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海藻糖合成酶结构及其抑制剂的研究进展

蒋志洋 韩清 王金娥 朱凯 张婧瑜 邓鸣飞 黄家兴 段红霞

蒋志洋, 韩清, 王金娥, 朱凯, 张婧瑜, 邓鸣飞, 黄家兴, 段红霞. 海藻糖合成酶结构及其抑制剂的研究进展[J]. 农药学学报, 2021, 23(2): 209-225. doi: 10.16801/j.issn.1008-7303.2021.0043
引用本文: 蒋志洋, 韩清, 王金娥, 朱凯, 张婧瑜, 邓鸣飞, 黄家兴, 段红霞. 海藻糖合成酶结构及其抑制剂的研究进展[J]. 农药学学报, 2021, 23(2): 209-225. doi: 10.16801/j.issn.1008-7303.2021.0043
Zhiyang JIANG, Qing HAN, Jin'e WANG, Kai ZHU, Jingyu ZHANG, Mingfei DENG, Jiaxing HUANG, Hongxia DUANG. Advances in structures and inhibitors of trehalose synthetase[J]. Chinese Journal of Pesticide Science, 2021, 23(2): 209-225. doi: 10.16801/j.issn.1008-7303.2021.0043
Citation: Zhiyang JIANG, Qing HAN, Jin'e WANG, Kai ZHU, Jingyu ZHANG, Mingfei DENG, Jiaxing HUANG, Hongxia DUANG. Advances in structures and inhibitors of trehalose synthetase[J]. Chinese Journal of Pesticide Science, 2021, 23(2): 209-225. doi: 10.16801/j.issn.1008-7303.2021.0043

海藻糖合成酶结构及其抑制剂的研究进展

doi: 10.16801/j.issn.1008-7303.2021.0043
基金项目: 国家重点研发计划项目 (2017YFD0200504)
详细信息
    作者简介:

    蒋志洋,男,硕士研究生,E­mail:joel_jiangzhiyang@hotmail.com

    通讯作者:

    段红霞,通信作者 (Author for correspondence),女,副教授,研究方向为新农药分子设计与创制,E­mail:hxduan@cau.edu.cn

  • 中图分类号: Q51;Q55; TQ450.1;S481.1

Advances in structures and inhibitors of trehalose synthetase

  • 摘要: 海藻糖是自然界中广泛存在的非还原性二糖,具有重要的生物学功能。除了可作为储能物质参与机体能量代谢外,更重要的是还可作为结构物质参与真菌细胞壁和昆虫体壁的形成,决定病原菌的致病性或调控昆虫的生长发育。海藻糖合成酶主要负责催化海藻糖的生物合成,包括海藻糖-6-磷酸合成酶和海藻糖-6-磷酸磷酸酯酶两个功能域。近年来,越来越多的研究表明海藻糖合成酶将有望成为新农药创制的候选靶标。本文主要综述了海藻糖-6-磷酸合成酶和海藻糖-6-磷酸磷酸酯酶的晶体结构、酶与底物的结合模式和已报道的海藻糖合成酶抑制剂,以期对以海藻糖合成酶为靶标的抑制剂的筛选、先导化合物的设计和改造以及新型农药的开发提供指导。
  • 图  1  海藻糖-6-磷酸合成酶和海藻糖-6-磷酸磷酸酯酶途径催化海藻糖的生物合成过程

    TPS/OtsA/TPS1:海藻糖-6-磷酸合成酶;TPP/OtsB/TPS2:海藻糖-6-磷酸磷酸酯酶

    Figure  1.  The biosynthetic processes of trehalose catalyzed by trehalose-6-phosphate synthetase and trehalose-6-phosphate phosphatase pathway

    图  2  昆虫的海藻糖代谢通路与几丁质代谢通路

    Figure  2.  Insect trehalose metabolic pathway and chitin metabolic pathway

    图  3  代表性GT-A折叠型和GT-B折叠型的糖基转移酶三维晶体结构对比

    A:枯草芽孢杆菌Bacillus subtilis SPSA酶的三维结构呈现GT-A折叠 (PDB号:1QGQ);B:大肠杆菌T4噬菌体(Coliphage T4) BGT酶的三维结构呈现GT-B折叠 (PDB号:1JG7)。

    Figure  3.  The comparisons between three-dimensional crystal structures of typical GT-A folding type and typical GT-B folding type glycosyltransferases

    A: GT-A folding type in the three-dimensional structure of Bacillus subtilis SPSA (PDB ID: 1QGQ); B: GT-B folding type in the three-dimensional structure of Coliphage T4 BGT (PDB ID: 1JG7).

