药学学报, 2018, 53(9): 1477-1483
引用本文:
李荣翠, 刘率男, 申竹芳. 果糖-1,6-二磷酸酶及其抑制剂的研究进展[J]. 药学学报, 2018, 53(9): 1477-1483.
LI Rong-cui, LIU Shuai-nan, SHEN Zhu-fang. Advances in the pharmacological function of FBPase and development of FBPase inhibitors[J]. Acta Pharmaceutica Sinica, 2018, 53(9): 1477-1483.

果糖-1,6-二磷酸酶及其抑制剂的研究进展
李荣翠, 刘率男, 申竹芳
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 晶型药物研究北京市重点实验室, 中国医学科学院糖尿病研究中心, 北京 100050
摘要:
果糖-1,6-二磷酸酶(fructose 1,6-bisphosptase,FBPase)是位于糖异生过程中第二步的限速酶,在机体血糖调控中发挥重要的生理作用。因此,针对该酶的抑制剂将具有抗糖尿病活性。目前,已有数个FBPase抑制剂分别进入不同临床研究阶段,提示针对该靶点的抗糖尿病药物研发前景十分可观。除此以外,近年研究发现,FBPase还可参与和调节其他疾病如肿瘤的发生、发展过程等。本文将围绕FBPase的结构特征、生理作用、其与2型糖尿病糖异生和胰岛素分泌的关系、FBPase抑制剂的研究进展以及该酶在其他疾病中调控作用等方面作一综述。
关键词:    果糖-1,6-二磷酸酶      2型糖尿病      糖异生      胰岛素分泌     
Advances in the pharmacological function of FBPase and development of FBPase inhibitors
LI Rong-cui, LIU Shuai-nan, SHEN Zhu-fang
Diabetes Research Center of Chinese Academy of Medical Sciences, Key Laboratory of Polymorphic Drugs of Beijing, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Fructose 1, 6-bisphosptase (FBPase), a second rate-limiting enzyme in gluconeogenesis, has an important role in the control of gluconeogenesis, which involves in energy metabolism and glucose homeostasis. Inhibitors of FBPase exhibit an anti-diabetic activity. Some of FBPase inhibitors have entered the stage of clinical trials, which indicates that FBPase is a promising therapeutic target for the discovery and development of hypoglycemic drugs. In addition, recent studies have shown that FBPase can be used to treat other diseases such as the initiation and development of tumors in several cancer types. Here, we provide a review of the biological characteristics of FBPase and contributions of FBPase on gluconeogenesis and insulin secretion, the research and development of FBPase inhibitors and the regulatory role of FBPase in other diseases.
Key words:    fructose-1,6-bisphosptase    type 2 diabetes mellitus    gluconeogenesis    insulin secretion   
收稿日期: 2018-03-30
DOI: 10.16438/j.0513-4870.2018-0282
基金项目: 国家科技重大专项重大新药创制基金项目(2018ZX09711002-003-012);中国医学科学院中央级公益性科研院所基本科研业务费(2016ZX350009);中国医学科学院医学与健康创新工程(2017-I2M-1-010).
通讯作者: 申竹芳,Tel:86-10-83172669,E-mail:shenzhf@imm.ac.cn
Email: shenzhf@imm.ac.cn
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参考文献:
[1] Paksu MS, Kalkan G, Asilioglu N, et al. Gluconeogenesis defect presenting with resistant hyperglycemia and acidosis mimicking diabetic ketoacidosis[J]. Pediatr Emerg Care, 2011, 12:1180-1181.
[2] Gomori G. Hexosediphosphatase[J]. J Biol Chem, 1943, 148:139-149.
[3] Tejwani GA. Regulation of fructose-bisphosphatase activity[J]. Adv Enzymol Relat Areas Mol Biol, 1983, 54:121-194.
