Kazuki Ishikawa

Faculty of Pharmaceutical Sciences,Department of Pharmaceutical SciencesLecturer
Graduate School of Pharmaceutical Sciences,Doctoral Program in Pharmaceutical SciencesLecturer
Last Updated :2026/06/26

■Researcher basic information

Degree

  • Mar. 2016

Field Of Study

  • Life sciences, Environmental and pharmaceutical development resources

■Career

Career

  • Apr. 2024 - Present
    Teikyo Heisei University, Faculty of Pharmaceutical Sciences

Member History

  • Sep. 2021
  • Sep. 2020
  • Sep. 2018

■Research activity information

Award

  • Oct. 2019
  • Apr. 2017
  • Mar. 2017

Paper

  • Functional characterization of Gra-6 as a branch-point enzyme directing (R)-DNPA formation in BIQ polyketide biosynthesis
    Kazuki Ishikawa; Minori Hashimoto; Noriko Kusuoku; Chiharu Nozaki; Makoto Hashimoto; Koji Ichinose
    The Journal of Antibiotics, 18 Mar. 2026, [Reviewed]
  • Synergistic effects of Cyp51 isozyme-specific azole antifungal agents on fungi with multiple cyp51 isozyme genes
    Masaki Ishii; Kazuki Ishikawa; Kazuhiro Mikami; Koji Ichinose; Atsushi Miyashita; Takashi Yaguchi; Tsuyoshi Yamada; Shinya Ohata
    Antimicrobial Agents and Chemotherapy, 26 Sep. 2025
  • Characterization of ActVI-ORF3 and ActVI-ORF4 as Lactonizing and Delactonizing Enzymes in Relation to Metabolic Flux in Actinorhodin Biosynthesis.
    Makoto Hashimoto; Kazuki Ishikawa; Yuri Fukushima; Sarina Shimazu; Mizuha Yabuzaki; Yuka Kamezawa; Takaaki Taguchi; Koji Ichinose
    Chembiochem : a European journal of chemical biology, 06 Mar. 2025, [Reviewed]
    Actinorhodin (ACT) from Streptomyces coelicolor A3(2) is an aromatic polyketide antibiotic with a benzoisochromanequinone (BIQ) skeleton. Although actVI-ORF3 and actVI-ORF4 are not essential for ACT biosynthesis, homologous genes to these are present in the biosynthetic gene clusters of BIQ lactones. In this study, ActVI-ORF3 was identified as a cofactor-independent enzyme with lactonization activity, using ACT as a substrate. ActVI-ORF3 recognized dihydrokalafungin and 8-hydroxykalafafungin, which share the same pyran-ring configuration as ACT, but not nanaomycin A, which has an opposite configuration. In contrast, ActVI-ORF4 functioned as an NAD(P)-dependent oxidoreductase, catalyzing the delactonization of BIQ lactones. Conversion experiments using isotopically labeled compounds revealed that both lactonization and delactonization reactions of these enzymes yielded products in which the carboxyl oxygen at the C1 position was retained. Subsequently, we reexamined the accumulation of ACT-related compounds in the actVI-ORF3 and actVI-ORF-4 disruptants. The results suggested that ACT intermediates are predominantly pooled in the bacteria as (S)-DNPA rather than in lactone-form. The contribution of ActVI-ORF4 to metabolic flux is not significant, and endogenous reductases can convert these intermediates to the dihydro form, which subsequently re-enters the ACT biosynthetic pathway.
  • Aszonapyrone A Isolated from Neosartorya spinosa IFM 47025 Inhibits the NF-κB Signaling Pathway Activated by Expression of the Ependymoma-Causing Fusion Protein ZFTA-RELA
    Kazuki Ishikawa; Nao Kamiya; Masaki Ishii; Takashi Yaguchi; Koji Ichinose; Shinya Ohata
    Advances in Microbiology, Sep. 2024, [Reviewed]
  • The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum.
    Masaki Ishii; Tsuyoshi Yamada; Kazuki Ishikawa; Koji Ichinose; Michel Monod; Shinya Ohata
    Antimicrobial agents and chemotherapy, 03 Apr. 2024, [Reviewed]
    The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae. Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.
  • Actinorhodin Biosynthesis Terminates with an Unprecedented Biaryl Coupling Reaction.
    Makoto Hashimoto; Susumu Watari; Takaaki Taguchi; Kazuki Ishikawa; Takuya Kumamoto; Susumu Okamoto; Koji Ichinose
    Angewandte Chemie (International ed. in English), 02 Dec. 2022, [Reviewed]
