural differences between prokaryotic UGM and AfUGM result from inserts in AfUGM. A notable difference from prokaryotic UGMs is that AfUGM contains a third flexible loop (loop III) above the si-face of the isoalloxazine ring that changes position depending on the redox state of the flavin cofactor. This loop flipping has not been observed in prokaryotic UGMs. In addition we have determined the crystals structures and steady-state kinetic constants of the reaction catalyzed by mutants R182K, R327K, R182A, and R327A. These results support our hypothesis that Arg-182 and Arg-327 play important roles in stabilizing the position of the diphosphates of the nucleotide sugar and help to facilitate the positioning of the galactose moiety for catalysis.
Carbohydrate-binding Protein; Cell Wall; Enzyme Mutation; Enzyme Structure; Membrane Biogenesis
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Preliminary X-ray crystallographic studies of UDP-glucose-4-epimerase from Aspergillus nidulans
Dalrymple, Sean A.
Sheoran, Inder
Kaminskyj, Susan G. W.
Sanders, David A. R.
Acta Crystallographica Section F: Structural Biology and Crystallization Communications
2011;67(Pt 8):885-887.
UDP-glucose-4-epimerase from A. nidulans has been crystallized as a complex with the substrate UDP-galactose using the microbatch method under paraffin oil.
UDP-glucose-4-epimerase (GALE) from Aspergillus nidulans was overexpressed in Escherichia coli, purified via His-tag affinity chromatography and cocrystallized with UDP-galactose using the microbatch method. The crystals diffracted to 2.4 Å resolution using synchrotron radiation on the Canadian Light Source 08ID-1 beamline. Examination of the data with d*TREK revealed nonmerohedral twinning, from which a single lattice was ultimately extracted for processing. The final space group was found to be C2, with unit-cell parameters a = 66.13, b = 119.15, c = 161.42 Å, β = 98.48°. An initial structure solution has been obtained via molecular replacement employing human GALE (PDB entry 1hzj) as a template model.
epimerases; galactose metabolism; short-chain dehydrogenases; Leloir pathway
Related Articles
Altered cofactor binding affects stability and activity of human UDP-galactose 4′-epimerase: implications for type III galactosemia
McCorvie, Thomas J.
Liu, Ying
Frazer, Andrew
Gleason, Tyler J.
Fridovich-Keil, Judith L.
Timson, David J.
Biochimica et biophysica acta
Deficiency of UDP-galactose 4′-epimerase is implicated in type III galactosemia. Two variants, p.K161N-hGALE and p.D175N-hGALE, have been previously found in combination with other alleles in patients with a mild form of the disease. Both variants were studied in vivo and in vitro and showed different levels of impairment. p.K161N-hGALE was severely impaired with substantially reduced enzymatic activity, increased thermal stability, reduced cofactor binding and inability to rescue the galactose-sensitivity of gal10-null yeast. Interestingly p.K161N-hGALE showed less impairment of activity with UDP-N-acetylgalactosamine in comparison to UDP-galactose. Differential scanning fluorimetry revealed that p.K161N-hGALE was more stable than the wild-type protein and only changed stability in the presence of UDP-N-acetylglucosamine and NAD+. p.D175N-hGALE essentially rescued the galactose-sensitivity of gal10-null yeast, was less stable than the wild-type protein but showed increased stability in the presence of substrates and cofactor. We postulate that p.K161N-hGALE causes its effects by abolishing an important interaction between the protein and the cofactor, whereas p.D175N-hGALE is predicted to remove a stabilizing salt bridge between the ends of two α-helices that contain residues that interact with NAD+. These results suggest that the cofactor binding is dynamic and that its loss results in significant structural changes that may be important in disease causation.
Type III galactosemia; yeast model; GALE; disease-associated mutation; UDP-galactose 4′-epimerase; Differential scanning fluorimetry
Related Articles
UDP-xylose and UDP-galactose synthesis in Trichomonas vaginalis
Rosenberger, Andrea F.N.
Hangelmann, Lydia
Hofinger, Andreas
Wilson, Iain B.H.
Molecular and Biochemical Parasitology
Graphical abstract
The genes encoding the enzymes required for UDP-xylose and UDP-galactose synthesis in Trichomonas vaginalis have been identified and the products of the recombinant enzymes analysed.
► Xylose and galactose are components of Trichomonas vaginalis glycans. ► T. vaginalis UDP-xylose synthase and UDP-galactose epimerase genes identified. ► Enzymes were expressed in recombinant form, purified and assayed.
The presence of xylose and galactose residues in the structure of trichomonad lipoglycans was indicated by previous studies and the modification of any glycoconjugate with either monosaccharide requires the respective presence of the nucleotide sugars, UDP-xylose and UDP-galactose. Biosynthesis of UDP-xylose de novo is mediated by UDP-xylose synthase (UXS; UDP-glucuronic acid decarboxylase), which converts UDP-glucuronic acid to UDP-xylose, whereas UDP-galactose can be generated from UDP-glucose by UDP-galactose epimerases (GalE). Trichomonas vaginalis cDNAs, encoding proteins with homology to these enzymes from other eukaryotes, were isolated. The recombinant T. vaginalis UDP-xylose synthase and UDP-galactose epimerase were expressed in Escherichia coli and tested via high pressure liquid chromatography to demonstrate their enzymatic activities. Thereby, in this first report on enzymes involved in glycoconjugate biosynthesis in this organism, we demonstrate the existence of xylose and galactose synthesising pathways in T. vaginalis.
