Transferases articles within Nature Communications

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  • Article
    | Open Access

    Coactivator-associated arginine methyltransferase 1 (CARM1) is an important target in hematologic malignancies. In this work, the authors show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates CARM1 which regulates its methyltransferase activity and alters its target specificity.

    • Hidehiro Itonaga
    • , Adnan K. Mookhtiar
    •  & Stephen D. Nimer

  • Article
    | Open Access

    Much is still unknown of the evolution of animal metabolic enzymes. This study describes a new enzyme family bridging the production of polyketides and membrane lipids. This expands the known biochemical repertoire of animals for making ecologically and biomedically important natural products.

    • Zhenjian Lin
    • , Feng Li
    •  & Eric W. Schmidt

  • Article
    | Open Access

    Apiosides are plant bioactive natural products containing apiose, but the details of the key apiosylation reaction in their biosynthesis are missing. Here, the authors identify the apiosyltransferase GuApiGT that could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, solve its crystal structure and obtain mutants with altered sugar selectivity.

    • Hao-Tian Wang
    • , Zi-Long Wang
    •  & Min Ye

  • Article
    | Open Access

    Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.

    • Douglas Sammon
    • , Anja Krueger
    •  & Erhard Hohenester

  • Article
    | Open Access

    The ability to rationally remodel enzyme conformational landscapes to modify catalytic properties is limited. Here, the authors, using a computational procedure, redesign the conformational landscape of an aminotransferase to stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate.

    • Antony D. St-Jacques
    • , Joshua M. Rodriguez
    •  & Roberto A. Chica

  • Article
    | Open Access

    Currently little is known about the acetylation on sugar moieties. Here the authors report a saponin acetyltransferase from Astragalus membranaceus, AmAT7-3, and utilise crystal structures and QM/MM computation to elucidate the catalytic mechanism: they generate mutants for specific site acetylation.

    • Linlin Wang
    • , Zhihui Jiang
    •  & Xue Qiao

  • Comment
    | Open Access

    Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.

    • Sara Weirich
    •  & Albert Jeltsch

  • Article
    | Open Access

    Bacterial resistance to sulfonamide antibiotics (sulfas) is mediated by acquisition of sul genes, which encode sulfa-insensitive versions of the target enzyme, dihydropteroate synthase. Here, Venkatesan et al. study Sul enzymes using biochemical, structural, mutational and functional analyses, revealing the molecular basis for Sul-mediated drug resistance.

    • Meenakshi Venkatesan
    • , Michael Fruci
    •  & Alexei Savchenko

  • Article
    | Open Access

    Diketopiperazine (DKP) natural products have diverse structures and biological functions. Here, the authors elucidate the biosynthetic pathway for indole alkaloid DKP nocardioazine B which includes DKP stereoisomerization by an unusual aspartate/glutamate racemase homolog and N- and C-methylation by a dual function methyltransferase.

    • Garrett Deletti
    • , Sajan D. Green
    •  & Amy L. Lane

  • Article
    | Open Access

    Monkeypox virus is a pathogen with pandemic potential, encoding for its own RNA capping machinery. Here, the authors present crystal structures of its 2′-O-RNA methyltransferase VP39 in complex with sub-micromolar inhibitors and reveal similarities to SARS-CoV−2 nsp14 methyltransferase.

    • Jan Silhan
    • , Martin Klima
    •  & Evzen Boura

  • Article
    | Open Access

    The enzyme ATE1 catalyzes eukaryotic post-translation arginylation, a key protein modification necessary for cellular homeostasis. Here, the authors show that ATE1s are previously unrealized iron-sulfur proteins that use this oxygen-sensitive inorganic cofactor to control cellular arginylation

    • Verna Van
    • , Janae B. Brown
    •  & Aaron T. Smith

  • Article
    | Open Access

    Retrosynthetic pathway design using promiscuous enzymes can provide a solution to the biosynthetic production of natural products. Here, the authors design a pathway for the production of cis-α-irone with a promiscuous methyltransferase using structure-guided enzyme engineering strategies.

    • Xixian Chen
    • , Rehka T
    •  & Isabelle André

  • Article
    | Open Access

    Access to glycoenzymes for basic and applied research is limited by difficulties with their recombinant expression. Here, the authors describe a universal strategy for converting membrane-bound glycosyltransferases into water-soluble biocatalysts, which are expressed at high levels with retention of activity.

    • Thapakorn Jaroentomeechai
    • , Yong Hyun Kwon
    •  & Matthew P. DeLisa

  • Article
    | Open Access

    Pyruvate Carboxylase is a multifunctional enzyme that follows a multi-pathway reaction. Here, the authors, using cryoEM and classification techniques, reveal several catalytic states at reaction sites, the interplay between them, and their relationship with motions in the tetrameric organization.