    A plethora of dimeric natural products exist with diverse chemical structures and biological activities. A major strategy for dimerization is aryl coupling reactions catalyzed by cytochrome P450 or laccase. Actinorhodin (ACT) from Streptomyces coelicolor has a dimeric pyranonaphthoquinone structure connected by a C-C bond. Here, we identified a NmrA-family dimerizing enzyme, ActVA-ORF4, and a cofactor independent oxidase, ActVA-ORF3, both involved in the last step of ACT biosynthesis. ActVA-ORF4 is a unique  NAD(P)H-dependent enzyme that catalyzes the inter-molecular C-C bond formation using 8-hydroxydihydrokalafungin (DHK-OH) as the sole substrate. On the other hand, ActVA-ORF3 was found to be a quinone-forming enzyme that produces the coupling substrate, DHK-OH, and the final product, ACT. Consequently, the functional assignment of all essential enzymes in ACT biosynthesis was completed, which would be a landmark in our understanding of the entire biosynthetic pathway for one of the best-known model natural products, ACT.
  • Characterization of stereospecific enoyl reductase ActVI-ORF2 for pyran ring formation in the actinorhodin biosynthesis of Streptomyces coelicolor A3(2).
    Kazuki Ishikawa; Makoto Hashimoto; Kunpei Komatsu; Takaaki Taguchi; Susumu Okamoto; Koji Ichinose
    Bioorganic & medicinal chemistry letters, 15 Jun. 2022, [Reviewed]
    Actinorhodin (ACT) is a benzoisochromanequinone antibiotic produced by Streptomyces coelicolor A3(2), which has served as a favored model organism for comprehensive studies of antibiotic biosynthesis and its regulation. (S)-DNPA undergoes various modifications as an intermediate in the ACT biosynthetic pathway, including enoyl reduction to DDHK. It has been suggested that actVI-ORF2 encodes an enoyl reductase (ER). However, its function has not been characterized in vitro. In this study, biochemical analysis of recombinant ActVI-ORF2 revealed that (S)-DNPA is converted to DDHK in a stereospecific manner with NADPH acting as a cofactor. (R)-DNPA was also reduced to 3-epi-DDHK with the comparable efficacy as (S)-DNPA, suggesting that the stereospecificity of ActVI-ORF2 was not affected by the stereochemistry at the C-3 of DNPA. ActVI-ORF2 is a new example of a discrete ER, which is distantly related to known ERs according to phylogenetic analysis.
  • epi-Aszonalenin B from Aspergillus novofumigatus inhibits NF-κB activity induced by ZFTA-RELA fusion protein that drives ependymoma.
    Kazuki Ishikawa; Masaki Ishii; Takashi Yaguchi; Toshiaki Katada; Koji Ichinose; Shinya Ohata
    Biochemical and biophysical research communications, 12 Mar. 2022, [Reviewed]
    Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA.
  • Cover Feature: Unveiling Two Consecutive Hydroxylations: Mechanisms of Aromatic Hydroxylations Catalyzed by Flavin‐Dependent Monooxygenases for the Biosynthesis of Actinorhodin and Related Antibiotics (ChemBioChem 5/2020)
    Makoto Hashimoto; Takaaki Taguchi; Kazuki Ishikawa; Ryuichiro Mori; Akari Hotta; Susumu Watari; Kazuaki Katakawa; Takuya Kumamoto; Susumu Okamoto; Koji Ichinose
    ChemBioChem, 02 Mar. 2020, [Invited]
  • Unveiling Two Consecutive Hydroxylations: Mechanisms of Aromatic Hydroxylations Catalyzed by Flavin-Dependent Monooxygenases for the Biosynthesis of Actinorhodin and Related Antibiotics.
    Makoto Hashimoto; Takaaki Taguchi; Kazuki Ishikawa; Ryuichiro Mori; Akari Hotta; Susumu Watari; Kazuaki Katakawa; Takuya Kumamoto; Susumu Okamoto; Koji Ichinose
    Chembiochem : a European journal of chemical biology, 02 Mar. 2020, [Reviewed]
    Flavin-dependent monooxygenases are ubiquitous in living systems and are classified into single- or two-component systems. Actinorhodin, produced by Streptomyces coelicolor, is a representative polycyclic polyketide that is hydroxylated through the action of the two-component ActVA-5/ActVB hydroxylase system. These homologous systems are widely distributed in bacteria, but their reaction mechanisms remain unclear. This in vitro investigation has provided chemical proof of two consecutive hydroxylations via hydroxynaphthalene intermediates involved in actinorhodin biosynthesis. The ActVA-5 oxygenase component catalyzed a stepwise dihydroxylation of the substrate, whereas the ActVB flavin reductase not only supplied a reduced cofactor, but also regulated the quinone-hydroquinone interconversion of an intermediate. Our study provides clues for understanding the general biosynthetic mechanisms of highly functionalized aromatic natural products with structural diversity.