GalE, UDP-galactose-4′-epimerase; UDP-GlcA, UDP-glucuronic acid; UXS, UDP-xylose synthase; UDP-xylose; UDP-galactose; Trichomonas vaginalis
Related Articles
In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants
Setzer, William N.
Ogungbe, Ifedayo V.
PLoS Neglected Tropical Diseases
Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. HAT is a re-emerging disease and currently threatens millions of people in sub-Saharan Africa. Many affected people live in remote areas with limited access to health services and, therefore, rely on traditional herbal medicines for treatment.
A molecular docking study has been carried out on phytochemical agents that have been previously isolated and characterized from Nigerian medicinal plants, either known to be used ethnopharmacologically to treat parasitic infections or known to have in-vitro antitrypanosomal activity. A total of 386 compounds from 19 species of medicinal plants were investigated using in-silico molecular docking with validated Trypanosoma brucei protein targets that were available from the Protein Data Bank (PDB): Adenosine kinase (TbAK), pteridine reductase 1 (TbPTR1), dihydrofolate reductase (TbDHFR), trypanothione reductase (TbTR), cathepsin B (TbCatB), heat shock protein 90 (TbHSP90), sterol 14α-demethylase (TbCYP51), nucleoside hydrolase (TbNH), triose phosphate isomerase (TbTIM), nucleoside 2-deoxyribosyltransferase (TbNDRT), UDP-galactose 4′ epimerase (TbUDPGE), and ornithine decarboxylase (TbODC).
This study revealed that triterpenoid and steroid ligands were largely selective for sterol 14α-demethylase; anthraquinones, xanthones, and berberine alkaloids docked strongly to pteridine reductase 1 (TbPTR1); chromenes, pyrazole and pyridine alkaloids preferred docking to triose phosphate isomerase (TbTIM); and numerous indole alkaloids showed notable docking energies with UDP-galactose 4′ epimerase (TbUDPGE). Polyphenolic compounds such as flavonoid gallates or flavonoid glycosides tended to be promiscuous docking agents, giving strong docking energies with most proteins.
This in-silico molecular docking study has identified potential biomolecular targets of phytochemical components of antitrypanosomal plants and has determined which phytochemical classes and structural manifolds likely target trypanosomal enzymes. The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations.
Author Summary
Traditional herbal medicine continues to play a key role in health, particularly in remote areas with limited access to "modern medicines". Many plants are used in traditional Nigerian medicine to treat parasitic diseases. While many of these plants have shown notable activity against parasitic protozoa, in most cases the mode of activity is not known. That is, it is not known what biochemical entities are being targeted by the plant chemical constituents. In this work, we have carried out molecular docking studies of known phytochemicals from Nigerian medicinal plants used to treat human African trypanosomiasis (sleeping sickness) with known biochemical targets in the Trypanosoma brucei parasite. The goals of this study were to identify the protein targets that the medicinal plants are affecting and to discern general trends in protein target selectivity for phytochemical classes. In doing so, we have theoretically identified strongly interacting plant chemicals and their biomolecular targets. These results should lead to further research to verify the efficacy of the phytochemical agents as well as delineate possible modifications of the active compounds to increase potency or selectivity.
Related Articles
Elucidation of Substrate Specificity in Aspergillus nidulans UDP-Galactose-4-Epimerase
Dalrymple, Sean A.
Ko, John
Sheoran, Inder
Kaminskyj, Susan G. W.
Sanders, David A. R.
PLoS ONE
The frequency of invasive fungal infections has rapidly increased in recent years. Current clinical treatments are experiencing decreased potency due to severe host toxicity and the emergence of fungal drug resistance. As such, new targets and their corresponding synthetic pathways need to be explored for drug development purposes. In this context, galactofuranose residues, which are employed in fungal cell wall construction, but are notably absent in animals, represent an appealing target. Herein we present the structural and biochemical characterization of UDP-galactose-4-epimerase from Aspergillus nidulans which produces the precursor UDP-galactopyranose required for galactofuranose synthesis. Examination of the structural model revealed both NAD+ and UDP-glucopyranose were bound within the active site cleft in a near identical fashion to that found in the Human epimerase. Mutational studies on the conserved catalytic motif support a similar mechanism to that established for the Human counterpart is likely operational within the A. nidulans epimerase. While the Km and kcat for the enzyme were determined to be 0.11 mM and 12.8 s-1, respectively, a single point mutation, namely L320C, activated the enzyme towards larger N-acetylated substrates. Docking studies designed to probe active site affinity corroborate the experimentally determined activity profiles and support the kinetic inhibition results.
Related Articles
UDP-galactose 4'-epimerase from the liver fluke, Fasciola hepatica: biochemical characterisation of the enzyme and identification of inhibitors
Zinsser, Veronika L.
Lindert, Steffen
Banford, Samantha
Hoey, Elizabeth M.
Trudgett, Alan
Timson, David J.
