研究者詳細 - 佐々木　栄太

論文 - 佐々木　栄太

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Trans-omics landscape of systemic vasculitis identified matrix metalloproteinase 12 as a novel signature molecule

Kotaro Matsumoto, Katsuya Suzuki, Mayu Magi, Shinichi Onishi, Hiroto Yoshida, Masaru Takeshita, Junko Kuramoto, Masaki Yazawa, Tatsuya Kato, Hideyuki Shimizu, Tsutomu Ito, Sota Yamada, Eita Sasaki, Kenjiro Hanaoka, Mariko Noguchi-Sasaki, Yoshihiro Matsumoto, Tsutomu Takeuchi, Yuko Kaneko

Rheumatology 2025年03月

研究論文（学術雑誌）, 共著, 査読有り

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In vitro selection of dye-fluorescence-enhancing peptide aptamer by cDNA display

Takashi Kubo, Tomoyuki Koike, Tomoki Ouchi, Nayab Khaliq, Eita Sasaki, Kouichi Kuroda, Mitsuyoshi Ueda, Kenjiro Hanaoka, Naoto Nemoto

Analytical Biochemistry （Elsevier） 698 115722 - 115722 2025年03月

研究論文（学術雑誌）, 共著, 査読有り

Heat-guided drug delivery via thermally induced crosslinking of polymeric micelles

Sota Yamada, Eita Sasaki, Hisashi Ohno, Kenjiro Hanaoka

Communications Chemistry （Springer Nature） 7 287 2024年12月

研究論文（学術雑誌）, 共著, 査読有り

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A general fluorescence off/on strategy for fluorogenic probes: Steric repulsion-induced twisted intramolecular charge transfer (sr-TICT).

Kenjiro Hanaoka, Takayuki Ikeno, Shimpei Iwaki, Sayaka Deguchi, Kazuo Takayama, Hiroyuki Mizuguchi, Fumiya Tao, Nobuhiko Kojima, Hisashi Ohno, Eita Sasaki, Toru Komatsu, Tasuku Ueno, Kazuya Maeda, Hiroyuki Kusuhara, Yasuteru Urano

Science advances 10 （ 7 ） eadi8847 2024年02月

研究論文（学術雑誌）, 共著, 査読有り

Various control strategies are available for building fluorogenic probes to visualize biological events in terms of a fluorescence change. Here, we performed the time-dependent density functional theory (TD-DFT) computational analysis of the twisted intramolecular charge transfer (TICT) process in rhodamine dyes. On the basis of the results, we designed and synthesized a series of rhodamine dyes and established a fluorescence quenching strategy that we call steric repulsion-induced TICT (sr-TICT), in which the fluorescence quenching process is greatly accelerated by simple intramolecular twisting. As proof of concept of this design strategy, we used it to develop a fluorogenic probe, 2-Me PeER (pentyloxyethylrhodamine), for the N-dealkylation activity of CYP3A4. We applied 2-Me PeER for CYP3A4 activity-based fluorescence-activated cell sorting (FACS), providing access to homogeneous, highly functional human-induced pluripotent stem cell (hiPSC)-derived hepatocytes and intestinal epithelial cells. Our results suggest that sr-TICT represents a general fluorescence control method for fluorogenic probes.

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Development of a Fluorescence Probe for Detecting Nitroreductase Activity Based on Steric Repulsion-Induced Twisted Intramolecular Charge Transfer (sr-TICT)

Mizuki Sugimoto, Eita Sasaki, Hisashi Ohno, Takayuki Ikeno, Sota Yamada, Kenjiro Hanaoka

Chemical and Pharmaceutical Bulletin 2024年

研究論文（学術雑誌）, 共著, 査読有り

Discovery of a Cystathionine γ-Lyase (CSE) Selective Inhibitor Targeting Active-site Pyridoxal 5’-Phosphate (PLP) via Schiff Base Formation

Honami Echizen, Kenjiro Hanaoka, Kazuhito Shimamoto, Ryota Hibi, Sachiko Toma-Fukai, Hisashi Ohno, Eita Sasaki, Toru Komatsu, Tasuku Ueno, Yukihiro Tsuchiya, Yasuo Watanabe, Takao Otsuka, Hiroaki Saito, Satoru Nagatoishi, Kouhei Tsumoto, Hirotatsu Kojima, Takayoshi Okabe, Toshiyuki Shimizu, Yasuteru Urano

Scientific Reports 13 （ 1 ） 16456 - 16456 2023年09月

研究論文（学術雑誌）, 共著, 査読有り

D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5'-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC50 = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures.