  • Antifungal Activity of Compounds Isolated from Bamboo Vermicompost against Rhizoctonia solani AG1-IB               
    Xiaodong You; Daigo Wakana; Kazuki Ishikawa; Tomoo Hosoe; Motoaki Tojo
    Advances in Microbiology, Dec. 2019, [Reviewed]
  • Antimicrobial agent isolated from Coptidis rhizome extract incubated with Rhodococcus sp. strain BD7100.
    Kazuki Ishikawa; Kazunori Takahashi; Syun Hosoi; Hisashi Takeda; Hinaka Yoshida; Daigo Wakana; Masayoshi Tsubuki; Fumihiko Sato; Motoaki Tojo; Tomoo Hosoe
    The Journal of antibiotics, Feb. 2019, [Reviewed]
    Coptidis rhizome (CR) is a widely used herbal medicine that contains protoberberine-type alkaloids. CR extract exhibits various pharmacologic activities. A previous study reported the isolation of Rhodococcus sp. strain BD7100 as a berberine (BBR)-utilizing bacterium, and the BBR-degradation pathway has been investigated. When we incubated strain BD7100 cells with CR extract, the number of viable cells declined with the degradation of components in the CR extract, and the culture broth exhibited antibacterial activity against strain BD7100. These results suggest that CR extract cultured in the presence of strain BD7100 contains one or more antibacterial agents. In this study, we isolated coptirhoquinone A (1) from CR extract incubated with strain BD7100 in Luria-Bertani (LB) medium, and the structure was elucidated using NMR and MS analysis. We also report the total synthesis and antimicrobial activities of 1 against bacteria, fungi, and Pythium sp.
  • FOUR CYCLODIPEPTIDES, ASNOVOLENINS A-B AND ASNOVOZINES A-B, FROM ASPERGILLUS NOVOFUMIGATUS
    Ishikawa Kazuki; Wakana Daigo; Itabashi Takeshi; Takeda Hisashi; Yaguchi Takashi; Kawai Ken-ichi; Hosoe Tomoo
    HETEROCYCLES, 01 Jun. 2018, [Reviewed]
  • A new cinnamoylphenethylamine derivative from a Mongolian Allium species, Allium carolinianum
    Tsutomu Tsuruoka; Kazuki Ishikawa; Tomoo Hosoe; Darikhand Davaajab; Suvd Duvjir; Unursaikhan Surenjav
    Journal of Natural Medicines, 01 Jan. 2018, [Reviewed]
  • Common origin of methylenedioxy ring degradation and demethylation in bacteria
    Hisashi Takeda; Kazuki Ishikawa; Hinaka Yoshida; Daisuke Kasai; Daigo Wakana; Masao Fukuda; Fumihiko Sato; Tomoo Hosoe
    SCIENTIFIC REPORTS, Aug. 2017, [Reviewed]
  • Asnovolins A-G, Spiromeroterpenoids Isolated from the Fungus Aspergillus novofumigatus, and Suppression of Fibronectin Expression by Asnovolin E
    Kazuki Ishikawa; Fumiaki Sato; Takeshi Itabashi; Hiroshi Wachi; Hisashi Takeda; Daigo Wakana; Takashi Yaguchi; Ken-ichi Kawai; Tomoo Hosoe
    JOURNAL OF NATURAL PRODUCTS, Sep. 2016, [Reviewed]
  • Isolation and identification of berberine and berberrubine metabolites by berberine-utilizing bacterium Rhodococcus sp strain BD7100
    Kazuki Ishikawa; Hisashi Takeda; Daigo Wakana; Fumihiko Sato; Tomoo Hosoe
    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, May 2016, [Reviewed]
  • 11-Hydroxylation of Protoberberine by the Novel Berberine-Utilizing Aerobic Bacterium Sphingobium sp Strain BD3100
    Hisashi Takeda; Kazuki Ishikawa; Daigo Wakana; Masao Fukuda; Fumihiko Sato; Tomoo Hosoe
    JOURNAL OF NATURAL PRODUCTS, Dec. 2015, [Reviewed]
  • Quinazolinobenzodiazepine derivatives, novobenzomalvins A-C: Fibronectin expression regulators from Aspergillus novofumigatus
    Kazuki Ishikawa; Tomoo Hosoe; Takeshi Itabashi; Fumiaki Sato; Hiroshi Wachi; Hiromasa Nagase; Takashi Yaguchi; Ken-Ichi Kawai
    Scientia Pharmaceutica, 2011, [Reviewed]
  • A NOVOFUMIGATAMIDE, NEW CYCLIC TRIPEPTIDE FROM ASPERGILLUS NOVOFUMIGATUS
    Kazuki Ishikawa; Tomoo Hosoe; Takeshi Itabashi; Kayoko Takizawa; Takashi Yaguchi; Ken-ichi Kawai
    HETEROCYCLES, Sep. 2010, [Reviewed]
  • Novoamauromine and ent-Cycloechinulin: Two New Diketopiperazine Derivatives from Aspergillus novofumigatus
    Kazuki Ishikawa; Tomoo Hosoe; Takeshi Itabashi; Daigo Wakana; Kayoko Takizawa; Takashi Yaguchi; Ken-ichi Kawai
    CHEMICAL & PHARMACEUTICAL BULLETIN, May 2010, [Reviewed]

