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Valerie J Winton, Alexander M Justen, Helen Deng, Laura L Kiessling
Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to anti-parasitic agents underscores the need to replenish our anthelmintic arsenal. The non-pathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation...
July 21, 2017: ACS Chemical Biology
Kittikhun Wangkanont, Valerie J Winton, Katrina T Forest, Laura L Kiessling
UDP-galactopyranose mutase (Glf or UGM) catalyzes the formation of uridine 5'-diphosphate-α-D-galactofuranose (UDP-Galf) from UDP-galactopyranose (UDP-Galp). The enzyme is required for the production of Galf-containing glycans. UGM is absent in mammals, but members of the Corynebacterineae suborder require UGM for cell envelope biosynthesis. The need for UGM in some pathogens has prompted the search for inhibitors that could serve as antibiotic leads. Optimizing inhibitor potency, however, has been challenging...
June 13, 2017: Biochemistry
Ankita Srivastava, Deepak Chandra
BACKGROUND: The unsatisfactory treatment options for Visceral Leishmaniasis (VL), needs identification of new drug targets. Among natural products, Alkaloids have been proved to be highly effective against number of diseases. In Leishmania UDP-galactopyranose mutase (UGM) is a critical enzyme required for cell wall synthesis and thus a drug target for structure based drug designing against L. donovani. OBJECTIVE: To build the homology model of UDP galactopyranse mutase and investigate the interaction of selected alkaloids with this modeled UDP galactopyranose mutase by molecular docking...
June 5, 2017: Infectious Disorders Drug Targets
Stephane Vincent, Sydney Villaume, Jian Fu, Inès N'Go, Huayong Lou, Hui Liang, Laurent Kremer, Weidong Pan
This study reports a novel class of inhibitors of UDP-galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids were found to be potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed to perform a structure-activity relationship analysis and to determine which functional groups and structural elements are required for UGM inhibition.The binding mode of one of the best inhibitor was found to be non-competitive...
May 11, 2017: Chemistry: a European Journal
Qinghua Zhu, Qi Chen, Yongxiang Song, Hongbo Huang, Jun Li, Junying Ma, Qinglian Li, Jianhua Ju
Galactose, a monosaccharide capable of assuming two possible configurational isomers (d-/l-), can exist as a six-membered ring, galactopyranose (Galp), or as a five-membered ring, galactofuranose (Galf). UDP-galactopyranose mutase (UGM) mediates the conversion of pyranose to furanose thereby providing a precursor for d-Galf Moreover, UGM is critical to the virulence of numerous eukaryotic and prokaryotic human pathogens and thus represents an excellent antimicrobial drug target. However, the biosynthetic mechanism and relevant enzymes that drive l-Galf production have not yet been characterized...
May 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
Rong Li, Sheng Quan, Xiaofang Yan, Sukumar Biswas, Dabing Zhang, Jianxin Shi
Molecular characterization lays a foundation for safety assessment and subsequent monitoring of genetically modified (GM) crops. Due to the target-specific nature, conventional polymerase chain reaction (PCR)-based methods cannot comprehensively detect unintended gene insertions, let alone unknown GM events. As more and more new developed GM crops including new plant breeding technology (NPBT) generated crops are in the pipeline for commercialization, alternative -omics approaches, particularly next generation sequencing, have been developed for molecular characterization of authorized or unauthorized GM (UGM) crops...
March 2017: Biotechnology Advances
Sweta Misra, Jyoti Gupta, Shailja Misra-Bhattacharya
BACKGROUND: Galactofuranose is an essential cell surface component present in bacteria, fungi and several nematodes such as Caenorhabditis spp., Brugia spp., Onchocerca spp. and Strongyloides spp. This sugar maintains the integrity of parasite surface and is essential for virulence. UDP-Galactopyranose mutase (bmugm) plays a key role in Galf biosynthesis by catalyzing conversion of UDP-Galactopyranose into UDP-galactofuranose and knockout studies of the gene in Leishmania major, Mycobacterium and Aspergillus fumigatus displayed attenuated virulence while RNA interference study in C...
