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Leading-edge Biotechnology Research Group

Project

Project1:Development of heterologous expression system for the biosynthesis of natural compounds
Researcher:Kazuo Shin-ya, Hikaru Suenaga, Takuya Hashimoto, Kei Kudo

Recent studies revealed that human beings can draw only 1/3 of total ability of the natural compound production by conventional fermentation technology. Our research program targets the development of the next-generation natural compound production technology which leads the production of novel compounds by heterologous expression system applying on cryptic biosynthetic genes. In addition, we perform natural compounds with complex structures which is essential for fine tunings in the drug developments such as improvement of pharmacokinetics, avoidance of side effects and so on. By employing these techniques, we contribute to drug developments.

Leading-edge Biotechnology Research Group02

Project

Project2:Drug screening with World-largest natural library
Researcher:Kazuo Shin-ya, Hikaru Suenaga, Takuya Hashimoto, Kei Kudo

Natural product library has been applied for drug development, therefore more than 60 percent of the clinical drugs are originated from natural compounds. Pharmaceutical companies provided their natural product library establishing World-largest natural library in our laboratory. We are developing wide range of drug screening for clinical drugs, animal drugs, agricultural chemicals, etc., on various drug targets provided by not only industrial companies but also basic research academia.

Leading-edge Biotechnology Research Group03

Project

Project3:Biosynthesis and function of sulfur-modification in tRNA
Researcher:Naoki Shigi

Post-transcriptional modification is one of the characteristic features of RNA. Among them, sulfur modifications of tRNA are important for tRNA functions, such as codon recognition and stabilization of the tertiary structure [Fig. 1].
In a thermophilic bacteria, activated sulfur which bond to a sulfur-carrier protein TtuB [Fig. 2] is transferred to tRNA by a sulfur transferase. TtuB may have evolved to safely deliver reactive sulfur to tRNAs. TtuB possesses ubiquitin-like structure and also function as post-translational modifier of many proteins [Fig. 2]. We are studying the biosynthesis mechanism of sulfur-modification and its regulation mechanisms in order to develop new drugs.

Leading-edge Biotechnology Research Group04

Project

Project4:Ultra-high-resolution and high precision mass spectrometry of animal and plant tissues
Researcher:Katsutoshi Takahashi

MALDI imaging mass spectrometry (imaging MS) has been a powerful tool to map the spatial distribution of molecules on the surface of biological materials. This technique has frequently been applied to animal tissue slices for the purpose to map proteins, peptides , lipids, sugars or small metabolites to find disease specific bio-markers or to study drag metabolism. We developed a new in-house built imaging mass spectrometer with modifying MALDI/LDI-FTICR-MS. Employing this mass spectrometer, the imaging MS with ultra-high-mass resolution (> 100,000), ultra-high-molecular mass accuracy (< 1 ppm) and high-spatial resolution (< 10 mm) can be applicable to both of animal and plant tissues, elucidating the precise localization of various small metabolites and unknown compounds with determining precise mass and elemental composition of them.

Leading-edge Biotechnology Research Group05

Member

Name Position
SHIN-YA Kazuo Research Group Leader
TAKAHASHI Katsutoshi Senior Researcher
SUENAGA Hikaru Senior Researcher
SHIGI Naoki Senior Researcher
HASHIMOTO Takuya Researcher
KUDO Kei Researcher