MISC

Lectures, oral presentations, etc.

  • ActVA-ORF4様酵素によるアリールカップリング反応を介したナフトキノン化合物の二量化               
    28 Mar. 2026
  • アクチノロジン生合成遺伝子クラスターに存在するactVI-Aの機能再解析(第2報)               
    27 Mar. 2026
  • 真菌および放線菌中のTLRシグナリングを抑制する物質の探索               
    27 Mar. 2026
  • 短編動画の活⽤による「有機化学」基礎事項の効果的な学習法               
    23 Aug. 2025
  • 帝京平成大学薬学部における 問題演習を中心とした 初年度化学教育の取り組みについて               
    23 Aug. 2025
  • 新規有用化合物の創製を目指した真菌二次代謝産物の微生物変換に関する研究               
    28 Mar. 2025
  • アクチノロジン生合成遺伝子クラスターに存在するactVI-Aの機能再解析               
    27 Mar. 2025
  • 真菌および放線菌中の感染症疾患治療薬候補物質の探索               
    27 Mar. 2025
  • アクチノロジン生合成に関与する新規酸化酵素ActVA-ORF3のAlphaFoldを利用した機能解析研究               
    27 Mar. 2025
  • アンメットメディカルニーズ克服を目指した真菌二次代謝産物によるNF-κBシグナル阻害物質の探索               
    30 Mar. 2024
  • ベンゾイソクロマンキノン系抗⽣物質⽣合成におけるラクトン化に関する酵 素学的研究(第2報)               
    15 Sep. 2022
  • Aspergillus felis IFM 62093株が産生する抗放線菌活性物質の探索               
    10 Sep. 2022
  • Search for antifungal compounds from Aspergillus speicies against Rhizopus oryzae (1)               
    Yuka Sawada; Kazuki Ishikawa; Masaki Ishii; Shinya Ohata; Takashi Yaguchi; Toshiaki Katada; Koji Ichinose
    27 Mar. 2022
  • Exploratory research of bioactive compounds from Fungi Aspergillus species to address unmet medical needs               
    Kazuki ISHIKAWA; Shinya OHATA; Masaki ISHII; Takashi YAGUCHI; Toshiaki KATADA; Koji ICHINOSE
    11th JSP-CSP-KSP Joint Symposium on Pharmacognosy, 18 Sep. 2021
  • Metabolomics analysis of Aspergillus sp for research of metabolites.               
    Kazuki Ishikaw; Takashi. Yaguchi; Koji. Ichinose
    Jun. 2020
  • アクチノロジン生合成における連続水酸化反応機構の解析(第5報)               
    23 Sep. 2019
  • サンシシ由来ゲニポシド類縁化合物の構造決定および学習効果の向上を目指した学生実習への応用               
    22 Sep. 2019
  • ベンゾイソクロマンキノン系抗生物質生合成に関わるフラビン依存型酸素添加酵素のホモロジーモデリングによる立体構造予測と機能選択性解析               
    14 Sep. 2019
  • ベンゾイソクロマンキノン系化合物生産株を用いた放線菌代謝能の活用               
    14 Sep. 2019
  • ベンゾイソクロマンキノン系抗生物質生合成における立体特異的エノイル還元酵素の機能解析               
    14 Sep. 2019
  • アクチノロジン生合成に関与する二機能性酵素の同定と特性解析               
    11 Sep. 2019
  • A multi-component berberine 11-hydroxylase identified from Burkholderia sp. strain CJ1               
    23 Mar. 2019
  • Functional analysis of stereospecific enoyl reductase involved in actinorhodin biosynthesis               
    20 Mar. 2019
  • アクチノロジン生合成における連続水酸化反応機構の解析(第4報)               