January 19, 2017: Parasites & Vectors
Darryl A Wesener, Matthew R Levengood, Laura L Kiessling
The suborder Corynebacterineae encompasses species like Corynebacterium glutamicum, which has been harnessed for industrial production of amino acids, as well as Corynebacterium diphtheriae and Mycobacterium tuberculosis, which cause devastating human diseases. A distinctive component of the Corynebacterineae cell envelope is the mycolyl-arabinogalactan (mAG) complex. The mAG is composed of lipid mycolic acids, and arabinofuranose (Araf) and galactofuranose (Galf) carbohydrate residues. Elucidating microbe-specific differences in mAG composition could advance biotechnological applications and lead to new antimicrobial targets...
February 17, 2017: Journal of Biological Chemistry
P G Shelton, Irma Corral, Brandon Kyle
Restructuring of undergraduate medical education (UGME) has occurred from time to time over the past century. Many influences, including the persuasive report of Abraham Flexner in 1910, acted to reorganize medical education in the early twentieth century [1, 2]. In his report, Flexner called on American medical schools to enact higher graduation standards and to stringently adhere to the protocols of mainstream science in their teaching. Prior to this report, UGME had changed little over the previous century but over the last several decades, reform within medical education has become routine...
November 5, 2016: Psychiatric Quarterly
Brandon N Kyle, Irma Corral, Nadyah Janine John, P G Shelton
Returning to the original emphasis of higher education, universities have increasingly recognized the value and scholarship of teaching, and medical schools have been part of this educational scholarship movement. At the same time, the preferred learning styles of a new generation of medical students and advancements in technology have driven a need to incorporate technology into psychiatry undergraduate medical education (UGME). Educators need to understand how to find, access, and utilize such educational technology...
June 2017: Psychiatric Quarterly
Colin Hamlin, Kanwar Bhangu, Alexander Villafranca, Manpreet Bhangu, Robert Brown, Marshall Tenenbein, Eric Jacobsohn
PURPOSE: Historically, anesthesiology departments have played a small role in teaching the pre-clerkship component of undergraduate medical education (UGME). The purpose of this study was to measure the current participation of Canadian anesthesiologists in UGME with a focus on pre-clerkship. METHODS: Three surveys were developed in collaboration with the Association of Canadian Departments of Anesthesia. After an initial series of validation procedures, the surveys were distributed to anesthesia department heads, UGME directors, and associate deans at the 17 Canadian medical schools...
January 2017: Canadian Journal of Anaesthesia, Journal Canadien D'anesthésie
Yousef Sakieh, Abdolrassoul Salmanmahiny, Seyed Hamed Mirkarimi
Continuous surface of urbanization suitability, as an input to many urban growth models (UGM), has a significant role on a proper calibration process. The present study evaluates and compares the simulation success of the Cellular Automata-Markov Chain (CA-MC) model through multiple methods. For this, a series of mapping algorithms are applied ranging from empirical methods such as multi-criteria evaluation (MCE) to statistical algorithms without spatially explicit suitability mapping rules such as logistic regression (LR) and multi-layer perceptron (MLP) neural network and finally statistical and spatially explicit rule-based methods such as SLEUTH-Genetic Algorithm (SLEUTH-GA) model...
November 2016: Environmental Monitoring and Assessment
Christophe J-M Frédéric, Abdellatif Tikad, Jian Fu, Weidong Pan, Ruixiang B Zheng, Akihiko Koizumi, Xiaochao Xue, Todd L Lowary, Stéphane P Vincent
This study reports a new methodology to synthesize exo-glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo-glycals displaying two electron-withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z/E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo-glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)-galactofuranose analogues...
September 15, 2016: Chemistry: a European Journal
Valerie J Winton, Claudia Aldrich, Laura L Kiessling
Uridine diphosphate galactopyranose mutase (UGM also known as Glf) is a biosynthetic enzyme required for construction of the galactan, an essential mycobacterial cell envelope polysaccharide. Our group previously identified two distinct classes of UGM inhibitors; each possesses a carboxylate moiety that is crucial for potency yet likely detrimental for cell permeability. To enhance the antimycobacterial potency, we sought to replace the carboxylate with a functional group mimic-an N-acylsulfonamide group. We therefore synthesized a series of N-acylsulfonamide analogs and tested their ability to inhibit UGM...