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Molecular design of near-infrared (NIR) fluorescent probes targeting exopeptidase and application for detection of dipeptidyl peptidase 4 (DPP-4) activity

Y Hoshino, K Hanaoka, K Sakamoto, M Yasunaga, T Kojima, D Kotani, ...

RSC Chemical Biology 3 (7), 859-867 （Royal Society of Chemistry (RSC)） 3 （ 7 ） 859 - 867 2022年03月

研究論文（学術雑誌）, 共著, 査読有り

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General design strategy to precisely control the emission of fluorophores via a twisted intramolecular charge transfer (TICT) process

K Hanaoka, S Iwaki, K Yagi, T Myochin, T Ikeno, H Ohno, E Sasaki, ...

Journal of the American Chemical Society 144 (43), 19778-19790 （American Chemical Society (ACS)） 144 （ 43 ） 19778 - 19790 2022年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-7863

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Studies of lincosamide formation complete the biosynthetic pathway for lincomycin A

Shao-An Wang, Chia-I Lin, Jiawei Zhang, Richiro Ushimaru, Eita Sasaki, Hung-wen Liu

Proceedings of the National Academy of Sciences （Proceedings of the National Academy of Sciences） 117 24794 - 24801 2020年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0027-8424

The structure of lincomycin A consists of the unusual eight-carbon thiosugar core methyllincosamide (MTL) decorated with a pendent <italic>N</italic>-methylprolinyl moiety. Previous studies on MTL biosynthesis have suggested GDP-ᴅ-<italic>erythro</italic>-α-ᴅ-<italic>gluco</italic>-octose and GDP-ᴅ-α-ᴅ-lincosamide as key intermediates in the pathway. However, the enzyme-catalyzed reactions resulting in the conversion of GDP-ᴅ-<italic>erythro</italic>-α-ᴅ-<italic>gluco</italic>-octose to GDP-ᴅ-α-ᴅ-lincosamide have not yet been elucidated. Herein, a biosynthetic subpathway involving the activities of four enzymes—LmbM, LmbL, CcbZ, and CcbS (the LmbZ and LmbS equivalents in the closely related celesticetin pathway)—is reported. These enzymes catalyze the previously unknown biosynthetic steps including 6-epimerization, 6,8-dehydration, 4-epimerization, and 6-transamination that convert GDP-ᴅ-<italic>erythro</italic>-α-ᴅ-<italic>gluco</italic>-octose to GDP-ᴅ-α-ᴅ-lincosamide. Identification of these reactions completes the description of the entire lincomycin biosynthetic pathway. This work is significant since it not only resolves the missing link in octose core assembly of a thiosugar-containing natural product but also showcases the sophistication in catalytic logic of enzymes involved in carbohydrate transformations.

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Self‐Assembly of Proteinaceous Shells around Positively Charged Gold Nanomaterials Enhances Colloidal Stability in High‐Ionic‐Strength Buffers

Eita Sasaki, Ryan M. Dragoman, Shiksha Mantri, Dmitry N. Dirin, Maksym V. Kovalenko, Donald Hilvert

ChemBioChem （Wiley） 21 （ 1-2 ） 74 - 79 2020年01月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 1439-4227

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Expanding the structural analysis capabilities on an Orbitrap-based mass spectrometer for large macromolecular complexes

Kyle L. Fort, Michiel van de Waterbeemd, Dmitriy Boll, Maria Reinhardt-Szyba, Mikhail E. Belov, Eita Sasaki, Reinhard Zschoche, Donald Hilvert, Alexander A. Makarov, Albert J. R. Heck

Analyst （Royal Society of Chemistry (RSC)） 143 （ 1 ） 100 - 105 2018年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-2654

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Structure and assembly of scalable porous protein cages

Eita Sasaki, Daniel Bohringer, Michiel van de Waterbeemd, Marc Leibundgut, Reinhard Zschoche, Albert J. R. Heck, Nenad Ban, Donald Hilvert

NATURE COMMUNICATIONS （NATURE PUBLISHING GROUP） 8 14663 2017年03月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 2041-1723