The Leloir pathway enzyme UDP-galactose 4'-epimerase from the common liver fluke Fasciola hepatica (FhGALE) was identified and characterised. The enzyme can be expressed in, and purified from, Escherichia coli. The recombinant enzyme is active: the Km (470 µM) is higher than the corresponding human enzyme (HsGALE), whereas the kcat (2.3 s−1) is substantially lower. FhGALE binds NAD+ and was shown to be dimeric by analytical gel filtration. Like the human and yeast GALEs, FhGALE is stabilised by the substrate UDP-galactose. Molecular modelling predicted that FhGALE adopts a similar overall fold to HsGALE and that tyrosine 155 is likely to be the catalytically critical residue in the active site. In silico screening of the NCI DTP library identified 40 potential inhibitors of FhGALE which were tested in vitro. Of these, six showed concentration-dependent inhibition of FhGALE, some with nanomolar IC50 values. Two inhibitors (5-fluoroorotate and N-[(benzyloxy)carbonyl]leucyltryptophan) demonstrated selectivity for FhGALE over HsGALE. These compounds also thermally destabilised FhGALE in a concentration-dependent manner. Interestingly the selectivity of 5-fluoroorotate was not shown by orotic acid, which differs in structure by one fluorine atom. These results demonstrate that, despite the structural and biochemical similarities of FhGALE and HsGALE, it is possible to discover compounds which preferentially inhibit FhGALE.
Neglected tropical disease; Leloir pathway; GALE; UDP-glucose 4'epimerase; 5-fluoroorotate; N-[(benzyloxy)carbonyl]leucyltryptophan
Related Articles
Characterization of GlaKP, a UDP-Galacturonic Acid C4-Epimerase from Klebsiella pneumoniae with Extended Substrate Specificity
Frirdich, Emilisa
Whitfield, Chris
Journal of Bacteriology
In Escherichia coli and Salmonella enterica, the core oligosaccharide backbone of the lipopolysaccharide is modified by phosphoryl groups. The negative charges provided by these residues are important in maintaining the barrier function of the outer membrane. In contrast, Klebsiella pneumoniae lacks phosphoryl groups in its core oligosaccharide but instead contains galacturonic acid residues that are proposed to serve a similar function in outer membrane stability. GlaKP is a UDP-galacturonic acid C4-epimerase that provides UDP-galacturonic acid for core synthesis, and the enzyme was biochemically characterized because of its potentially important role in outer membrane stability. High-performance anion-exchange chromatography was used to demonstrate the UDP-galacturonic acid C4-epimerase activity of GlaKP, and capillary electrophoresis was used for activity assays. The reaction equilibrium favors UDP-galacturonic acid over UDP-glucuronic acid in a ratio of 1.4:1, with the Km for UDP-glucuronic acid of 13.0 μM. GlaKP exists as a dimer in its native form. NAD+/NADH is tightly bound by the enzyme and addition of supplementary NAD+ is not required for activity of the purified enzyme. Divalent cations have an unexpected inhibitory effect on enzyme activity. GlaKP was found to have a broad substrate specificity in vitro; it is capable of interconverting UDP-glucose/UDP-galactose and UDP-N-acetylglucosamine/UDP-N-acetylgalactosamine, albeit at much lower activity. The epimerase GalE interconverts UDP-glucose/UDP-galactose. Multicopy plasmid-encoded glaKP partially complemented a galE mutation in S. enterica and in K. pneumoniae; however, chromosomal glaKP could not substitute for galE in a K. pneumoniae galE mutant in vivo.
Related Articles
Structure and Mechanism of Human UDP-xylose Synthase
Eixelsberger, Thomas
Sykora, Sabine
Egger, Sigrid
Brunsteiner, Michael
Kavanagh, Kathryn L.
Oppermann, Udo
Brecker, Lothar
Nidetzky, Bernd
The Journal of Biological Chemistry
Background: Human UDP-xylose synthase (hUXS1) is responsible for conversion of UDP-glucuronic acid to UDP-xylose.
Results: Crystal structure, molecular dynamics simulations, and reaction course analysis give conclusive insight into the enzymatic mechanism in three catalytic steps.
Conclusion: Distortion of sugar pyranose ring in bound substrate facilitates enzymatic reaction.
Significance: A detailed mechanism for catalysis by hUXS1 is proposed.
UDP-xylose synthase (UXS) catalyzes decarboxylation of UDP-d-glucuronic acid to UDP-xylose. In mammals, UDP-xylose serves to initiate glycosaminoglycan synthesis on the protein core of extracellular matrix proteoglycans. Lack of UXS activity leads to a defective extracellular matrix, resulting in strong interference with cell signaling pathways. We present comprehensive structural and mechanistic characterization of the human form of UXS. The 1.26-Å crystal structure of the enzyme bound with NAD+ and UDP reveals a homodimeric short-chain dehydrogenase/reductase (SDR), belonging to the NDP-sugar epimerases/dehydratases subclass. We show that enzymatic reaction proceeds in three chemical steps via UDP-4-keto-d-glucuronic acid and UDP-4-keto-pentose intermediates. Molecular dynamics simulations reveal that the d-glucuronyl ring accommodated by UXS features a marked 4C1 chair to BO,3 boat distortion that facilitates catalysis in two different ways. It promotes oxidation at C4 (step 1) by aligning the enzymatic base Tyr147 with the reactive substrate hydroxyl and it brings the carboxylate group at C5 into an almost fully axial position, ideal for decarboxylation of UDP-4-keto-d-glucuronic acid in the second chemical step. The protonated side chain of Tyr147 stabilizes the enolate of decarboxylated C4 keto species (2H1 half-chair) that is then protonated from the Si face at C5, involving water coordinated by Glu120. Arg277, which is positioned by a salt-link interaction with Glu120, closes up the catalytic site and prevents release of the UDP-4-keto-pentose and NADH intermediates. Hydrogenation of the C4 keto group by NADH, assisted by Tyr147 as catalytic proton donor, yields UDP-xylose adopting the relaxed 4C1 chair conformation (step 3).
