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https://www.readbyqxmd.com/read/28760597/human-and-plasmodium-serine-hydroxymethyltransferases-differ-in-rate-limiting-steps-and-ph-dependent-substrate-inhibition-behavior
#1
Watcharee Amornwatcharapong, Somchart Maenpuen, Penchit Chitnumsub, Ubolsree Leartsakulpanich, Pimchai Chaiyen
Serine hydroxymethyltransferase (SHMT), an essential enzyme for cell growth and development, catalyzes the transfer of -CH2OH from l-serine to tetrahydrofolate (THF) to form glycine and 5,10-methylenetetrahydrofolate (MTHF) which is used for nucleotide synthesis. Insights into the ligand binding and inhibition properties of human cytosolic SHMT (hcSHMT) and Plasmodium SHMT (PvSHMT) are crucial for designing specific drugs against malaria and cancer. The results presented here revealed strong and pH-dependent THF inhibition of hcSHMT...
July 29, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28537728/antimalarial-inhibitors-targeting-serine-hydroxymethyltransferase-shmt-with-in-vivo-efficacy-and-analysis-of-their-binding-mode-based-on-x-ray-cocrystal-structures
#2
Geoffrey Schwertz, Matthias C Witschel, Matthias Rottmann, Roger Bonnert, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Aritsara Jaruwat, Wanwipa Ittarat, Anja Schäfer, Raphael A Aponte, Susan A Charman, Karen L White, Abhijit Kundu, Surajit Sadhukhan, Mel Lloyd, Gail M Freiberg, Myron Srikumaran, Marc Siggel, Adrian Zwyssig, Pimchai Chaiyen, François Diederich
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3...
June 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28515048/essential-function-of-the-serine-hydroxymethyl-transferase-shmt-gene-during-rapid-syncytial-cell-cycles-in-drosophila
#3
Franziska Winkler, Maria Kriebel, Michaela Clever, Stephanie Gröning, Jörg Großhans
Many metabolic enzymes are evolutionarily highly conserved and serve a central function in the catabolism and anabolism of cells. The serine hydroxymethyl transferase (SHMT) catalyzing the conversion of serine and glycine and vice versa feeds into tetrahydrofolate (THF)-mediated C1 metabolism. We identified a Drosophila mutation in SHMT (CG3011) in a screen for blastoderm mutants. Embryos from SHMT mutant germline clones specifically arrest the cell cycle in interphase 13 at the time of the midblastula transition (MBT) and prior to cellularization...
July 5, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28461497/folate-rescues-vitamin-b12-depletion-induced-inhibition-of-nuclear-thymidylate-biosynthesis-and-genome-instability
#4
Ashley M Palmer, Elena Kamynina, Martha S Field, Patrick J Stover
Clinical vitamin B12 deficiency can result in megaloblastic anemia, which results from the inhibition of DNA synthesis by trapping folate cofactors in the form of 5-methyltetrahydrofolate (5-methylTHF) and subsequent inhibition of de novo thymidylate (dTMP) biosynthesis. In the cytosol, vitamin B12 functions in the remethylation of homocysteine to methionine, which regenerates THF from 5-methylTHF. In the nucleus, THF is required for de novo dTMP biosynthesis, but it is not understood how 5-methylTHF accumulation in the cytosol impairs nuclear dTMP biosynthesis...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28400561/a-hybrid-stochastic-model-of-folate-mediated-one-carbon-metabolism-effect-of-the-common-c677t-mthfr-variant-on-de-novo-thymidylate-biosynthesis
#5
Karla Misselbeck, Luca Marchetti, Martha S Field, Marco Scotti, Corrado Priami, Patrick J Stover
Folate-mediated one-carbon metabolism (FOCM) is an interconnected network of metabolic pathways, including those required for the de novo synthesis of dTMP and purine nucleotides and for remethylation of homocysteine to methionine. Mouse models of folate-responsive neural tube defects (NTDs) indicate that impaired de novo thymidylate (dTMP) synthesis through changes in SHMT expression is causative in folate-responsive NTDs. We have created a hybrid computational model comprised of ordinary differential equations and stochastic simulation...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28384049/intestinal-iga-as-a-modulator-of-the-gut-microbiota
#6
Shinsaku Okai, Fumihito Usui, Misa Ohta, Hiroshi Mori, Ken Kurokawa, Satoshi Matsumoto, Tamotsu Kato, Eiji Miyauchi, Hiroshi Ohno, Reiko Shinkura
Accumulating evidence suggests that dysbiosis plays a role in the pathogenesis of intestinal diseases including inflammatory bowel disease (IBD) as well as extra-intestinal disorders. As a modulator of the intestinal microbiota, we isolated a mouse monoclonal IgA antibody (clone W27) with high affinities for multiple commensal bacteria, but not for beneficial bacteria such as Lactobacillus casei (L. casei). Via specific recognition of an epitope in serine hydroxymethyltransferase (SHMT), a bacterial metabolic enzyme, W27 IgA selectively inhibited the in vitro growth of bound bacteria, including Escherichia coli (E...