[4] Zhu H. The Study with Fluorescent Probe TNP-AMP on Binding Sites of Inhibitors to Cyanobacteria FBPase (荧光探针分子TNP-AMP识别蓝藻FBPase抑制剂作用位点的研究)[D]. Wuhan:Central China Normal University, 2015.
[5] Marcus F, Edelstein I, Reardon I, et al. Complete amino acid sequence of pig kidney fructose-1,6-bisphosphatase[J]. Proc Natl Acad Sci U S A, 1982, 23:7161-7165.
[6] Mcininch JK, Kantrowitz ER. Use of silicate sol-gels to trap the R and T quaternary conformational states of pig kidney fructose-1,6-bisphosphatase[J]. Biochim Biophys Acta, 2001, 2:320-328.
[7] Zhang Y, Liang JY, Huang S, et al. Toward a mechanism for the allosteric transition of pig kidney fructose-1,6-bisphosphatase[J]. J Mol Biol, 1994, 5:609-624.
[8] Li ZM, Bie JB, Song HR, et al. Recent advance in the discovery of allosteric inhibitors binding to the AMP site of fructose-1, 6-bisphosphatase[J]. Acta Pharm Sin (药学学报), 2011, 11:1291-1300.
[9] Chiadmi M, Navaza A, Miginiac-Maslow M, et al. Redox signalling in the chloroplast:structure of oxidized pea fructose-1,6-bisphosphate phosphatase[J]. EMBO J, 1999, 23:6809-6815.
[10] Tillmann H, Eschrich K. Isolation and characterization of an allelic cDNA for human muscle fructose-1,6-bisphosphatase[J]. Gene, 1998, 2:295-304.
[11] Gizak A, Sok AJ, Lipinska A, et al. A comparative study on the sensitivity of Cyprinus carpio muscle and liver FBPase toward AMP and calcium[J]. Comp Biochem Physiol B Biochem Mol Biol, 2012, 1-3:51-55.
[12] Mamczur P, Sok AJ, Rzechonek A, et al. Cell cycledependent expression and subcellular localization of fructose 1,6-bisphosphatase[J]. Histochem Cell Biol, 2012, 1:121-136.
[13] Yanez AJ, Nualart F, Droppelmann C. Broad expression of fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase provide evidence for gluconeogenesis in human tissues other than liver and kidney[J]. J Cell Physiol, 2003, 1:189-197.
[14] Yanez AJ, Garcia-Rocha M, Bertinat R, et al. Subcellular localization of liver FBPase is modulated by metabolic conditions[J]. FEBS Lett, 2004, 1-2:154-158.
[15] Ke HM, Liang JY, Zhang YP, et al. Conformational transition of fructose-1,6-bisphosphatase:structure comparison between the AMP complex (T form) and the fructose 6-phosphate complex (R form)[J]. Biochemistry, 1991, 18:4412-4420.
[16] Kaur R, Dahiya L, Kumar M. Fructose-1,6-bisphosphatase inhibitors:a new valid approach for management of type 2 diabetes mellitus[J]. Eur J Med Chem, 2017, 141:473-505.
[17] Shi R, Chen ZY, Zhu DW, et al. Crystal structures of human muscle fructose-1,6-bisphosphatase:novel quaternary states, enhanced AMP affinity, and allosteric signal transmission pathway[J]. PLoS One, 2013, 9:e71242.
[18] El-Maghrabi MR, Lange AJ, Kummel L, et al. The rat fructose-1,6-bisphosphatase gene. Structure and regulation of expression[J]. J Biol Chem, 1991, 4:2115-2120.
[19] Pilkis SJ, Claus TH. Hepatic gluconeogenesis/glycolysis:regulation and structure/function relationships of substrate cycle enzymes[J]. Annu Rev Nutr, 1991, 11:465-515.
[20] Fujisawa K, Umesono K, Kikawa Y, et al. Identification of a response element for vitamin D 3 and retinoic acid in the promoter region of the human fructose-1,6-bisphosphatase gene[J]. J Biochem, 2000, 3:373-382.