Carbohydrate Biosynthesis; Decarboxylase; Dehydrogenase; Enzyme Mechanisms; Enzyme Structure; Glycosaminoglycan; Enzyme Reaction Coordinate; Short-chain Dehydrogenase/Reductase; Substrate Distortion/Destabilization; UDP-glucuronic Acid
Related Articles
Structure and Mechanism of Human UDP-glucose 6-Dehydrogenase
Egger, Sigrid
Chaikuad, Apirat
Kavanagh, Kathryn L.
Oppermann, Udo
Nidetzky, Bernd
The Journal of Biological Chemistry
Elevated production of the matrix glycosaminoglycan hyaluronan is strongly implicated in epithelial tumor progression. Inhibition of synthesis of the hyaluronan precursor UDP-glucuronic acid (UDP-GlcUA) therefore presents an emerging target for cancer therapy. Human UDP-glucose 6-dehydrogenase (hUGDH) catalyzes, in two NAD+-dependent steps without release of intermediate aldehyde, the biosynthetic oxidation of UDP-glucose (UDP-Glc) to UDP-GlcUA. Here, we present a structural characterization of the hUGDH reaction coordinate using crystal structures of the apoenzyme and ternary complexes of the enzyme bound with UDP-Glc/NADH and UDP-GlcUA/NAD+. The quaternary structure of hUGDH is a disc-shaped trimer of homodimers whose subunits consist of two discrete α/β domains with the active site located in the interdomain cleft. Ternary complex formation is accompanied by rigid-body and restrained movement of the N-terminal NAD+ binding domain, sequestering substrate and coenzyme in their reactive positions through interdomain closure. By alternating between conformations in and out of the active site during domain motion, Tyr14, Glu161, and Glu165 participate in control of coenzyme binding and release during 2-fold oxidation. The proposed mechanism of hUGDH involves formation and breakdown of thiohemiacetal and thioester intermediates whereby Cys276 functions as the catalytic nucleophile. Stopped-flow kinetic data capture the essential deprotonation of Cys276 in the course of the first oxidation step, allowing the thiolate side chain to act as a trap of the incipient aldehyde. Because thiohemiacetal intermediate accumulates at steady state under physiological reaction conditions, hUGDH inhibition might best explore ligand binding to the NAD+ binding domain.
Dehydrogenase; Enzyme Mechanisms; Enzyme Structure; Glycosaminoglycan; Hyaluronate; NAD; Tumor Marker; Conformational Changes and Catalysis; Covalent Intermediate; UDP-glucuronic Acid
Related Articles
Insights into role of the hydrogen bond networks in substrate recognition by UDP-GalNAc 4-epimerases
Bhatt, Veer Sandeep
Guan, Wanyi
Xue, Mengyang
Yuan, Huiqing
Wang, Peng George
Biochemical and biophysical research communications
UDP-hexose 4-epimerases are critical in galactose metabolism and often important in lipopolysaccharide biosynthesis as well. Three groups of these enzymes have been reported based on their substrate specificity towards non-acetylated substrates (group 1), dual specificity towards N-acetylated and non-acetylated substrates (group 2) and specificity towards N-acetylated substrates (group 3). We recently reported the structure of a novel UDP-GalNAc 4-epimerase called WbgU and based on the structure proposed a model of specific substrate recognition by UDP-GalNAc 4-epimerases. In this work, we present an analysis of the proposed model of substrate recognition using site-directed mutagenesis of WbgU and crystal structure of the His305Ala mutant. This investigation reveals that the wild-type activity of WbgU is retained in most single-point mutants targeting the active site. However, a graded loss in activity is observed in double-and triple-point mutants with the quadruple-point mutant being completely inactive corroborating the proposed rationale of substrate recognition. Furthermore, crystal structure of the His305Ala mutant shows that the structure is significantly similar to the wild-type WbgU, albeit a loss in the critical hydrogen bond network seated at His305 and ensuing minor conformational changes. It is inferred that the specific and non-specific interactions throughout the active site confer it sufficient elasticity to sustain wild-type activity for several of the single-point mutations.
Lipopolysaccharide; N-acetylglucosamine; Rossmann fold; 4-Epimerase; Galactose metabolism
Related Articles
Crystal structure of UDP-glucose:anthocyanidin 3-O-glucosyltransferase from Clitoria ternatea
Hiromoto, Takeshi
Honjo, Eijiro
Tamada, Taro
Noda, Naonobu
Kazuma, Kohei
Suzuki, Masahiko
Kuroki, Ryota
Journal of Synchrotron Radiation
2013;20(Pt 6):894-898.
The anthocyanidin 3-O-glucosyltransferase from Clitoria ternatea (Ct3GT-A) was expressed in Escherichia coli, and the three-dimensional structure of Ct3GT-A was determined using X-ray crystallography. This report describes the architecture of Ct3GT-A, including the structures of the donor- and acceptor-binding sites.