Proteins that self-assemble into regular shell-like polyhedra are useful, both in nature and in the laboratory, as molecular containers. Here we describe cryo-electron microscopy (EM) structures of two versatile encapsulation systems that exploit engineered electrostatic interactions for cargo loading. We show that increasing the number of negative charges on the lumenal surface of lumazine synthase, a protein that naturally assembles into a similar to 1-MDa dodecahedron composed of 12 pentamers, induces stepwise expansion of the native protein shell, giving rise to thermostable similar to 3-MDa and similar to 6-MDa assemblies containing 180 and 360 subunits, respectively. Remarkably, these expanded particles assume unprecedented tetrahedrally and icosahedrally symmetric structures constructed entirely from pentameric units. Large keyhole-shaped pores in the shell, not present in the wild-type capsid, enable diffusion-limited encapsulation of complementarily charged guests. The structures of these supercharged assemblies demonstrate how programmed electrostatic effects can be effectively harnessed to tailor the architecture and properties of protein cages.

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Characterization of Enzymes Catalyzing Transformations of Cysteine S-Conjugated Intermediates in the Lincosamide Biosynthetic Pathway

Richiro Ushimaru, Chia-I Lin, Eita Sasaki, Hung-wen Liu

ChemBioChem （WILEY-V C H VERLAG GMBH） 17 （ 17 ） 1606 - 1611 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-4227

Lincosamides such as lincomycinA, celesticetin, and Bu-2545, constitute an important group of antibiotics. These natural products are characterized by a thiooctose linked to a l-proline residue, but they differ with regards to modifications of the thioacetal moiety, the pyrrolidine ring, and the octose core. Here we report that the pyridoxal 5-phosphate-dependent enzyme CcbF (celesticetin biosynthetic pathway) is a decarboxylating deaminase that converts a cysteine S-conjugated intermediate into an aldehyde. In contrast, the homologous enzyme LmbF (lincomycin biosynthetic pathway) catalyzes C-S bond cleavage of the same intermediate to afford a thioglycoside. We show that Ccb4 and LmbG (downstream methyltransferases) convert the aldehyde and thiol intermediates into a variety of methylated lincosamide compounds including Bu-2545. The substrates used in these studies are the -anomers of the natural substrates. The findings not only provide insight into how the biosynthetic pathway of lincosamide antibiotics can bifurcate to generate different lincosamides, but also reveal the promiscuity of the enzymes involved.

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Protein Nanocontainers from Nonviral Origin: Testing the Mechanics of Artificial and Natural Protein Cages by AFM

K. Heinze, E. Sasaki, N. P. King, D. Baker, D. Hilvert, G. J. L. Wuite, W. H. Roos

JOURNAL OF PHYSICAL CHEMISTRY B （AMER CHEMICAL SOC） 120 （ 26 ） 5945 - 5952 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1520-6106

Self-assembling protein nanocontainers are promising candidates for an increasingly wide scope of purposes. Their applications range from drug delivery vehicles and imaging agents to nanocompartments for controlled enzymatic activity. In order to exploit their full potential in these different fields, characterization of their properties is vital. For example, their mechanical properties give insight into the stability of a particle as a function of their internal content. The mechanics can be probed by atomic force microscopy nanoindentation, and while this single particle method is increasingly used to probe material properties of viral nanocages, it has hardly been used to characterize nonviral nanocages. Here we report nanoindentation studies on two types of nonviral nanocontainers: (i) lumazine synthase from Aquifex aeolicus (AaLS), which naturally self-assembles into icosahedral cages, and (ii) the artificial protein cage O3-33 originating from a computational design approach. In addition, we tested particles that had been engineered toward improved cargo loading capacity and compared these nanocages in empty and loaded states. We found that the thermostable AaLS cages are stiffer and resist higher forces before breaking than the O3-33 particles, but that mutations affecting the size of AaLS particles have a dramatic effect on their structural stability. Furthermore, we show that cargo packaging can occur while maintaining the age's mechanical properties.