August 12, 2016: ACS Infectious Diseases
Shu Yang, Ming Jiang, Magdalena M Grabowska, Jiahe Li, Zachary M Connelly, Jianghong Zhang, Simon W Hayward, Justin M Cates, Guichun Han, Xiuping Yu
Androgens regulate the proliferation and differentiation of prostatic epithelial cells, including prostate cancer (PCa) cells in a context-dependent manner. Androgens and androgen receptor (AR) do not invariably promote cell proliferation; in the normal adult, endogenous stromal and epithelial AR activation maintains differentiation and inhibits organ growth. In the current study, we report that activation of AR differentially regulates the proliferation of human prostate epithelial progenitor cells, NHPrE1, in vitro and in vivo...
October 25, 2016: Oncotarget
Sweta Misra, Guru R Valicherla, Mohd Shahab, Jyoti Gupta, Jiaur R Gayen, Shailja Misra-Bhattacharya
Lymphatic filariasis, a vector-borne neglected tropical disease affects millions of population in tropical and subtropical countries. Vaccine unavailability and emerging drug resistance against standard antifilarial drugs necessitate search of novel drug targets for developing alternate drugs. Recently, UDP-galactopyranose mutases (UGM) have emerged as a promising drug target playing an important role in parasite virulence and survival. This study deals with the cloning and characterization of Brugia malayi UGM and further exploring its antifilarial drug target potential...
2016: Pathogens and Disease
Geng-Min Lin, He G Sun, Hung-Wen Liu
Uridine 5'-diphosphate-5-fluorogalactopyranose (UDP-5F-Galp, 7) was synthesized, and its effect on UDP-Galp mutase (UGM) was investigated. UGM facilitated the hydrolysis of 7 to yield UDP and 5-oxogalactose (24), but no 11 was detected. (19)F NMR and trapping experiments demonstrated that the reaction involves the initial formation of a substrate-cofactor adduct followed by decomposition of the resulting C5 gem-fluorohydrin to generate a 5-oxo intermediate (10). The results support the current mechanistic proposal for UGM and suggest new directions for designing mechanism-based inhibitors...
July 15, 2016: Organic Letters
Bruno D A Sanches, Bruno C Zani, Juliana S Maldarine, Manoel F Biancardi, Fernanda C A Santos, Rejane M Góes, Patricia S L Vilamaior, Sebastião R Taboga
The development of the prostate in male rodents, which involves complex epithelial-mesenchymal interactions between the urogenital sinus epithelium (UGE) and the urogenital sinus mesenchyme (UGM), has been deeply studied. In females, however, this process is not very clear. In this study, the postnatal development of the prostate in female Mongolian gerbils employing three-dimensional (3D) reconstructions, histochemical, and immunohistochemical techniques was characterized. It was observed that prostatic branching and differentiation in females was induced by a single mesenchyme localized at a ventrolateral position, which was named as ventrolateral mesenchyme (VLM); furthermore, the canalization of solid buds began on the third postnatal day (P3) and the branching morphogenesis on P5...
May 2016: Microscopy Research and Technique
Ritcha Mehra-Chaudhary, Yumin Dai, Pablo Sobrado, John J Tanner
UDP-galactopyranose mutase (UGM) plays an essential role in galactofuranose biosynthesis in pathogens by catalyzing the conversion of UDP-galactopyranose to UDP-galactofuranose. Here we report the first crystal structure of a covalent intermediate in the UGM reaction. The 2.3 Å resolution structure reveals UDP bound in the active site and galactopyranose linked to the FAD through a covalent bond between the anomeric C of galactopyranose and N5 of the FAD. The structure confirms the role of the flavin as nucleophile and supports the hypothesis that the proton destined for O5 of galactofuranose is shuttled from N5 of the FAD via O4 of the FAD...
February 16, 2016: Biochemistry
Yasaman Mahdavi-Amiri, Sankar Mohan, Silvia Borrelli, Kathryn Slowski, David A R Sanders, B Mario Pinto
Uridine diphosphate-galactopyranose mutase (UGM), an enzyme found in many eukaryotic and prokaryotic human pathogens, catalyzes the interconversion of UDP-galactopyranose (UDP-Galp) and UDP-galactofuranose (UDP-Galf), the latter being used as the biosynthetic precursor of the galactofuranose polymer portion of the mycobacterium cell wall. We report here the synthesis of a sulfonium and selenonium ion with an appended polyhydroxylated side chain. These compounds were designed as transition state mimics of the UGM-catalyzed reaction, where the head groups carrying a permanent positive charge were designed to mimic both the shape and positive charge of the proposed galactopyranosyl cation-like transition state...
January 2016: Carbohydrate Research
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