Results

  • Gadgil RY, Romer EJ, Goodman CC, Rider SD Jr, Damewood FJ 4th, Barthelemy JR, Shin-Ya K, Hanenberg H, Leffak M.
    Replication stress at microsatellites causes DNA double strand breaks and break induced replication.
    J BIOL CHEM jbc.RA120.013495. (2020)doi: 10.1074/jbc.RA120.013495
  • Jo T, Nishikori M, Kogure Y, Arima H, Sasaki, K; Sasaki Y, Nakagawa T, Iwai F, Momose S; Shiraishi A; Kiyonari H, Kagaya N, Onuki T, Shin-ya K, Yoshida M, Kataoka K, Ogawa S, Iwai K, Takaori-Kondo A
    LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
    BLOOD 136 (6) :684-697 (2020) doi: 10.1182/blood.2019002654
  • Hayakawa Y, Yoshida T, Kimata S,Shin-Ya K
    Dunaimycin C3, a new GRP78 downregulator fromStreptomyces sp. RAN389
    J. Antibiotics 32: 0 (2020) doi: 10.1038/s41429-020-0356-8
  • Kataura T, Tashiro E, Nishikawa S, Shibahara K, Muraoka Y, Miura M, Sakai S, Katoh N, Totsuka M, Onodera M,Shin-Ya K,Miyamoto K, Sasazawa Y, Hattori N, Saiki S, Imoto M
    A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers
    AUTOPHAGY; Aug 7;1-17 (2020) doi: 10.1080/15548627.2020.1794590
  • Kudo K,Hashimoto T,Hashimoto J, Kozone I, Kagaya N,Ueoka R,Nishimura T, Komatsu M,Suenaga H,Ikeda H,Shin-Ya K
    In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives
    Nat Commun. 11:4022. (2020) doi: 10.1038/s41467-020-17769-2
  • Hayakawa Y, Yaguchi R, Akimoto M, Kimata S, Shin-Ya K
    Neocurromycin A, a new GRP78 downregulator from Streptomyces sp. RAI364
    J Antibiot 0: 0 (2020) doi: 10.1038/s41429-020-0339-9
  • Kurosawa S, Matsuda K, Hasebe F, Shiraishi T, Shin-Ya K, Kuzuyama T, Nishiyama M
    Guanidyl modification of the 1-azabicyclo[3.1.0]hexane ring in ficellomycin essential for its biological activity
    Org Biomol Chem. 25: 0 (2020) doi: 10.1039/d0ob00339e
  • Hashimoto T, Kozone I, Hashimoto J, Suenaga H, Fujie M, Satoh N, Ikeda H, Shin-Ya K
    Identification, Cloning and Heterologous Expression of Biosynthetic Gene Cluster for Desertomycin
    J Antibiot. (2020) doi: 10.1038/s41429-020-0319-0
  • Maruyama C, Chinone Y, Sato S, Kudo F, Ohsawa K, Kubota J, Hashimoto J, Kozone I, Doi T, Shin-Ya K, Eguchi T, Hamano Y
    C-Methylation of S-adenosyl-L-Methionine Occurs Prior to Cyclopropanation in the Biosynthesis of 1-Amino-2-Methylcyclopropanecarboxylic Acid (Norcoronamic Acid) in a Bacterium
    Biomolecules 10: E775 (2020) doi: 10.3390/biom10050775
  • Jo T, Nishikori M, Kogure Y, Arima H, Sasaki K, Sasaki Y, Nakagawa T, Iwai F, Momose S, Shiraishi A, Kiyonari H, Kagaya N, Onuki T, Shin-Ya K, Yoshida M, Kataoka K, Ogawa S, Iwai K, Takaori-Kondo A.
    LUBAC Accelerates B-cell Lymphomagenesis by Conferring B Cells Resistance to Genotoxic Stress
    Blood (2020) doi: 10.1182/blood.2019002654
  • Kawahara T, Itoh M, Izumikawa M, Kagaya N, Sakata N, Tsuchida T, Shin-Ya K
    New phenylspirodrimane metabolites MBJ-0030, MBJ-0031, and MBJ-0032 isolated from the soil fungal strain Stachybotrys sp. f23793
    Biosci Biotechnol Biochem.(2020) doi: 10.1080/09168451.2020.1757402
  • Chen MH, Ishizaka M, Narai S, Horitani M, Shigi N, Yao M, Tanaka Y
    The [4Fe-4S] cluster of sulfurtransferase TtuA desulfurizes TtuB during tRNA modification in Thermus thermophilus