April 6, 2017: Gut Microbes
https://www.readbyqxmd.com/read/28265077/arsenic-trioxide-targets-mthfd1-and-sumo-dependent-nuclear-de-novo-thymidylate-biosynthesis
#7
Elena Kamynina, Erica R Lachenauer, Aislyn C DiRisio, Rebecca P Liebenthal, Martha S Field, Patrick J Stover
Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)- and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As2O3), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27458476/soybean-cyst-nematode-resistance-emerged-via-artificial-selection-of-duplicated-serine-hydroxymethyltransferase-genes
#8
Xiao-Yi Wu, Guang-Can Zhou, Yun-Xia Chen, Ping Wu, Li-Wei Liu, Fang-Fang Ma, Mian Wu, Cheng-Chen Liu, Ying-Jie Zeng, Alexander E Chu, Yue-Yu Hang, Jian-Qun Chen, Bin Wang
A major soybean (Forrest cultivar) quantitative trait locus (QTL) gene, Rhg4, which controls resistance to soybean cyst nematodes (SCN), encodes the enzyme serine hydroxylmethyltransferase (SHMT). The resistant allele possesses two critical missense mutations (P130R and N358Y) compared to that of the sensitive allele, rhg4. To understand the evolutionary history of this gene, sequences of 117 SHMT family members from 18 representative plant species were used to reconstruct their phylogeny. According to this phylogeny, the plant SHMT gene family can be divided into two groups and four subgroups (Ia, Ib, IIa, and IIb)...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27443667/overexpression-of-halophilic-serine-hydroxymethyltransferase-in-fresh-water-cyanobacterium-synechococcus-elongatus-pcc7942-results-in-increased-enzyme-activities-of-serine-biosynthetic-pathways-and-enhanced-salinity-tolerance
#9
Rungaroon Waditee-Sirisattha, Hakuto Kageyama, Yoshito Tanaka, Minoru Fukaya, Teruhiro Takabe
Serine hydroxymethyltransferase (SHMT) catalyzes the conversion of serine to glycine and provides activated one-carbon units required for synthesis of nucleic acids, proteins and numerous biological compounds. SHMT is involved in photorespiratory pathway of oxygenic photosynthetic organisms. Accumulating evidence revealed that SHMT plays vital role for abiotic stresses such as low CO2 and high salinity in plants, but its role in cyanobacteria remains to be clarified. In this study, we examined to overexpress the SHMT from halotolerant cyanobacterium Aphanothece halophytica in freshwater cyanobacterium, Synechococcus elongatus PCC7942...
January 2017: Archives of Microbiology
https://www.readbyqxmd.com/read/27347936/the-role-of-genetic-polymorphisms-as-related-to-one-carbon-metabolism-vitamin-b6-and-gene-nutrient-interactions-in-maintaining-genomic-stability-and-cell-viability-in-chinese-breast-cancer-patients
#10
Xiayu Wu, Weijiang Xu, Tao Zhou, Neng Cao, Juan Ni, Tianning Zou, Ziqing Liang, Xu Wang, Michael Fenech
Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene-nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls...