    图  4  海藻糖-6-磷酸合成酶与供体底物NDPG结合关键氨基酸残基

    A:EcOtsA与UDPG结合关键氨基酸残基 (PDB号:1UQU);B:MtrOtsA与ADPG结合关键氨基酸残基 (PDB号:5K41);C:MtrOtsA与GPDG结合关键氨基酸残基 (PDB号:5K42);D:CaTPS1与UDP结合关键氨基酸残基 (PDB号:5HUU);E:AfTPS1B与UDP结合关键氨基酸残基 (PDB号:5HVO);F:MoTPS1与UDPG结合关键氨基酸残基 (PDB号:6JBW)。

    Figure  4.  The key amino acid residues of trehalose-6-phosphate synthetase binding to donor substrate NDPG

    A: The key amino acid residues of EcOtsA binding to UDPG (PDB ID: 1UQU); B: The key amino acid residues of MtrOtsA binding to ADPG (PDB ID: 5K41); C: The key amino acid residues of MtrOtsA binding to GDPG (PDB ID: 5K42); D: The key amino acid residues of CaTPS1 binding to UDP (PDB ID: 5HUU); E: The key amino acid residues of AfTPS1B binding to UDP (PDB ID: 5HVO); F: The key amino acid residues of MoTPS1 binding to UDPG (PDB ID: 6JBW).

    图  5  海藻糖-6-磷酸合成酶与受体底物G6P结合关键氨基酸残基

    A:EcOtsA与G6P结合关键氨基酸残基 (PDB号:1GZ5);B:异食旁支原体 (Paraburkholderia xenovoranss)OtsA与G6P结合关键氨基酸残基 (PDB号:5V0T);C:MtrOtsA与G6P结合关键氨基酸残基 (PDB号:5JIO);D:CaTPS1与G6P结合关键氨基酸残基(PDB号:5HUU);E:MoTPS1与G6P结合关键氨基酸残基 (PDB号:6JBR)。

    Figure  5.  The key amino acid residues of trehalose-6-phosphate synthetase binding to acceptor substrate G6P

    A: The key amino acid residues of EcOtsA binding to G6P (PDB ID: 1GZ5); B: The key amino acid residues of PxOtsA binding to G6P (PDB ID: 5V0T); C: The key amino acid residues of MtrOtsA binding to G6P (PDB ID: 5JIO); D: The key amino acid residues of CaTPS1 binding to G6P (PDB ID: 5HUU); E: The key amino acid residues of MoTPS1 binding to G6P (PDB ID: 6JBR).

    图  6  不同物种海藻糖-6-磷酸合成酶的氨基酸序列比对

    Figure  6.  Amino acid sequence alignments of trehalose-6-phosphate synthetases from different organisms