[21] Li B. Recent proceedings in research of tumor-associated disorders of glucose metabolism[J]. J Sun Yat-sen Univ (Med Sci) (中山大学学报(医学科学版)), 2017, 2:222-228.
[22] Penhoat A, Fayard L, Stefanutti A, et al. Intestinal gluconeogenesis is crucial to maintain a physiological fasting glycemia in the absence of hepatic glucose production in mice[J]. Metabolism, 2014, 1:104-111.
[23] Yip J, Geng X, Shen J, et al. Cerebral gluconeogenesis and diseases[J]. Front Pharmacol, 2016, 7:521.
[24] Yanez AJ, Bertinat R, Concha Ⅱ, et al. Nuclear localization of liver FBPase isoenzyme in kidney and liver[J]. FEBS Lett, 2003, 1-3:35-40.
[25] Visinoni S, Fam BC, Blair A, et al. Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver[J]. Am J Physiol Endocrinol Metab, 2008, 5:E1132-E1141.
[26] Laybutt DR, Sharma A, Sgroi DC, et al. Genetic regulation of metabolic pathways in beta-cells disrupted by hyperglycemia[J]. J Biol Chem, 2002, 13:10912-10921.
[27] Zhang Y, Xie Z, Zhou G, et al. Fructose-1,6-bisphosphatase regulates glucose-stimulated insulin secretion of mouse pancreatic beta-cells[J]. Endocrinology, 2010, 10:4688-4695.
[28] Zhang Y, Xie Z, Zhou L, et al. The zinc finger protein ZBTB20 regulates transcription of fructose-1,6-bisphosphatase 1 and beta cell function in mice[J]. Gastroenterology, 2012, 7:1571-1580.e6.
[29] Fam BC, Joannides CN, Andrikopoulos S. The liver:key in regulating appetite and body weight[J]. Adipocyte, 2012, 4:259-264.
[30] Chen M, Zhang J, Li N, et al. Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer[J]. PLoS One, 2011, 10:e25564.
[31] Li B, Qiu B, Lee DS, et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression[J]. Nature, 2014, 7517:251-255.
[32] Yang J, Jin X, Yan Y, et al. Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression[J]. Sci Rep, 2017, 7:43864.
[33] Rakus D, Tillmann H, Wysocki R, et al. Different sensitivities of mutants and chimeric forms of human muscle and liver fructose-1,6-bisphosphatases towards AMP[J]. Biol Chem, 2003, 1:51-58.
[34] Wright SW, Carlo AA, Carty MD, et al. Anilinoquinazoline inhibitors of fructose 1,6-bisphosphatase bind at a novel allosteric site:synthesis, in vitro characterization, and X-ray crystallography[J]. J Med Chem, 2002, 18:3865-3877.
[35] Wright SW, Hageman DL, Mcclure LD, et al. Allosteric inhibition of fructose-1,6-bisphosphatase by anilinoquinazolines[J]. Bioorg Med Chem Lett, 2001, 1:17-21.
[36] Erion MD, Dang Q, Reddy MR, et al. Structure-guided design of AMP mimics that inhibit fructose-1,6-bisphosphatase with high affinity and specificity[J]. J Am Chem Soc, 2007, 50:15480-15490.
[37] Erion MD, Van Poelje PD, Dang Q, et al. A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes[J]. Proc Natl Acad Sci U S A, 2005, 22:7970-7975.
[38] Dang Q, Liu Y, Cashion DK, et al. Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase[J]. J Med Chem, 2011, 1:153-165.
[39] Bie JB, Liu SN, Zhou J, et al. Design, synthesis and biological evaluation of 7-nitro-1H-indole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase[J]. Bioorg Med Chem, 2014, 6:1850-1862.
[40] Bie JB, Liu SN, Li ZM, et al. Discovery of novel indole derivatives as allosteric inhibitors of fructose-1,6 bisphosphatase[J]. Eur J Med Chem, 2015, 90:394-405.