Flowers of the butterfly pea (Clitoria ternatea) accumulate a group of polyacylated anthocyanins, named ternatins, in their petals. The first step in ternatin biosynthesis is the transfer of glucose from UDP-glucose to anthocyanidins such as delphinidin, a reaction catalyzed in C. ternatea by UDP-glucose:anthocyanidin 3-O-glucosyltransferase (Ct3GT-A; AB185904). To elucidate the structure–function relationship of Ct3GT-A, recombinant Ct3GT-A was expressed in Escherichia coli and its tertiary structure was determined to 1.85 Å resolution by using X-ray crystallography. The structure of Ct3GT-A shows a common folding topology, the GT-B fold, comprised of two Rossmann-like β/α/β domains and a cleft located between the N- and C-domains containing two cavities that are used as binding sites for the donor (UDP-Glc) and acceptor substrates. By comparing the structure of Ct3GT-A with that of the flavonoid glycosyltransferase VvGT1 from red grape (Vitis vinifera) in complex with UDP-2-deoxy-2-fluoro glucose and kaempferol, locations of the catalytic His-Asp dyad and the residues involved in recognizing UDP-2-deoxy-2-fluoro glucose were essentially identical in Ct3GT-A, but certain residues of VvGT1 involved in binding kaempferol were found to be substituted in Ct3GT-A. These findings are important for understanding the differentiation of acceptor-substrate recognition in these two enzymes.
glucosylation; glucosyltransferase; anthocyanidin; crystal structure
Related Articles
Mapping the UDP-Glucuronic Acid Binding Site in UDP-Glucuronosyltransferase-1 A10 by Homology-based Modeling: Confirmation with Biochemical Evidence†
Banerjee, Rajat
Pennington, Matthew W.
Garza, Amanda
Owens, Ida S.
The UDP-glucuronosyltransferase (UGT) isozyme system is critical for protecting the body against endogenous and exogenous chemicals by linking glucuronic acid donated by UDP-glucuronic acid to a lipophilic acceptor substrate. UGTs convert metabolites, dietary constituents and environmental toxicants to highly excretable glucuronides. Because of difficulties associated with purifying endoplasmic reticulum-bound UGTs for structural studies, we carried out homology-based computer modeling to aid analysis. The search found structural homology in Escherichia coli UDP-galactose 4-epimerase. Consistent with predicted similarities involving the common UDP-moiety in substrates, UDP-glucose and UDP-hexanol amine caused competitive inhibition by Lineweaver-Burk plots. Among predicted binding sites N292, K314, K315 and K404 in UGT1A10, two informative sets of mutants K314R/Q/A/E /G and K404R/E had null activities or 2.7-fold higher/50% less activity, respectively. Scatchard analysis of binding data of affinity-ligand, 5-azido-uridine-[β-32P]-diphosphoglucuronic acid, to purified UGT1A10-His or UGT1A7-His revealed high and low affinity binding sites. 2-Nitro 5-thiocyanobenzoic acid-digested UGT1A10-His bound with radiolabeled affinity-ligand revealed an 11.3- and 14.3-kDa peptide associated with K314 and K404, respectively, in a discontinuous SDS-PAGE system. Similar treatment of 1A10His-K314A bound with the ligand lacked both peptides; 1A10-HisK404R- and 1A10-HisK404E showed 1.3-fold greater- and 50% less-label in the 14.3-kDa peptide, respectively, compared to 1A10-His without affecting the 11.3-kDa peptide. Scatchard analysis of binding data of affinity-ligand to 1A10His-K404R and -K404E showed a 6-fold reduction and a large increase in Kd, respectively. Our results indicate: K314 and K404 are required UDP-glcA binding sites in 1A10, that K404 controls activity and high affinity sites and that K314 and K404 are strictly conserved in 70 aligned UGTs, except for S321--equivalent to K314-- in UGT2B15 and 2B17 and I321 in the inactive UGT8, which suggests UGT2B15 and 2B17 contain suboptimal activity. Hence our data strongly support UDPglcA binding to K314 and K404 in UGT1A10.
Related Articles
Structural and Functional Studies of WlbA: a Dehydrogenase Involved in the Biosynthesis of 2,3-Diacetamido-2,3-Dideoxy-D-Mannuronic Acid¶
Thoden, James B.
Holden, Hazel M.
2,3-diacetamido-2,3-dideoxy-D-mannuronic acid or ManNAc3NAcA is an unusual dideoxysugar first identified nearly 30 years ago in the lipopolysaccharide of Pseudomonas aeruginosa O:3a,d. It has since been observed in other organisms including Bordetella pertussis, the causative agent of whooping cough. Five enzymes are required for the biosynthesis of UDP-ManNAc3NAcA starting from UDP-N-acetyl-D-glucosamine. Here we describe a structural study of WlbA, the NAD-dependent dehydrogenase that catalyzes the second step in the pathway, namely the oxidation of the C-3′ hydroxyl group on the UDP-linked sugar to a keto moiety and the reduction of NAD+ to NADH. This enzyme has been shown to use α-ketoglutarate as an oxidant to regenerate the reduced dinucleotide. For this investigation three different crystal structures were determined: the enzyme with bound NAD(H), the enzyme complexed with NAD(H) and α-ketoglutarate, and the enzyme complexed with NAD(H) and its substrate (UDP-N-acetyl-D-glucosaminuronic acid). The tetrameric enzyme assumes an unusual quaternary structure with the dinucleotides positioned quite closely to one another. Both α-ketoglutarate and the UDP-linked sugar bind in the WlbA active site with their carbon atoms (C-2 or C3′, respectively) abutting the re face of the cofactor. They are positioned at ~3 Å from the nicotinamide C-4. The UDP-linked sugar substrate adopts a high unusual curved conformation when bound in the WlbA active site cleft. Lys 101 and His 185 most likely play key roles in catalysis.
Related Articles
Computer-Aided Identification of Trypanosoma brucei Uridine Diphosphate Galactose 4′-Epimerase Inhibitors: Toward the Development of Novel Therapies for African Sleeping Sickness
Durrant, Jacob D.
Urbaniak, Michael D.
Ferguson, Michael A. J.
McCammon, J. Andrew
Journal of Medicinal Chemistry
Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4′-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 μM, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.