    • Jorge Pedro López-Alonso
    • , Melisa Lázaro
    •  & Mikel Valle

  • Article
    | Open Access

    The market demand for acarbose, a drug used for treatment of patients affected by type-2 diabetes, has increased. In this article, the authors report the acarbose complete biosynthetic pathway, clarifying previously unknown steps and identifying a pseudoglycosyltransferase enzyme, AcbS, a homologue of AcbI that catalyzes the formation of a non-glycosidic C-N bond.

    • Takeshi Tsunoda
    • , Arash Samadi
    •  & Taifo Mahmud

  • Article
    | Open Access

    Glycogen is a major energy reserve in eukaryotes and is synthesised in part by glycogenin (GN) and glycogen synthase (GS). Here, authors describe the structural basis of GS regulation, specifically the mechanism of inactivation by phosphorylation.

    • Laura Marr
    • , Dipsikha Biswas
    •  & Elton Zeqiraj

  • Article
    | Open Access

    S-methyl methionine (SMM) is a key molecule in production of dimethylsulfoniopropionate (DMSP), an important marine anti-stress compound, with roles in global nutrient cycling. Here, the authors determine the mechanism of SMM synthesis and uncover unexpected roles for SMM in archaea, CPR bacteria and animals.

    • Ming Peng
    • , Chun-Yang Li
    •  & Yu-Zhong Zhang

  • Article
    | Open Access

    The colonic mucus layer is an organized system providing a physical barrier against pathogens and simultaneously harbouring the commensal flora. Here the authors report that transglutaminase 3 activity contributes to homeostasis of the colonic mucus layer and the lack of this enzymatic activity leads to increased susceptibility against DSS-induced colitis in mice.

    • Jack D. A. Sharpen
    • , Brendan Dolan
    •  & Christian V. Recktenwald

  • Article
    | Open Access

    The modification of proteins with O-linked β-N-acetylglucosamine (OGlcNAc) plays roles in regulation of numerous cellular functions while incorrect O-GlcNAcylation patterns are linked to disease. Here, the authors report a cryo-EM structure of full-length O-GlcNAc transferase (OGT), the only enzyme responsible for O-GlcNAcylation.

    • Richard W. Meek
    • , James N. Blaza
    •  & Gideon J. Davies

  • Article
    | Open Access

    The Clostridium difficile virulence factors TcdA and TcdB contain a glucosyltransferase domain (GTD), which has both glucohydrolase (GH) and glucosyltransferase (GT) activities. Here, the authors characterize the transition state features of the TcdA and TcdB GH reactions by measuring kinetic isotope effects and they identify two transition state analogues, isofagomine and noeuromycin that inhibit TcdA and TcdB. They also present the crystal structures of TcdB-GTD bound to these inhibitors and the reaction product UDP.

    • Ashleigh S. Paparella
    • , Briana L. Aboulache
    •  & Vern L. Schramm

  • Article
    | Open Access

    The polycomb repressive complex 2 (PRC2) is a histone methyltransferase regulating cell differentiation and identity. Here, the authors show that the vertebrate-specific PRC2 accessory subunit PALI1 facilitates substrate binding by the complex and elucidate the allosteric mechanism of PALI1- mediated PRC2 activation.

    • Qi Zhang
    • , Samuel C. Agius
    •  & Chen Davidovich

  • Article
    | Open Access

    Histone H3K9 methylation (H3K9me) states define repressed chromatin in eukaryotic cells. Here the authors reveal complete loss of all H3K9me in mammalian cells through successive deletion of H3K9 methyltransferase genes that results in the dissolution of heterochromatin and the derepression of nearly all repeat families.

    • Thomas Montavon
    • , Nicholas Shukeir
    •  & Thomas Jenuwein

  • Article
    | Open Access

    Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, an intracrine mediator of cell death. Structural, biochemical and computational analyses of human MGST2 suggest a mechanism employed by the enzyme to restrict catalysis to only one active site within the MGST2 trimer.

    • Madhuranayaki Thulasingam
    • , Laura Orellana
    •  & Jesper Z. Haeggström

  • Article
    | Open Access

    PARP1 is the target of clinically approved anti-cancer drugs whose in vivo efficacy has been hard to predict. Here the authors show how an altered active site formed between PARP1 and Histone PARylation Factor 1 (HPF1) changes the efficacy of some of these inhibitors.

    • Johannes Rudolph
    • , Genevieve Roberts
    •  & Karolin Luger

  • Article
    | Open Access

    Saponins such as glycyrrhizin, a natural sweetener found in licorice root, are a class of triterpenoids synthesized that are characterized by a glucoronic acid moiety at the C-3 position. Here the authors show that saponin glucuronosylation is catalyzed by cellulose-synthase like enzymes and reconstitute glycyrrhizin synthesisin yeast.