    表  1  目前已报道的不同细菌OtsA的晶体结构信息

    Table  1.   The reported crystal structures of different bacteria OtsAs

    PDB编号
    PDB ID
    物种
    Organism
    配体
    Ligand
    分辨率/Åa
    Resolution/ Åa
    参考文献
    Reference
    1GZ5 大肠杆菌 Escherichia coli G6P, UDP 2.43 [14]
    1UQU 大肠杆菌 Escherichia coli UDPG 2.00 [36]
    1UQT 大肠杆菌 Escherichia coli UDP-2-fluoro glucose 2.00 [36]
    2WTX 大肠杆菌 Escherichia coli VDO, UDP 2.20 [38]
    5LQD 委内瑞拉链霉菌 Streptomyces venezuelae apo form 1.95 [39]
    5HXA 嗜异源化合物伯克氏菌 Paraburkholderia xenovorans apo form 2.00 Mayclin S J et al., 2016b
    5TVG 越南伯克氏菌 Burkholderia vietnamiensis UDP 2.30 Edwards T E et al., 2016b
    5JIJ 越南伯克氏菌 Mycobacterium thermoresistibile apo form 1.82 [40]
    5K41 越南伯克氏菌 Mycobacterium thermoresistibile ADPG 1.97 [40]
    5K42 越南伯克氏菌 Mycobacterium thermoresistibile GDPG 1.92 [40]
    5JIO 越南伯克氏菌 Mycobacterium thermoresistibile G6P, ADP 1.71 [40]
    5K5C 越南伯克氏菌 Mycobacterium thermoresistibile TRE 1.85 [40]
    5K44 越南伯克氏菌 Mycobacterium thermoresistibile T6P 1.96 [40]
    5L3K 越南伯克氏菌 Mycobacterium thermoresistibile F6P, ADP 2.31 [40]
    5UOF 多噬伯克霍尔德氏菌 Burkholderia multivorans apo form 1.70 Irwin R M et al., 2017b
    5V0T 嗜异源化合物伯克氏菌 Paraburkholderia xenovoranss G6P, UDP 1.95 Mayclin S J et al., 2017b
    6JAK 大肠杆菌 Escherichia coli apo form 2.41 [41]
    注:a 1 Å = 0.1 nm;b蛋白质三维晶体结构已经存入蛋白质数据库 (http://www1.rcsb.org) 中,但尚未见相关文献报道。Note: a 1 Å = 0.1 nm. b The three-dimensional crystal structures of those proteins were imported in the Protenin Data Bank Databse (http://www1.rcsb.org), which were not reported in the literatures.
    下载: 导出CSV

    表  2  目前已报道的不同真菌TPS1晶体结构信息

    Table  2.   The reported crystal structures of different fungi TPS1s

    PDB编号
    PDB ID
    物种
    Organism
    配体
    Ligand
    分辨率
    Resolution/Åa
    参考文献
    Reference
    5HUT 白色念珠菌 Candida albicans UDPG 1.90 [42]
    5HUU 白色念珠菌 Candida albicans G6P, UDP 2.73 [42]
    5HVL 白色念珠菌 Candida albicans VDM, UDP 1.80 [42]
    5HVM 烟曲霉菌 Aspergillus fumigatus TPS1Ab VDM, UDP 2.82 [42]
    5HVO 烟曲霉菌 Aspergillus fumigatus TPS1Bb VDM, UDP 2.45 [42]
    5HUV 白色念珠菌 Candida albicans UDPG 2.00 Miao Y et al., 2017 c
    6JBI 稻瘟病菌 Magnaporthe oryzae apo form 2.50 [41]
    6JBW 稻瘟病菌 Magnaporthe oryzae UDPG 2.65 [41]
    6JBR 稻瘟病菌 Pyricularia oryzae T6P, UDP 2.03 [41]
    注:a 1 Å = 0.1 nm;b烟曲霉Aspergillus fumigantus 内包含两段编码TPS1基因,分别标记为TPS1A和TPS1B;c蛋白质三维晶体结构已存入蛋白质数据库 (http://www1.rcsb.org) 中,但尚未见相关文献报道。Note: a 1 Å = 0.1 nm. bA. Fumigantus contains two genes encoding TPS1, labeled as TPS1A and TPS1B, respectively. cThe three-dimensional crystal structures of those proteins were imported in the Protenin Data Bank Database (http://www1.rcsb.org), which were not reported in the literatures.
    下载: 导出CSV

    表  3  目前已报道的不同海藻糖-6-磷酸磷酸酯酶晶体结构信息

    Table  3.   The reported crystal structures of different trehalose-6-phosphate phospholipase