    Commun Biol. 3: 168 (2020) doi: 10.1038/s42003-020-0895-3
  • Shigi N, Horitani M, Miyauchi K, Suzuki T, Kuroki M
    An ancient type of MnmA protein is an iron-sulfur cluster-dependent sulfurtransferase for tRNA anticodons
    RNA 26: 240-250 (2020) doi: 10.1261/rna.072066.119
  • Hashimoto T, Kozone I, Hashimoto J, Ueoka R, Kagaya N, Fujie M, Sato N, Ikeda H, Shin-ya K
    Novel macrolactam compound produced by the heterologous expression of a large cryptic biosynthetic gene cluster of Streptomyces rochei IFO12908
    J Antibiot. 73: 171-174 (2020) doi: 10.1038/s41429-019-0265-x
  • Demachi A, Uchida R, Arima S, Nagamitsu T, Hashimoto J, Komatsu M, Kozone I, Shin-Ya K, Tomoda H, Ikeda H
    An Unusual Extender Unit Is Incorporated into the Modular Polyketide Synthase of Scopranones Biosynthesis
    Biochem. 58: 5066-5073 (2019) doi: 10.1021/acs.biochem.9b00908
  • Yamamoto K, Takahashi K, Caputi L, Mizuno H, Rodriguez-Lopez CE, Iwasaki T, Ishizaki K, Fukaki H, Ohnishi M, Yamazaki M, Masujima T, OConnor SE, Mimura T
    The complexity of intercellular localisation of alkaloids revealed by single-cell metabolomics
    New Phytol. 224: 848-859 (2019) doi: 10.1111/nph.16138
  • Romo AJ, Shiraishi T, Ikeuchi H, Lin GM, Geng YJ, Lee YH, Liem, PH, Ma TL, Ogasawara Y, Shin-Ya K, Nishiyama M, Kuzuyama T, Liu HW
    The Amipurimycin and Miharamycin Biosynthetic Gene Clusters: Unraveling the Origins of 2-Aminopurinyl Peptidyl Nucleoside Antibiotics
    J Am Chem Soc. 141: 14152-14159 (2019) doi: 10.1021/jacs.9b03021
  • Takase S, Kurokawa R, Kondoh Y, Honda K, Suzuki T, Kawahara T, Ikeda H, Dohmae N, Osada H, Shin-Ya K, Kushiro T, Yoshida M, Matsumoto K
    Mechanism of Action of Prethioviridamide, an Anticancer Ribosomally Synthesized and Post-Translationally Modified Peptide with a Polythioamide Structure
    ACS Chem Biol. 14: 1819-1828 (2019) doi: 10.1021/acschembio.9b00410
  • Murashima A, Shinjo K, Katsushima K, Onuki T, Kondoh Y, Osada H, Kagaya N, Shin-ya K, Kimura H, Yoshida M, Murakami S, Kondo Y
    Identification of a chemical modulator of EZH2-mediated silencing by cell-based high-throughput screening assay
    J Biochem. 166: 41-50 (2019) doi: 10.1093/jb/mvz007
  • Kudo K, Koiwai H, Kagaya N, Nishiyama M, Kuzuyama T, Shin-Ya K, Ikeda H
    Comprehensive Derivatization of Thioviridamides by Heterologous Expression
    ACS Chem Biol.14: 1135-1140 (2019) doi: 10.1021/acschembio.9b00330
  • Hirose J, Fujihara H, Watanabe T, Kimura N, Suenaga H, Futagami T, Goto M, Suyama A, Furukawa K
    Biphenyl/PCB Degrading bph Genes of Ten Bacterial Strains Isolated from Biphenyl-Contaminated Soil in Kitakyushu, Japan: Comparative and Dynamic Features as Integrative Conjugative Elements (ICEs)
    Genes 10: 10 (2019) doi: 10.3390/genes10050404
  • Kobayashi M, Tomita T, Shin-ya K, Nishiyama M, Kuzuyama T
    An Unprecedented Cyclization Mechanism in the Biosynthesis of Carbazole Alkaloids in Streptomyces
    Angew Chem Int Ed Engl. 189: 233-248 (2019) doi: 10.1002/anie.201906864
  • Oda S, Nomura S, Nakagawa M, Shin-Ya K, Kagaya N, Kawahara T
