色氨酸2,3-双加氧酶在中枢神经系统疾病中的作用及其治疗策略思考
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摘要
色氨酸2,3-双加氧酶(Tryptophan-2,3-dioxygenase, TDO)是一种具有特异性L-色氨酸酶活性的含血红素四聚体蛋白,能协助氧气进入催化色氨酸吲哚基团变成犬尿氨酸(kynurenine, KYN)。神经组织是人体重要且不可再生组织,而色氨酸代谢与神经组织生理功能密切相关。TDO活化导致色氨酸耗竭及其代谢产物犬尿氨酸的累积,这些代谢产物能影响神经元的功能并造成相关免疫失调。越来越多的证据表明,TDO在某些脑疾病病理生理中发挥重要作用。因此,本综述就TDO在阿尔茨海默病(Alzheimer’s disease, AD)、精神分裂症和神经胶质瘤三种中枢神经系统疾病中的作用作一总结,希望强调TDO在色氨酸代谢途径及在相关神经疾病中的作用,并指导TDO特异性抑制剂的开发和应用,从而为某些中枢神经系统疾病提供新的治疗思路和方法。
Tryptophan-2,3-dioxygenase(TDO) is a heme-containing tetrameric protein that exhibits specific catalytic activity for L-tryptophan. TDO assists oxygen into the indole gene of tryptophan and then catalyzes it into kynurenine(KYN). Nervous tissues play an important role in the human body, but cannot regenerate. Tryptophan metabolism is closely related to the physiological function of nerves. Activation of TDO leads to the depletion of tryptophan and the accumulation of KYN and its metabolites, which can affect the function of neurons and cause related immune disorders. Mounting evidence obtained in recent studies indicates that TDO play an important role in the pathophysiology of several brain diseases. This paper summarizes the biological functions of TDO in the neurological diseases schizophrenia, Alzheimer's disease, and glioma, with the aim of emphasizing TDO's effect in tryptophan metabolic pathways and related neurological diseases. This should guide the development and application of TDO-specific inhibitors, which could provide new treatments for certain neurological diseases.
Tryptophan-2,3-dioxygenase(TDO) is a heme-containing tetrameric protein that exhibits specific catalytic activity for L-tryptophan. TDO assists oxygen into the indole gene of tryptophan and then catalyzes it into kynurenine(KYN). Nervous tissues play an important role in the human body, but cannot regenerate. Tryptophan metabolism is closely related to the physiological function of nerves. Activation of TDO leads to the depletion of tryptophan and the accumulation of KYN and its metabolites, which can affect the function of neurons and cause related immune disorders. Mounting evidence obtained in recent studies indicates that TDO play an important role in the pathophysiology of several brain diseases. This paper summarizes the biological functions of TDO in the neurological diseases schizophrenia, Alzheimer's disease, and glioma, with the aim of emphasizing TDO's effect in tryptophan metabolic pathways and related neurological diseases. This should guide the development and application of TDO-specific inhibitors, which could provide new treatments for certain neurological diseases.
引文
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[23] Hayes MD, Ovcinnikovs V, Smith AG, et al. The aryl hydrocarbon receptor: differential contribution to T helper 17 and T cytotoxic 17 cell development[J]. PLoS One, 2014, 9(9):e106955.
[24] DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro-versus anti-tumor immunity[J]. Cancer Metastasis Rev, 2010, 29(2):309-316.
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[2] Pantouris G, Mowat CG. Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase[J]. Biochem Biophys Res Commun, 2014, 443(1):28-31.
[3] Alsadany MA, Shehata HH, Mohamad MI, et al. Histone deacetylases enzyme, copper, and IL-8 levels in patients with Alzheimer’s disease[J]. Am J Alzheimers Dis Other Demen, 2013, 28(1):54-61.
[4] Bonda DJ, Mailankot M, Stone JG, et al. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer’s disease[J]. Redox Rep, 2010, 15(4):161-168.
[5] Breda C, Sathyasaikumar KV, Sograte Idrissi S, et al. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites[J]. Proc Natl Acad of Sci U S A, 2016, 113(19):5435-5440.
[6] Wu W, Nicolazzo JA, Wen L, et al. Expression of Tryptophan 2,3-Dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human alzheimer’s disease brain[J]. PLoS One, 2013, 8(4):e59749.
[7] Guillemin GJ, Brew BJ, Noonan CE, et al. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus[J]. Neuropathol Appl Neurobiol, 2005, 31(4):395-404.
[8] 王丽莎, 刘新民, 冯利, 等. 犬尿氨酸通路在神经退行性疾病中的研究进展[J]. 中国比较医学杂志, 2015, 25(11):69-75.
[9] Lanz TV, Williams SK, Stojic A, et al. Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis[J]. Sci Rep, 2017, 7:41271.
[10] Linderholm KR, Skogh E, Olsson SK, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia[J]. Schizophr Bull, 2012, 38(3):426-432.
[11] 杨修登, 唐亚梅, 郎雯竞, 等. 精神分裂症患者血清中犬尿氨酸及犬尿氨酸-3-单加氧酶浓度变化及临床意义[J]. 湖南师范大学学报医学版, 2016, 13(1):18-20.
[12] Miller CL, Llenos IC, Dulay JR, et al. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder[J]. Brain Res, 2006, 1073-1074(3):25-37.
[13] Miller CL, Llenos IC, Dulay JR, et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia[J]. Neurobiol Dis, 2004, 15(3):618-629.
[14] Chiappelli J, Postolache TT, Kochunov P, et al. Tryptophan metabolism and white matter integrity in schizophrenia[J]. Neuropsychopharmacol, 2016, 41(10):2587-2595.
[15] Réus GZ, Becker IRT, Scaini G, et al. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 81:55-63.
[16] Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism[J]. Dev Neurobiol, 2012, 72(10):1272-1276.
[17] Anderson G, Maes M. Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2013, 42(8):5-19.
[18] Bosnyák E, Kamson DO, Robinette NL, et al. Tryptophan PET predicts spatial and temporal patterns of post-treatment glioblastoma progression detected by contrast-enhanced MRI[J]. J Neurooncol, 2015, 126(2):317-325.
[19] Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase[J]. Nat Med, 2003, 9(10):1269-1274.
[20] Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor[J]. Nature, 2011, 478(7368):197-203.
[21] Adams S, Teo C, McDonald KL, et al. Involvement of the kynurenine pathway in human glioma pathophysiology[J]. PLoS One, 2014, 9(11):e112945.
[22] Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells[J]. J Immunol, 2006, 176(11):6752-6761.
[23] Hayes MD, Ovcinnikovs V, Smith AG, et al. The aryl hydrocarbon receptor: differential contribution to T helper 17 and T cytotoxic 17 cell development[J]. PLoS One, 2014, 9(9):e106955.
[24] DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro-versus anti-tumor immunity[J]. Cancer Metastasis Rev, 2010, 29(2):309-316.
[25] Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal[J]. Genes Dev. 2005, 19(17):1951-1967.
[26] Fouquerel E, Sobol RW. ARTD1 (PARP1) activation and NAD+ in DNA repair and cell death[J]. DNA Repair(Amst), 2014, 23:27-32.
[27] Campesan S, Green EW, Breda C, et al. The Kynurenine pathway modulates neurodegeneration in a drosophila model of huntington’s disease[J]. Curr Biol, 2011, 21(11):961-966.
[28] van der Goot AT, Zhu W, Vázquez-Manrique RP, et al. Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation[J]. Proc Natl Acad Sci U S A, 2012, 109(37):14912-14917.