    • Soo Yeon Chung
    • , Hikaru Seki
    •  & Toshiya Muranaka

  • Article
    | Open Access

    The human cis-prenyltransferase (hcis-PT) complex synthesizes the precursor of the glycosyl carrier dolichol-phosphate and as such it is essential for protein N-glycosylation. The crystal structure of the complex reveals unusual tetrameric architecture and provides insights into dolichol synthesis mechanism and functional consequences of disease-associated hcis-PT mutations.

    • Michal Lisnyansky Bar-El
    • , Pavla Vaňková
    •  & Moshe Giladi

  • Article
    | Open Access

    Impaired oligodendrocyte (OL) differentiation and remyelination after myelin damage in multiple sclerosis is associated with neurodegeneration. The authors show that Gsta4 is expressed during adult OL differentiation and identify it as a regulator of OL differentiation, survival, and remyelination.

    • Karl E. Carlström
    • , Keying Zhu
    •  & Fredrik Piehl

  • Article
    | Open Access

    The cryo-EM structure of Mycobacterium smegmatis arabinosyltransferase B EmbB involved in mycobacterial cell wall biosynthesis provides insights into the substrate binding and reaction mechanism. Mapping of the ethambutol resistance associated mutations onto the structure suggests the location of the drug binding site.

    • Yong Zi Tan
    • , José Rodrigues
    •  & Filippo Mancia

  • Article
    | Open Access

    Mutation of the C-terminal extension of 5′-aminolevulinate synthase 2 (ALAS2) is the molecular cause for X-linked protoporphyria, but the underlying mechanism is unclear. Based on crystal structures and MD simulations of ALAS2, the authors here show how the C-terminal extension regulates ALAS2 activity.

    • Henry J. Bailey
    • , Gustavo A. Bezerra
    •  & Wyatt W. Yue

  • Article
    | Open Access

    Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.

    • Magdalena M. Szewczyk
    • , Yoshinori Ishikawa
    •  & Dalia Barsyte-Lovejoy

  • Article
    | Open Access

    The DNA methyltransferase DNMT3A plays an important role in establishing the DNA methylation patterns during development and deregulation of DNMT3A is associated with hematological cancers, with the R882H mutation the most frequently occurring DNMT3A missense mutation in acute myeloid leukemia. Here, the authors present the crystal structures of wild-type and R882H DNMT3A in complex with different DNA substrates and explain why the R882H mutation compromises the enzymatic activity of DNMT3A.

    • Hiwot Anteneh
    • , Jian Fang
    •  & Jikui Song

  • Article
    | Open Access

    N-terminal glycine myristoyl transferases (NMTs) catalyse the myristoylation of eukaryotic proteins. Here, the authors provide insights into the catalytic mechanism of NMTs by determining the crystal structures of human NMT1 in complex with reactive cognate lipid and peptide substrates and further show that NMT1 also catalyses the acylation of N-terminal lysines.

    • Cyril Dian
    • , Inmaculada Pérez-Dorado
    •  & Carmela Giglione

  • Article
    | Open Access

    PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays

    • Abdellah Allali-Hassani
    • , Magdalena M. Szewczyk
    •  & Masoud Vedadi

  • Article
    | Open Access

    The N6-methyladenosine (m6A) RNA modification is an evolutionarily conserved epitranscriptomic mechanism that impacts several cellular processes. Here the authors present a structure-function analysis of the ZCCHC4, 28S RNA-specific m6A methyltransferase, shedding light on its regulation and mechanisms that ensure substrate specificity.

    • Wendan Ren
    • , Jiuwei Lu
    •  & Jikui Song

  • Article
    | Open Access

    Phosphonate modifications can be present on microbial cell surfaces. Here the authors perform bioinformatics analyses and observe a widespread occurrence of nucleotidyltransferase-encoding genes in bacterial phosphonate biosynthesis and functionally characterize two of the identified phosphonate specific cytidylyltransferases (PntCs) and determine the crystal structure of T. denticola PntC.

    • Kyle Rice
    • , Kissa Batul
    •  & Geoff P. Horsman

  • Article
    | Open Access

    Phospho-MurNAc-pentapeptide translocase (MraY) is a bacterial integral membrane enzyme that is essential for peptidoglycan biosynthesis. Here the authors present the crystal structures of MraY from Aquifex aeolicus bound to caprazamycin, capuramycin and mureidomycin and discuss the implications for antibiotic development.

    • Ellene H. Mashalidis
    • , Benjamin Kaeser
    •  & Seok-Yong Lee

  • Article
    | Open Access

    Rotaviruses are of great medical significance because they cause gastroenteritis in children. Here the authors provide insights into the mechanism of viral mRNA transcription by determining the in situ cryo-EM structures of a working rotavirus’ RNA-dependent-RNA polymerase, which is of interest for antiviral drug design.

    • Ke Ding
    • , Cristina C. Celma
    •  & Z. Hong Zhou

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