    Solid-liquid Interface Screening SystemApplication to the Screening of Antibiotic and Cytotoxic Substance-producing Fungi
    Biocontrol Sci. 24: 47-56 (2019) doi: 10.4265/bio.24.47
  • Xiao A, Brenneman B, Floyd D, Comeau L, Spurio K, Olmez I, Lee J, Nakano I, Godlewski J, Bronisz A, Kagaya N, Shin-Ya K, Purow B
    Statins affect human glioblastoma and other cancers through TGF-beta inhibition
    Oncotarget 10: 1716-1728 (2019) doi: 10.18632/oncotarget.26733
  • Hashimoto T, Hashimoto J, Kozone I, Amagai K, Kawahara T, Takahashi S, Ikeda H, Shin-Ya K
    Biosynthesis of Quinolidomicin, the Largest Known Macrolide of Terrestrial Origin: Identification and Heterologous Expression of a Biosynthetic Gene Cluster over 200 kb
    Org Lett. 20: 7996-7999 (2018) doi: 10.1021/acs.orglett.8b03570
  • Ohsawa K, Yoshida M, Izumikawa M, Takagi M, Shin-Ya K, Goshima N, Hirokawa T, Natsume T, Doi T
    Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer
    Bioorg Med Chem. 10: 185 (2018) doi: 10.1016/j.bmc.2018.11.001
  • Thong WL, Shin-Ya K, Nishiyama M, Kuzuyama T
    Discovery of an Antibacterial Isoindolinone-Containing Tetracyclic Polyketide by Cryptic Gene Activation and Characterization of Its Biosynthetic Gene Cluster
    ACS Chem Biol. 13: 2615-2622 (2018) doi: 10.1021/acschembio.8b00553
  • Awakawa T, Fujioka T, Zhang L, Hoshino S, Hu Z, Hashimoto J, Kozone I, Ikeda H, Shin-Ya K, Liu W, Abe I
    Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution
    Nat Commun. 9: 3534 (2018) doi: 10.1038/s41467-018-05877-z
  • Matsuda K, Tomita T, Shin-Ya K, Wakimoto T, Kuzuyama T, Nishiyama M
    Discovery of Unprecedented Hydrazine-Forming Machinery in Bacteria
    J Am Chem Soc. 140: 9083-9086 (2018) doi: 10.1021/jacs.8b05354
  • Bharti SK, Sommers JA, Awate S, Bellani MA, Khan I, Bradley L, King GA, Seol Y, Vidhyasagar V, Wu Y, Abe T, Kobayashi K, Shin-Ya K, Kitao H, Wold MS, Branzei D, Neuman KC, Brosh RM Jr
    A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair
    Nucleic Acids Res. 46: 6238-6256 (2018) doi: 10.1093/nar/gky403
  • Kim JH, Komatsu M, Shin-Ya K, Omura S, Ikeda H
    Distribution and functional analysis of the phosphopantetheinyl transferase superfamily in Actinomycetales microorganisms
    Proc Natl Acad Sci U S A. 115: 6828-6833 (2018) doi: 10.1073/pnas.1800715115
  • Tsutsumi H, Katsuyama Y, Izumikawa M, Takagi M, Fujie M, Satoh N, Shin-ya K, Ohnishi Y
    Unprecedented Cyclization Catalyzed by a Cytochrome P450 in Benzastatin Biosynthesis
    J Am Chem Soc. 140: 6631-6639 (2018) doi: 10.1021/jacs.8b02769
  • Kimura N, Watanabe T, Suenaga H, Fujihara H, Futagami T, Goto M, Hanada S, Hirose J
    Pseudomonas furukawaii sp nov., a polychlorinated biphenyl-degrading bacterium isolated from biphenyl-contaminated soil in Japan
    Int J Sys Evol Microbiol. 68: 1429-1435 (2018) doi: 10.1099/ijsem.0.002670
  • Shigi N
    Recent Advances in Our Understanding of the Biosynthesis of Sulfur Modifications in tRNAs
    Front Microbiol. 67: 347-353 (2018) doi: 10.3389/fmicb.2018.02679
  • Kawahara T, Fujiwara T, Kagaya N, Shin-Ya K
    JBIR-150, a novel 20-membered polyene macrolactam from marine-derived Streptomyces sp. OPMA00071