[41] Rudnitskaya A, Huynh K, Torok B, et al. Novel heteroaromatic organofluorine inhibitors of fructose-1,6-bisphos-phatase[J]. J Med Chem, 2009, 3:878-882.
[42] Heng S, Harris KM, Kantrowitz ER. Designing inhibitors against fructose 1,6-bisphosphatase:exploring natural products for novel inhibitor scaffolds[J]. Eur J Med Chem, 2010, 4:1478-1484.
[43] Baker L,Winegrad AI. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity[J]. Lancet, 1970, 7662:13-16.
[44] Nagahara K, Ariyasu D, Igaki J, et al. A Japanese boy with fructose-1,6-bisphosphatase deficiency who had a novel FBP1 mutation[J]. Clin Pediatr Endocrinol, 2017, 4:275-278.
[45] Ijaz S, Zahoor MY, Imran M, et al. Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families[J]. J Pediatr Endocrinol Metab, 2017, 11:1203-1210.
[46] Xu K, Liu XQ, Zhang C, et al. Genetic diagnosis of fructose-1,6-bisphosphatase deficiency:a case report[J]. J Peking Univ (Health Sci) (北京大学学报(医学版)), 2014, 46:681-685.
[47] Dong C, Yuan T, Wu Y, et al. Loss of FBP1 by Snailmediated repression provides metabolic advantages in basallike breast cancer[J]. Cancer Cell, 2013, 3:316-331.
[48] Hirata H, Sugimachi K, Komatsu H, et al. Decreased expression of fructose-1,6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma[J]. Cancer Res, 2016, 11:3265-3276.
[49] Li K, Ying M, Feng D, et al. Fructose-1,6-bisphosphatase is a novel regulator of Wnt/beta-catenin pathway in breast cancer[J]. Biomed Pharmacother, 2016, 84:1144-1149.
[50] Zhang J, Wang J, Xing H, et al. Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells[J]. Mol Cell Biochem, 2016, 1-2:331-340.
[51] Liu X, Wang X, Zhang J, et al. Warburg effect revisited:an epigenetic link between glycolysis and gastric carcinogenesis[J]. Oncogene, 2010, 3:442-450.
[52] Chen J, Lee HJ, Wu X, et al. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain[J]. Cancer Res, 2015, 3:554-565.
[53] Liu GM, Zhang YM. Targeting FBPase is an emerging novel approach for cancer therapy[J]. Cancer Cell Int, 2018, 18:36.
[54] Dai J, Ji Y, Wang W, et al. Loss of fructose-1,6-bisphosphatase induces glycolysis and promotes apoptosis resistance of cancer stem-like cells:an important role in hexavalent chromium-induced carcinogenesis[J]. Toxicol Appl Pharmacol, 2017, 331:164-173.
[55] Liu Y, Jiang Y, Wang N, et al. Invalidation of mitophagy by FBP1-mediated repression promotes apoptosis in breast cancer[J]. Tumour Biol, 2017, 6:1-13.
[56] Jin X, Pan Y, Wang L, et al. Fructose-1,6-bisphosphatase inhibits ERK activation and bypasses gemcitabine resistance in pancreatic cancer by blocking IQGAP1-MAPK interaction[J]. Cancer Res, 2017, 16:4328-4341.
[57] Van Poelje PD, Potter SC, Erion MD. Fructose-1,6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in type 2 diabetes[J]. Handb Exp Pharmacol, 2011, 203:279-301.
[58] Giaccari A, Morviducci L, Pastore L, et al. Relative contribution of glycogenolysis and gluconeogenesis to hepatic glucose production in control and diabetic rats. A re-examination in the presence of euglycaemia[J]. Diabetologia, 1998, 3:307-314.
[59] Visinoni S, Khalid NF, Joannides CN, et al. The role of liver fructose-1,6-bisphosphatase in regulating appetite and adiposity[J]. Diabetes, 2012, 5:1122-1132.