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Self-Assembly of Proteinaceous Multishell Structures Mediated by a Supercharged Protein

Eita Sasaki, Donald Hilvert

JOURNAL OF PHYSICAL CHEMISTRY B （AMER CHEMICAL SOC） 120 （ 26 ） 6089 - 6095 2016年07月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 1520-6106

Engineered variants of the capsid-forming enzyme lumazine synthase can exploit electrostatic interactions to encapsulate complementarily charged guest macromolecules. Here we investigate the effect of ionic strength and cargo molecules on assembly of AaLS-13, a negatively supercharged lumazine synthase protein cage, and we show that multishell structures are produced upon mixing the capsid core with free capsomers and a positively supercharged variant of the green fluorescent protein GFP(+36). The assembly process is mediated by favorable electrostatic interactions between the negatively charged capsid shells/capsomers and GFP(+36) molecules, and it is therefore strongly dependent on ionic strength. The mechanism of formation of these assemblages is likely similar to the assembly of multishell structures of some virus-like particles, where outer shells organize as nonicosahedral structures with larger radii of curvature than the templating inner shell. In contrast to the viral multishell structures, the positively charged mediator was found to be essential for the assembly of multilayered structures of different shapes and sizes constituted of AaLS-13 capsomers. This mediator-bridging approach may be widely applicable to create protein-based hierarchical nanostructures for various nanotechnology applications such as drug delivery and bioimaging.

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Insights into Complex Oxidation during BE-7585A Biosynthesis: Structural Determination and Analysis of the Polyketide Monooxygenase BexE

David R. Jackson, Xia Yu, Guojung Wang, Avinash B. Patel, Jordi Calveras, Jesus F. Barajas, Eita Sasaki, Mikko Metsa-Ketela, Hung-wen Liu, Juergen Rohr, Shiou-Chuan Tsai

ACS CHEMICAL BIOLOGY （AMER CHEMICAL SOC） 11 （ 4 ） 1137 - 1147 2016年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1554-8929

Cores of aromatic polyketides are essential for their biological activities. Most type II polyketide synthases (PKSs) biosynthesize these core structures involving the minimal PKS, a PKS-associated ketoreductase (KR) and aromatases/cyclases (ARO/CYCs). Oxygenases (OXYs) are rarely involved. BE-7585A is an anticancer polyketide with an angucyclic core. C-13 isotope labeling experiments suggest that its angucyclic core may arise from an oxidative rearrangement of a linear anthracyclinone. Here, we present the crystal structure and functional analysis of BexE, the oxygenase proposed to catalyze this key oxidative rearrangement step that generates the angucyclinone framework. Biochemical assays using various linear anthracyclinone model compounds combined with docking simulations narrowed down the substrate of BexE to be an immediate precursor of aklaviketone, possibly 12-deoxy-aklaviketone. The structural analysis, docking simulations, and biochemical assays provide insights into the role of BexE in BE-7585A biosynthesis and lay the groundwork for engineering such framework-modifying enzymes in type II PKSs.

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Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases

Grace Caldara-Festin, David R. Jackson, Jesus F. Barajas, Timothy R. Valentic, Avinash B. Patel, Stephanie Aguilar, MyChi Nguyen, Michael Vo, Avinash Khanna, Eita Sasaki, Hung-wen Liu, Shiou-Chuan Tsai

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （NATL ACAD SCIENCES） 112 （ 50 ） E6844 - E6851 2015年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0027-8424

Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-beta-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7-C12 and C9-C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7-C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: "nonreducing" ARO/CYCs, which act on nonreduced poly-beta-ketones, and "reducing" ARO/CYCs, which act on cyclized C9 reduced poly-beta-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono-and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

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Co-opting sulphur-carrier proteins from primary metabolic pathways for 2-thiosugar biosynthesis

Eita Sasaki, Xuan Zhang, He G. Sun, Mei-Yeh Jade Lu, Tsung-lin Liu, Albert Ou, Jeng-yi Li, Yu-hsiang Chen, Steven E. Ealick, Hung-wen Liu

NATURE （NATURE PUBLISHING GROUP） 510 （ 7505 ） 427 - 431 2014年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 0028-0836