Related Articles
The Molecular Dynamics of Trypanosoma brucei UDP-Galactose 4′-Epimerase: A Drug Target for African Sleeping Sickness
Friedman, Aaron J
Durrant, Jacob D
Pierce, Levi C T
McCorvie, Thomas J
Timson, David J
McCammon, J Andrew
Chemical Biology & Drug Design
During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10 000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose synthesis pathway is one potential therapeutic target. Although galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4′-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and is therefore of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.
African sleeping sickness; molecular dynamics; protein structure; TbGalE; Trypanosoma brucei; UDP-Galactose-4′-Epimerase
Related Articles
The Molecular Dynamics of Trypanosoma brucei UDP-Galactose 4′-Epimerase: A Drug Target for African Sleeping Sickness
Friedman, Aaron J.
Durrant, Jacob D.
Pierce, Levi C. T.
McCorvie, Thomas J.
Timson, David J.
McCammon, J. Andrew
Chemical biology & drug design
During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10,000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose-synthesis pathway is one potential therapeutic target. Though galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4′-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and so is of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug-discovery efforts targeting this protein.
TbGalE; Trypanosoma brucei; UDP-Galactose-4'-Epimerase; African Sleeping Sickness; Molecular Dynamics; Protein Structure
Related Articles
Crystal Structures of Active Fully Assembled Substrate- and Product-Bound Complexes of UDP-N-Acetylmuramic Acid:l-Alanine Ligase (MurC) from Haemophilus influenzae
Mol, Clifford D.
Brooun, Alexei
Dougan, Douglas R.
Hilgers, Mark T.
Tari, Leslie W.
Wijnands, Robert A.
Knuth, Mark W.
McRee, Duncan E.
Swanson, Ronald V.
Journal of Bacteriology
UDP-N-acetylmuramic acid:l-alanine ligase (MurC) catalyzes the addition of the first amino acid to the cytoplasmic precursor of the bacterial cell wall peptidoglycan. The crystal structures of Haemophilus influenzae MurC in complex with its substrate UDP-N-acetylmuramic acid (UNAM) and Mg2+ and of a fully assembled MurC complex with its product UDP-N-acetylmuramoyl-l-alanine (UMA), the nonhydrolyzable ATP analogue AMPPNP, and Mn2+ have been determined to 1.85- and 1.7-Å resolution, respectively. These structures reveal a conserved, three-domain architecture with the binding sites for UNAM and ATP formed at the domain interfaces: the N-terminal domain binds the UDP portion of UNAM, and the central and C-terminal domains form the ATP-binding site, while the C-terminal domain also positions the alanine. An active enzyme structure is thus assembled at the common domain interfaces when all three substrates are bound. The MurC active site clearly shows that the γ-phosphate of AMPPNP is positioned between two bound metal ions, one of which also binds the reactive UNAM carboxylate, and that the alanine is oriented by interactions with the positively charged side chains of two MurC arginine residues and the negatively charged alanine carboxyl group. These results indicate that significant diversity exists in binding of the UDP moiety of the substrate by MurC and the subsequent ligases in the bacterial cell wall biosynthesis pathway and that alterations in the domain packing and tertiary structure allow the Mur ligases to bind sequentially larger UNAM peptide substrates.
Related Articles
Genetic Loci for Coaggregation Receptor Polysaccharide Biosynthesis in Streptococcus gordonii 38
Xu, De-Qi
Thompson, John
Cisar, John O.
Journal of Bacteriology
The cell wall polysaccharide of Streptococcus gordonii 38 functions as a coaggregation receptor for surface adhesins on other members of the oral biofilm community. The structure of this receptor polysaccharide (RPS) is defined by a heptasaccharide repeat that includes a GalNAcβ1→3Gal-containing recognition motif. The same RPS has now been identified from S. gordonii AT, a partially sequenced strain. PCR primers designed from sequences in the genomic database of strain AT were used to identify and partially characterize the S. gordonii 38 RPS gene cluster. This cluster includes genes for seven putative glycosyltransferases, a polysaccharide polymerase (Wzy), an oligosaccharide repeating unit transporter (Wzx), and a galactofuranose mutase, the enzyme that promotes synthesis of UDP-Galf, one of five predicted RPS precursors. Genes outside this region were identified for the other four nucleotide-linked sugar precursors of RPS biosynthesis, namely, those for formation of UDP-Glc, UDP-Gal, UDP-GalNAc, and dTDP-Rha. Two genes for putative galactose 4-epimerases were identified. The first, designated galE1, was identified as a pseudogene in the galactose operon, and the second, designated galE2, was transcribed with three of the four genes for dTDP-Rha biosynthesis (i.e., rmlA, rmlC, and rmlB). Insertional inactivation of galE2 abolished (i) RPS production, (ii) growth on galactose, and (iii) both UDP-Gal and UDP-GalNAc 4-epimerase activities in cell extracts. Repair of the galE1 pseudogene in this galE2 mutant restored growth on galactose but not RPS production. Cell extracts containing functional GalE1 but not GalE2 contained UDP-Gal 4-epimerase but not UDP-GalNAc 4-epimerase activity. Thus, provision of both UDP-Gal and UDP-GalNAc for RPS production by S. gordonii 38 depends on the dual specificity of the epimerase encoded by galE2.
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Product details
Dulux Matt Emulsion Paint has excellent coverage that minimises imperfections creating the most contemporary look for walls and ceilings.
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January 28, 2013
Retired Navy, amateur with about a years experience, mostly self taught. Took a few workshops on Bird and nature photography last year. Doing on line Photoshop course now.