    11 Sep. 2018
  • ベルベリン資化性菌Rhodococcus sp. BD7100株がオウレンエキス添加培養時に産生する抗菌物質に関する検討               
    Aug. 2017
  • Berberine資化性菌Rhodococcus sp. BD7100株はオウレン抽出エキスから抗菌物質を産生する               
    Mar. 2017
  • Berberine資化性菌Sphingobium sp. BD3100株由来berberine脱メチレン化酵素による11-hydroxyberberineの脱メチレン化               
    Mar. 2017
  • Berberine 資化性菌Sphingobium sp. BD3100株によるpalmatine水酸化酵素遺伝子の同定と解析               
    Mar. 2017
  • 新規モルヒネ生産システムの構築を目指したベルベリン資化性菌によるベルベリン分解能の解析               
    Oct. 2016
  • ベルベリン資化性菌Rhodococcus sp. BD7100 株のベルベリン誘導プロモーターの探索               
    28 Mar. 2016
  • Sphingobium sp. BD3100株のベルベリン脱メチレン化酵素遺伝子の解析               
    Mar. 2016
  • Berberine 資化性菌GBD-1 株の単離およびその berberine 分解能に関する検討               
    Mar. 2016
  • Berberine 資化性菌Rhodococcus sp. BD7100株によるberberineの脱メチレン化遺伝子brdAの単離と解析               
    Mar. 2016
  • Investigation of berberine-degradation pathway in berberine-utilizing bacteria               
    Dec. 2015
  • Identification of berberine metabolites and metabolic gene in BBR-utilizing bacteria               
    Oct. 2015
  • Investigation of BBR-degradation pathway in BBR utilizing bacteria.               
    Jul. 2015
  • Aspergillus novofumigatus の第二次代謝産物の立体化学に関する考察               
    May 2015
  • Berberine資化性菌のBerberine分解酵素の誘導性と基質特異性               
    Mar. 2015
  • Berberine資化性菌のberberrubine分解性に関する研究               
    Mar. 2015
  • Berberine資化性菌によるオウレン由来アルカロイドの分解挙動について               
    Mar. 2015
  • ベルベリン資化菌 Rhodococcus sp. BD7100 株の単離と解析               
    Sep. 2014
  • Isolation and Characterization of Berberine Utilizing Bacterium Rhodococcus sp. BD7100               
    May 2014
  • ベルベリン資化性菌 BD3100株の単離と解析               
    Mar. 2014
  • Aspergillus novofumigatus CBS117520 から単離された新規環状テトラペプタイドおよびメロテルペノイド               
    Mar. 2011
  • Aspergillus novofumigatus より単離された新規メロテルペノイド               
    Mar. 2010
  • Aspergillus novofumigatus の産生するジケトピペラジン化合物の立体化学               
    Oct. 2009
  • Aspergillus novofumigatus より得られる新規環状ペプチド及びベンゾジアゼピン誘導体の構造               
    Oct. 2009
  • Aspergillus novofumigatusの産生するジケトピペラジン化合物の立体化学               
    Mar. 2009

Affiliated academic society

  • SOCIETY FOR ACTINOMYCETES JAPAN               
  • THE MYCOLOGICAL SOCIETY OF JAPAN               
  • THE JAPANESE SOCIETY OF PHARMACOGNOSY               
  • THE PHARMACEUTICAL SOCIETY OF JAPAN