Sulphur is an essential element for life and is ubiquitous in living systems(1,2). Yet how the sulphur atom is incorporated into many sulphur-containing secondary metabolites is poorly understood. For bond formation between carbon and sulphur in primary metabolites, the major ionic sulphur sources are the persulphide and thiocarboxylate groups on sulphur-carrier (donor) proteins(3,4). Each group is post-translationally generated through the action of a specific activating enzyme. In all reported bacterial cases, the gene encoding the enzyme that catalyses the carbon-sulphur bond formation reaction and that encoding the cognate sulphur-carrier protein exist in the same gene cluster(5). To study the production of the 2-thiosugar moiety in BE-7585A, an antibiotic from Amycolatopsis orientalis, we identified a putative 2-thioglucose synthase, BexX, whose protein sequence and mode of action seem similar to those of ThiG, the enzyme that catalyses thiazole formation in thiamine biosynthesis(6,7). However, no gene encoding a sulphur-carrier protein could be located in the BE-7585A cluster. Subsequent genome sequencing uncovered a few genes encoding sulphur-carrier proteins that are probably involved in the biosynthesis of primary metabolites but only one activating enzyme gene in the A. orientalis genome. Further experiments showed that this activating enzyme can adenylate each of these sulphur carrier proteins and probably also catalyses the subsequent thiolation, through its rhodanese domain. A proper combination of these sulphur-delivery systems is effective for BexX-catalysed2-thioglucose production. The ability of BexX to selectively distinguish sulphur-carrier proteins is given a structural basis using X-ray crystallography. This study is, to our knowledge, the first complete characterization of thiosugar formation in nature and also demonstrates the receptor promiscuity of the A. orientalis sulphur-delivery system. Our results also show that co-opting the sulphur-delivery machinery of primary metabolism for the biosynthesis of sulphur-containing natural products is probably a general strategy found in nature.

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In vitro characterization of LmbK and LmbO: identification of GDP-D-erythro-α-D-gluco-octose as a key intermediate in lincomycin A biosynthesis.

Lin CI, Sasaki E, Zhong A, Liu HW

Journal of the American Chemical Society （AMER CHEMICAL SOC） 136 （ 3 ） 906 - 909 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-7863

Lincomycin A is a clinically useful antibiotic isolated from Streptomyces lincolnensis. It contains an unusual methylmercapto-substituted octose, methylthiolincosamide (MTL). While it has been demonstrated that the C-8 backbone of MTL moiety is derived from D-fructose 6-phosphate and D-ribose 5-phosphate via a transaldol reaction catalyzed by LmbR, the subsequent enzymatic transformations leading to the MTL moiety remain elusive. Here, we report the identification of GDP-D-etythro-alpha-D-gluco-octose (GDP-D-alpha-D-octose) as a key intermediate in the MTL biosynthetic pathway. Our data show that the octose 1,8-bisphosphate intermediate is first converted to octose 1-phosphate by a phosphatase, LmbK. The subsequent conversion of the octose 1-phosphate to GDP-D-alpha-D-octose is catalyzed by the octose 1-phosphate guanylyltransferase, LmbO. These results provide significant insight into the lincomycin biosynthetic pathway, because the activated octose likely serves as the acceptor for the installation of the C1 sulfur appendage of MTL.

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Construction of the Octose 8-Phosphate Intermediate in Lincomycin A Biosynthesis: Characterization of the Reactions Catalyzed by LmbR and LmbN

Eita Sasaki, Chia-I Lin, Ke-Yi Lin, Hung-wen Liu

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY （AMER CHEMICAL SOC） 134 （ 42 ） 17432 - 17435 2012年10月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 0002-7863

Lincomycin A is a potent antimicrobial agent noted for its unusual C1 methylmercapto-substituted 8-carbon sugar. Despite its long clinical history for the treatment of Gram-positive infections, the biosynthesis of the C-8-sugar, methylthiolincosamide (MTL), is poorly understood. Here, we report our studies of the two initial enzymatic steps in the MTL biosynthetic pathway leading to the identification of D-erythro-D-gluco-octose 8-phosphate as a key intermediate. Our experiments demonstrate that this intermediate is formed via a transaldol reaction catalyzed by LmbR using D-fructose 6-phosphate or D-sedoheptulose 7-phosphate as the C-3 donor and D-ribose 5-phosphate as the C-5 acceptor. Subsequent 1,2-isomerization catalyzed by LmbN converts the resulting 2-keto C-8-sugar (octulose 8-phosphate) to octose 8-phosphate. These results provide, for the first time, in vitro evidence for the biosynthetic origin of the C-8 backbone of MTL.

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佐々木 栄太

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佐々木　栄太

論文 - 佐々木　栄太