We need to formally get together again for a meet and greet,,thanks Wayne for organizing this..Lots of talent with the various individuals..let's share some experience...Harry
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Google to rename Picasa, Blogger, reports say
The names of two popular Google services, Picasa and Blogger, will soon go away, although the services themselves will remain key components of Google's product family.
The names of two popular Google services, Picasa and Blogger, will soon go away, although the services themselves will remain key components of Google's product family.
Google has asked a California court to throw out the testimony of an expert witness who said Google should pay Oracle as much as US$6 billion for allegedly infringing on Java patents and copyright.
Google has shut down its Realtime Search offering after its agreement to include Twitter results expired.
The world is already abuzz about Google+, even though it's not accessible to most. Still, many doubt that anyone, even the mighty one from Mountain View, can catch up to Facebook's half a billion (at least) active users. Unless, maybe there was a sim...
Google Plus (aka Google+), Google's new social network, might offer the right mix of sharing and privacy to woo you away from your Facebook account.
I have been using Google+ for a few days now, and so far I have had had a few complaints about the new Google social network.
Microsoft's Bing search engine will provide English-language search results for Baidu, China's largest search engine, the companies announced Monday.
Google+ is awesome. Or -- at least -- I'm assuming it is. Although I've had an invitation to join Google's social networking experiment for several days, every time I attempt to check out the service I'm told "We've temporarily exceeded our capacity....
It's the hottest invitation in technology right now -- an e-mail telling you how to "learn more about Google+." If you get one, though, be careful about clicking on it. It may be spam.
Tech companies this week enjoyed an end-of-quarter market rally as concerns about the recovery abated somewhat and reports from market analysts indicated that IT spending would stay ahead of overall economic growth.
Nortel Networks has auctioned off its remaining patents and patent applications to a consortium of key technology companies for a cash purchase price of US$4.5 billion.
Google recently launched Google+, the company's latest attempt to get social networking right after its social disaster, Google Buzz. After trying out Google's new social network for several hours, I think Google may have finally figured out how to d...
Whether Google says so or not, Google+ is a direct shot at Facebook, a social networking project that attempts, from the ground up, to let users control who sees what. But building a new social network in the Facebook era isn't easy--even for Google-...
Microsoft signed two deals this week with companies that agreed to pay royalties for technology used in Android devices, following a similar deal the software giant made with HTC last year.
Microsoft is improving accommodations for Java developers on the Windows Azure cloud, with an upgraded plug-in for Eclipse-based software developers.
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First impression on unpacking the Q702 test unit was the solid feel and clean, minimalist styling.
For work use, Microsoft Word and Excel programs pre-installed on the device are adequate for preparing short documents.
The Fujitsu LifeBook UH574 allowed for great mobility without being obnoxiously heavy or clunky. Its twelve hours of battery life did not disappoint.
The screen was particularly good. It is bright and visible from most angles, however heat is an issue, particularly around the Windows button on the front, and on the back where the battery housing is located.
My first impression after unboxing the Q702 is that it is a nice looking unit. Styling is somewhat minimalist but very effective. The tablet part, once detached, has a nice weight, and no buttons or switches are located in awkward or intrusive positions.


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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Showing Results: Most Recent
This review is from: Canon CanoScan 5600F 2925B002 9600 x 4800 dpi 48bit USB 2.0 Hi-Speed Interface Flatbed Scanner
Pros: Good quality scan, as always from Canon.
Cons: I had a LIDE first and when it got obsolete due to windows newer ver. I bought the 3200F which was even better. However I recently broke the glass and thought about fixing but since it was old I decided to get a newer one which was on sale. After reading the specs I decided to go for it. I unpacked and installed it.
1 it's heavy and bulky. The 3200 is thin and light.
The Canoscan toolbox was a great thing and is not available with this model in it stead there is Solution Menu and MP navigator. Not intuitive at all. I thought progress is moving FORWARD and simplify things NOT make things more complicated.
The previous "Toolbox" made it EZ to choose what was wanted/needed AND it would open the program and load the scan into it depending on your choice.
It is now taking me 3 times longer to do my work. I may get used to it but I hate having to go through another learning curve.
Other Thoughts: It is not fast as I believed. The 3200 was as quick however the dpi was lower.
Also the glass surface for docs was longer and I was able to use longer (obviously) documents to scan.
Why did they have to change a good thing for so-so interface? I would NOT recommend this unit. Better get a sheet feed scanner if you have lots of scanning to do.
This review is from: ASUS P8Z68-V PRO/GEN3 LGA 1155 Intel Z68 HDMI SATA 6Gb/s USB 3.0 ATX Intel Motherboard with UEFI BIOS
Pros: Great board. lots of features.
Cons: tried to run 3 monitors to no avail.
Strangely enough all of the Asus board show no video on board but mine has it???
So I tried to connect 3 monitors on the MoBo.