    J Antibiot. 71: 390-392 (2018) doi: 10.1038/s41429-017-0010-2
  • Kawahara T, Izumikawa M, Kozone I, Hashimoto J, Kagaya N, Koiwai H, Komatsu M, Fujie M, Sato N, Ikeda H, Shin-Ya K
    Neothioviridamide, a Polythioamide Compound Produced by Heterologous Expression of a Streptomyces sp. Cryptic RiPP Biosynthetic Gene Cluster
    J Nat Prod. 81: 264-269 (2018) doi: 10.1021/acs.jnatprod.7b00607
  • Du D, Katsuyama Y, Shin-Ya K, Ohnishi Y
    Reconstitution of a Type II Polyketide Synthase that Catalyzes Polyene Formation
    Angew Chem Int Ed Engl. 57: 1954-1957 (2018) doi: 10.1002/anie.201709636
  • Niikura H, Maruyama C, Ogasawara Y, Shin-ya K, Dairi T, Hamano Y
    Functional analysis of methyltransferases participating in streptothricin-related antibiotic biosynthesis
    J Biosci Bioeng. 125: 148-154 (2018) doi: 10.1016/j.jbiosc.2017.09.004
  • Ito S, Ogawa K, Takeuchi K, Takagi M, Yoshida M, Hirokawa T, Hirayama S, Shin-ya K, Shimada I, Doi T, Goshima N, Natsume T, Nagata K
    A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis
    J Biol Chem. 292: 20076-20085 (2017) doi: 10.1074/jbc.M117.815936
  • Suenaga H, Fujihara H, Kimura N, Hirose J, Watanabe T, Futagami T, Goto M, Shimodaira J, Furukawa K
    Insights into the genomic plasticity of Pseudomonas putida KF715, a strain with unique biphenyl-utilizing activity and genome instability properties
    Environ Microbiol Rep. 9: 589-598 (2017) doi: 10.1111/1758-2229.12561
  • Takeda K, Kemmoku K, Satoh Y, Ogasawara Y, Shin-ya K, Dairi T
    N-Phenylacetylation and Nonribosomal Peptide Synthetases with Substrate Promiscuity for Biosynthesis of Heptapeptide Variants, JBIR-78 and JBIR-95
    ACS Chem Biol. 12: 1813-1819 (2017) doi: 10.1021/acschembio.7b00314
  • Amagai K, Ikeda H, Hashimoto J, Kozone I, Izumikawa M, Kudo F, Eguchi T, Nakamura T, Osada H, Takahashi S, Shin-ya K
    Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
    Sci Rep. 7: 3382 (2017) doi: 10.1038/s41598-017-03308-5
  • Nakamura T, Okabe S, Yoshida H, Iida K, Ma Y, Sasaki S, Yamori T, Shin-Ya K, Nakano I, Nagasawa K, Seimiya H
    Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole
    Sci Rep. 7: 3605 (2017) doi: 10.1038/s41598-017-03785-8
  • Chen M, Asai SI, Narai S, Nambu S, Omura N, Sakaguchi Y, Suzuki T, Ikeda-Saito M, Watanabe K, Yao M, Shigi N, Tanaka Y
    Biochemical and structural characterization of oxygen-sensitive 2-thiouridine synthesis catalyzed by an iron-sulfur protein TtuA
    Proc Natl Acad Sci U S A. 114: 4954-4959 (2017) doi: 10.1073/pnas.1615585114
  • Kudo K, Ozaki T, Shin-ya K, Nishiyama M, Kuzuyama T
    Biosynthetic Origin of the Hydroxamic Acid Moiety of Trichostatin A: Identification of Unprecedented Enzymatic Machinery Involved in Hydroxylamine Transfer
    J Am Chem Soc. 139: 6799-6802 (2017) doi: 10.1021/jacs.7b0207110.1093/dnares/dsw055
  • Takami H, Toyoda A, Uchiyama I, Itoh T, Takaki Y, Arai W, Nishi, S, Kawai M, Shin-ya K, Ikeda H
    Complete genome sequence and expression profile of the commercial lytic enzyme producer Lysobacter enzymogenes M497-1
    DNA Res. 24: 169-177 (2017) doi: 10.1093/dnares/dsw055
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