June 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27323148/genetic-diversity-of-rhg1-and-rhg4-loci-in-wild-soybeans-resistant-to-soybean-cyst-nematode-race-3
#11
C P Yuan, Y J Wang, H K Zhao, L Zhang, Y M Wang, X D Liu, X F Zhong, Y S Dong
Over-utilization of germplasms that are resistant to the soybean cyst nematode (SCN) in soybean breeding programs can lead to genetic vulnerability in resistant cultivars. Resistant wild soybean (Glycine soja) is considered an invaluable gene source for increasing the genetic diversity of SCN resistance. In this study, we genotyped 23 G. soja accessions that are resistant to SCN race 3 for polymorphisms in the resistance genes, rhg1, Rhg4, and SHMT, and investigated their genetic relationship with eight Glycine max resistant cultivars...
June 10, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27277113/expression-of-serine-glycine-metabolism-related-proteins-is-different-according-to-the-thyroid-cancer-subtype
#12
Woo Young Sun, Hye Min Kim, Woo-Hee Jung, Ja Seung Koo
BACKGROUND: The aim of this study was to investigate the expression and clinical implications of proteins related to serine/glycine metabolism in different subtypes of thyroid cancer. METHODS: Tissue microarray (TMA) was constructed with tissues from 557 thyroid cancers, consisting of 244 papillary thyroid carcinomas (PTC), 112 follicular carcinomas (FC), 70 medullary carcinomas (MC), 23 poorly differentiated carcinomas (PDC), and 8 anaplastic carcinomas (AC). Immunohistochemical staining of the serine/glycine metabolism-related molecules phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase, (PSAT), phosphoserine phosphatase (PSPH), serine hydromethyl transferase (SHMT), and glycine decarboxylase (GLDC) was performed with the TMA blocks and the results were analyzed together with clinicopathologic parameters...
2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27258742/purification-and-characterization-of-serine-hydroxymethyltransferase-from-mitochondria-of-euglena-gracilis-z
#13
Masako Sakamoto, Tsutomu Masuda, Yukio Yanagimoto, Yoshihisa Nakano, Shozaburo Kitaoka, Yoshinori Tanigawa
Mitochondrial serine hydroxymethyltransferase, l-serine: tetrahydrofolate 5,10-hydroxymethyl-transferase (EC 2.1.2.1), (m-SHMT) was extracted and highly purified from Euglena gracilis z. The specific activity increased from the crude extract with 10% yield up to 580-fold through the following steps: ammonium sulfate fractionation, DEAE-cellulose column chromatography and rechromatography, and affinity chromatography with l-lysine-Sepharose 4B. The molecular weight of the purified m-SHMT was 88,000 by gel filtration through Sephadex G-200, and 44,000 by SDS-PAGE...
January 1996: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/27198213/possible-selection-of-host-folate-pathway-gene-polymorphisms-in-patients-with-malaria-from-a-malaria-endemic-region-in-north-east-india
#14
Darshana Mirgal, Kanjaksha Ghosh, Jagadish Mahanta, Prafulla Dutta, Shrimati Shetty
BACKGROUND: Recent studies in experimental mice have shown that mild deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme confers protection against malaria, thus providing an important basis for the hypothesis that MTHFR polymorphism, i.e. C677T, might have been subjected to selection pressure against malaria. The present study was undertaken in a malaria endemic region in North East India to assess whether a similar selection advantage exists for other genes in folate metabolism pathway...
May 2016: Transactions of the Royal Society of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/26993328/elucidation-of-salt-tolerance-metabolic-pathways-in-contrasting-rice-genotypes-and-their-segregating-progenies
#15
Pragya Mishra, Vagish Mishra, Teruhiro Takabe, Vandna Rai, Nagendra Kumar Singh
Differentially expressed antioxidant enzymes, amino acids and proteins in contrasting rice genotypes, and co-location of their genes in the QTLs mapped using bi-parental population, indicated their role in salt tolerance. Soil salinity is a major environmental constraint limiting rice productivity. Salt-tolerant 'CSR27', salt-sensitive 'MI48'and their extreme tolerant and sensitive recombinant inbred line (RIL) progenies were used for the elucidation of salt stress tolerance metabolic pathways. Salt stress-mediated biochemical and molecular changes were analyzed in the two parents along with bulked-tolerant (BT) and bulked-sensitive (BS) extreme RILs...