    PDB编号
    PDB ID
    物种
    Organism
    配体
    Ligand
    分辨率
    Resolution/Åa
    参考文献
    Reference
    1U02 嗜酸热原体菌 Thermoplasma acidophilum Mg2+, Na+ 1.92 [45]
    4OFZ 马来丝虫 Brugia malayi Mg2+ 3.00 [48]
    5E0O 马来丝虫 Brugia malayi Mg2+, SO42− 3.00 Agarwal A et al., 2015b
    5GVX 结核分枝杆菌 Mycobacterium tuberculosis Mg2+ 2.60 [49]
    5DXF 白色念珠菌(N-端结构域) Candida albicans (N-terminal domain) apo form 2.56 [50]
    5DX9 新型隐球菌 Cryptococcus neoformans Mg2+ 2.15 [50]
    5DXI 白色念珠菌(C-端结构域) Candida albicans (C-terminal domain) Mg2+ 2.00 [50]
    5DXL 烟曲霉菌 Aspergillus fumigatus apo form 1.57 [50]
    5DXN 烟曲霉菌 Aspergillus fumigatus Mg2+ 1.65 [50]
    5DXO 烟曲霉菌 Aspergillus fumigatus Mg2+ 1.90 [50]
    6CJ0 铜绿假单胞菌 Pseudomonas aeruginosa Mg2+, CO32− 1.90 [46]
    6D3V 假单胞菌 Pseudomonas sp. Ni2+, ACY 1.80 [46]
    6D3W 假单胞菌 Pseudomonas sp. Ca2+, ACY 1.90 [46]
    6QJ6 类鼻疽伯克霍尔德氏菌 Burkholderia pseudomallei Mg2+, Cl 1.74 [47]
    6RCZ 类鼻疽伯克霍尔德氏菌 Burkholderia pseudomallei Mg2+, Cl 1.74 [47]
    6UPC 伤寒沙门氏菌 Salmonella typhimurium Mg2+, T6S 2.51 [51]
    6UPE 伤寒沙门氏菌 Salmonella typhimurium Mg2+, OGS 2.24 [51]
    6UPD 伤寒沙门氏菌 Salmonella typhimurium Mg2+, Tre 2.05 [51]
    6UPB 伤寒沙门氏菌 Salmonella typhimurium apo form 1.89 [51]
    注:a 1 Å = 0.1 nm;b 蛋白质三维晶体结构已存入蛋白质数据库 (http://www1.rcsb.org) 中,但尚未见相关文献报道。Note: a 1 Å = 0.1 nm. b The three-dimensional crystal structures of those proteins were imported in the Protenin Data Bank Database (http://www1.rcsb.org), which were not reported in the literatures.
    下载: 导出CSV

    表  4  目前已报道的不同海藻糖-6-磷酸合成酶抑制剂

    Table  4.   The reported inhibitors of different trehalose-6-phosphate synthetase