When I plug 2 in it works but 3 won't work. So I tried to set it up in several different ways (Auto, x4, x1) and even added first one other PCIe graphic card then 2 but still can't run 3 monitors. Next I will purchase a better card that does handle 3 or 4 monitors and maybe try to go crossfire or sli


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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Showing Results: Most Recent
This review is from: Samsung Galaxy S4 I9500 (Unlocked) 16GB White Frost 3G 5" Super AMOLED I9500
Pros: big screen
Cons: software is a messy, too many useless functions
Other Thoughts: the display just suddenly went dark at all, still functional but no display. I don't know if I can replace one or return it.READ FULL REVIEW
This review is from: ASUS PCE-N15 Wireless Adapter IEEE 802.11b/g/n PCI Express 300/300Mbps Transfer/Receive Rate 64-bit WEP, 128-bit WEP, WPA2-PSK, WPA-PSK, WPS support
Pros: ships fast, good package, easy to install
Cons: I have to say, even though I saw some bad rating, i still would give asus a try cuz i have a lot of asus stuff and they are all very good. however, this card, I installed it, then it just can't open a webpage. it says connected with the internet, just can't open a webpage, always says my network is unindentified. I just don't know who to contact to solve this problem, I might just return it.
btw, i had a rosewill usb wireless adapter and it works fine, I am buying this for playing games and give the rosewill one to my girlfriend and she's using it well. so i dont think is my computer's problem.


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Academy Hotel
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TripAdvisor Reviews Academy Hotel Berlin
Travel Blogs from Berlin
... They have an interesting permanent collection that focuses on the history of Germany and includes an impressive selection of arms and armour, but what I really went there to see was their 1945 exhibition.
This dealt with 12 European countries - including all the key players like Germany, Britain, France and Russia - and the social and political environment that each one faced immediately after the end of World War II. Each country had it's own section which contained mostly day ...
Day 24 - Berlin
We decided to stay in our apartment, just probably not spend much time here. It's raining today so were going to bring the umbrella and check out the Berlin Wall. Berlin Wall History After the war ender in 1945 Berlin was divided in four between the allies - Britain, France, USA and Russia. Britain, France and the USA were democratic countries while Russia was communist. The allies got along at the beginning but it turned competitive, with Russia wanting to conquer it. ...
Nazis and Communists
... emigrating (leaving the country). Those who somehow got through were easily accepted as immigrants (entering the country) in West Berlin, practically a western government surrounded by socialism. This wasn't as easy as it sounds since between the wall and the true boundary was an area known as the "death strip" which came with orders to shoot to kill any trespassers. Enough history, back to now. There is a portion of the wall remaining next to the Topography ...
The Berlin experience
... tour guide was quite entertaining and told us that the people staying in the bunkers had to watch their tongue in case an enemy spy was with them or in case they said something wrong and a Nazi was nearby. That didn't stop their humour though. Apparently a common joke was: what does a pessimist carry in his suitcase? (Everyone brought a suitcase to the bunker with them that contained their valuables) Answer: A Russian dictionary. After the tour, it ...
Bumblin' 'round Berlin!
... and destruction had spread during the War. It can't be said that we enjoyed the museum, but I think it was really important to have learned about it all.
We were exhausted after the museum, so we walked back to the hostel via the Brandenburg Gate - which was beautiful lit up in the dark - and relaxed for a while in our room. We talked lots about what we had seen in the museum, and reflected upon what we had learned. We were really hungry at ...


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Re: Nintendo balancing the gender bias
Suicune wrote:
People like to say videogames are art, but you dont see people wanting to put lady parts on the Statue of David.
You're right, retconning historically male characters into females isn't the answer. However, your analogy is flawed. In terms of Link, it's not about asking that the Statue of David be granted ladyparts, we're asking that perhaps Michelangelo consider a female option for his next great masterpiece in the series, since they're all (well, with few exceptions) different people.
also, @Dreamz, i would play the hell outta that game, no lie. Too bad Nintendo doesn't take suggestions from the public ;___;
Edited on by theblackdragon
future of NL >:3
[16:43] James: I should learn these site rules more clearly
[16:44] LztheBlehBird: James doesn't know the rules? For shame!!!
[16:44] Vintage: We have rules?
[16:44] Reala: don't expose the staff to sunlight, don't get them wet and don't feed them after midnight
Nintendo Network ID: gentlemen_cat | Twitter: theblackdragon


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Check in from 2:00 PM / Check out prior to 10:00 AM
A Special Place: Find photos, reviews, information, amenities and compare prices for 2 stars hotels in Corinth, United States.
A Special Place is located in Corinth and provides guests with internet.
Hotel description
A Special Place Hotel Corinth has 2 rooms that are filled with all the essentials to ensure a comfortable stay.
Lebanon Municipal Airport is a 50-minute drive from the hotel. Fairlee and Orford are located a short drive away.
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Results 1 to 5 of 5
- 09-09-2013, 12:58 PM Thread Author #1
Unable to factory reset properly?
Hey, I recently update my software on my HTC Desire X from 4.0 to 4.1 or something, ever since my phone as been generally slow. Everytime I hit home button it loads for 3-5s and when I use apps they usally crash. This sucked, so I disabled all the animations etc, all apps non-required, the problem presists so I google it. Just like me others had a similar issue, a factory reset was recommended and so I did. But after factory reseting(which I've done multply times now) it's not reseting back to 4.0 it's still 4.1 and the lagging presists, what do I do?
- Posts
- 13,676 Posts
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- 13,715 Global Posts
- Carrier
- Stock 4.4 (KitKat)
Re: Unable to factory reset properly?
Nova Launcher, Apex Launcher, ADW Launcher) and see if any of those help with the lag associated with the stock launcher.
Hope this helps.
- Posts
- 2,735 Posts
Re: Unable to factory reset properly?
By chance when you do the factory reset and set your phone up all over again are you telling it to go ahead and download all of your apps? If so, do not do that. Reset without the apps and add one at a time until you find what may be slowing your phone down.
- 09-09-2013, 03:24 PM Thread Author #4
- 09-10-2013, 03:15 PM Thread Author #5
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