June 2016: Plant Cell Reports
https://www.readbyqxmd.com/read/26868981/inactivation-of-the-cytosolic-and-mitochondrial-serine-hydroxymethyl-transferase-genes-in-leishmania-major
#16
Gaétan Roy, Marc Ouellette
Leishmania has two serine hydroxylmethyl transferase (SHMT) genes, one coding for a cytosolic and the other for a mitochondrial enzyme. Trypanosoma cruzi has only the gene coding for the cytosolic enzyme and Trypanosoma brucei has no SHMT. We tested whether these genes were dispensable for growth in Leishmania major. By gene inactivation we succeeded in generating three cells lines one without the cytosolic cSHMT, one without the mitochondrial mSHMT, and finally one L. major line without any SHMT. SHMT is thus dispensable for growth of Leishmania in rich medium...
December 2015: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/26717037/a-pyrazolopyran-derivative-preferentially-inhibits-the-activity-of-human-cytosolic-serine-hydroxymethyltransferase-and-induces-cell-death-in-lung-cancer-cells
#17
Marina Marani, Alessio Paone, Alessio Fiascarelli, Alberto Macone, Maurizio Gargano, Serena Rinaldo, Giorgio Giardina, Valentino Pontecorvi, David Koes, Lee McDermott, Tianyi Yang, Alessandro Paiardini, Roberto Contestabile, Francesca Cutruzzolà
Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients and NSCLC cell lines. Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis...
January 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/26673393/methylation-diet-and-methyl-group-genetics-in-risk-for-adenomatous-polyp-occurrence
#18
Mark Lucock, Zoë Yates, Charlotte Martin, Jeong-Hwa Choi, Emma Beckett, Lyndell Boyd, Kathleen LeGras, Xiaowei Ng, Virginia Skinner, Ron Wai, Jeremy Kho, Paul Roach, Martin Veysey
PURPOSE: The aim of this study is to explore whether a methylation diet influences risk for adenomatous polyps (AP) either independently, or interactively with one-carbon metabolism-dependent gene variants, and whether such a diet modifies blood homocysteine, a biochemical phenotype closely related to the phenomenon of methylation. METHODS: 249 subjects were examined using selective fluorescence, PCR and food frequency questionnaire to determine homocysteine, nine methylation-related gene polymorphisms, dietary methionine, 5-methyltetrahydrofolate, vitamins B6 and B12...
June 2015: BBA Clinical
https://www.readbyqxmd.com/read/26574511/2-aminoacrylate-stress-induces-a-context-dependent-glycine-requirement-in-rida-strains-of-salmonella-enterica
#19
Dustin C Ernst, Diana M Downs
UNLABELLED: The reactive enamine 2-aminoacrylate (2AA) is a metabolic stressor capable of damaging cellular components. Members of the broadly conserved Rid (RidA/YER057c/UK114) protein family mitigate 2AA stress in vivo by facilitating enamine and/or imine hydrolysis. Previous work showed that 2AA accumulation in ridA strains of Salmonella enterica led to the inactivation of multiple target enzymes, including serine hydroxymethyltransferase (GlyA). However, the specific cause of a ridA strain's inability to grow during periods of 2AA stress had yet to be determined...
November 16, 2015: Journal of Bacteriology
https://www.readbyqxmd.com/read/26441084/metabolic-flux-analysis-of-the-halophilic-archaeon-haladaptatus-paucihalophilus
#20
Guangxiu Liu, Manxiao Zhang, Tianlu Mo, Lian He, Wei Zhang, Yi Yu, Qi Zhang, Wei Ding
This work reports the (13)C-assisted metabolic flux analysis of Haladaptatus paucihalophilus, a halophilic archaeon possessing an intriguing osmoadaption mechanism. We showed that the carbon flow is through the oxidative tricarboxylic acid (TCA) cycle whereas the reductive TCA cycle is not operative in H. paucihalophilus. In addition, both threonine and the citramalate pathways contribute to isoleucine biosynthesis, whereas lysine is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway...
November 27, 2015: Biochemical and Biophysical Research Communications
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