    抑制剂名称
    Names of inhibitors
    抑制剂结构
    Structues of inhibitors
    靶标
    Target
    IC50/
    (mmol/L)
    参考文献
    Reference
    海藻糖-6-磷酸
    Trehalose-6-phosphate
    CtTPS1 0.125 [52-53]
    海藻糖
    Trehalose
    MtrOtsA
    CgOtsA
    HcTPS
    24 [40, 54-55]
    井冈羟胺 A
    Validoxylamine A
    EcOtsA
    CaTPS1
    AfTPS1
    [30, 38, 42]
    6′-井冈羟胺 A 磷酸
    6′-Validoxylamine A phosphate
    EcOtsA 5.3 ± 1.4 [30, 38]
    酮戊二酸
    2-Oxoglutarate
    MtrOtsA 1.8 [40]
    2-磷酸甘油酸
    2-Phosphoglyceric acid
    MtrOtsA 2.3 [40]
    烟酰胺腺嘌呤二核苷酸磷酸 (还原型)
    Nicotinamide adenine dinucleotide phosphate(Reduced form)
    MoTPS1 −11.3 kcal/mol
    (−47.30 kJ/mol)a
    [58]
    先导 25
    Lead 25
    MoTPS1 −13.8 kcal/mol
    (−57.76 kJ/mol)a
    [58]
    5-(2-噻吩基) 烟酸
    5-(2-Thineyl) nicotinic acid
    MtrOtsA 0.5 [59]
    4-羟基-6-(三氟甲基)-3-喹啉羧酸
    4-Hydroxy-6-(trifluoromethyl)-3-quinolinecarboxylic acid
    MtrOtsA 0.53 [59]
    5-氨基吲哚
    5-Aminoindole
    MtrOtsA 0.65 [59]
    克罗散泰
    Closanthal
    CnOtsA
    CgOtsA
    1 mg/Lb [60]
    2,6-二氨基-4-(3,4-二氯苯基)-3,5-
    二氰基-4-H-噻喃
    2,6-Diamino-4-(3,4-dichlorophenyl)-3,5-dicyano-4-H-thiopyrans
    DmTPS 0.2 [61]
    化合物 3
    Compound 3
    DmTPS 1.4 [61]
    化合物 4
    Compound 4
    DmTPS 2.8 [61]
    2,6-二氨基-4-(3-环己烯基)-3,5-
    二氰基-4-H-噻喃
    2,6-Diamino-4-(3-cyclohexenyl)-3,5-
    dicyano-4-H-thiopyrans
    CfTPS 3.1 [61]
    2,6-二氨基-4-(2-硝基噻吩基)-3,5-二氰基-4-H-噻喃
    2,6-Diamino-4-(2-nitrothienyl)-3,5-dicyano-4-H-thiopyrans
    DmTPS 5.4 [61]
    化合物 7
    Compound 7
    DmTPS 6.2 [61]
    注:a该文献以抑制剂与MoTPS1的结合自由能作为评价其抑制效果指标,单位为kcal/mol (1 kcal/mol = 4.18 kJ/mol);b该文献以抑制剂的最小抑菌浓度 (MIC) 作为评价其抑制效果指标,单位为mg/L。Note: aThe binding free energy between the inhibitor and MoTPS1 was used as an index to evaluate its inhibitory effect, the unit is kcal/mol (1 kcal/mol = 4.18 kJ/mol); bThe minimum inhibitory concentration (MIC) of the inhibitor was used as an index to evaluate its inhibitory effect, the unit is mg/L.
    下载: 导出CSV

    表  5  目前已报道的不同海藻糖-6-磷酸磷酸酯酶抑制剂

    Table  5.   The reported inhibitors of different trehalose-6-phosphate phosphatase

    抑制剂名称
    Names of inhibitors
    抑制剂结构
    Structues of inhibitors
    靶标
    Target
    IC50/
    (mmol/L)
    参考文献
    Reference
    海藻糖-6-磷酸
    Trehalose-6-phosphate
    MtOtsB
    SbOtsB
    AsTPP
    SdTPP
    (50 ± 5)~(340 ± 40) μmol/La [62]
    1S-1-(4-辛基苯氧基)-葡萄糖-6硫酸
    1S-1-(4-octylphenoxy)-glucose-6 sulfate
    BmTPP
    AsTPP
    SbOtsB
    StOtsB
    (13 ± 2)~(180 ± 20) μmol/La [63]
    1R-1-(4-辛基苯氧基)-葡萄糖-6硫酸
    1R-1-(4-octylphenoxy)-glucose-6 sulfate
    BmTPP
    AsTPP
    SbOtsB
    StOtsB
    (5.3 ± 0.6)~(80 ± 10) μmol/La [63]
    1R-1-(4-己基苯氧基)-葡萄糖-6硫酸
    1R-1-(4-hexylphenoxy)-glucose-6-sulfate
    BmTPP
    AsTPP
    SbOtsB
    StOtsB
    (78 ± 9)~(350 ± 30) μmol/La [63]
    6-氨基磷酸海藻糖
    Trehalose-6-aminophosphate
    MtbOtsB
    MltOtsB
    MtxOtsB
    0.42~1.03 [64]
    有效霉素 A
    Validamycin A
    MtbOtsB 12.6~15.0 [64-65]
    N-苯硫基邻苯二甲酰亚胺
    N-(phenylthio)phthalimide
    AceyTPP
    TcanTPP
    HconTPP
    PaerTPP
    8.9 × 10−4~6.6 × 10−3 [66]
    注:a该文献以抑制常数 (Ki) 作为评价抑制剂对酶抑制效果指标,单位为μmol/L。Note: aThe inbition constant (Ki) was used as an index to evaluate its inhibitory effect, the unit is μmol/L.
    下载: 导出CSV
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  • 收稿日期:  2020-10-31
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