雷帕霉素生物合成及其分子调控的研究进展
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摘要
雷帕霉素是一种31元大环内酯类抗生素,由雷帕链霉菌(Streptomyces rapamycinicus)、游动放线菌N902-109(Actinoplanes sp. N902-109)与伊氏链霉菌(Streptomyces iranensis)等放线菌菌株产生,具有广泛的生物活性,包括抗真菌、免疫抑制、抗肿瘤、神经保护和抗衰老等,市场应用前景非常广阔。目前,其生物合成途径已被清楚解析,研究证实它由一种杂合I型聚酮合酶(PKS, polyketide synthase)/非核糖体肽合成酶(NRPS, nonribosomal peptide synthetase)负责合成。基因簇全长约107.3kb,共含有26个基因,其中5个编码调控蛋白,参与调控雷帕霉素的生物合成。鉴于雷帕霉素及其衍生物在临床上的重要用途,其生物合成及其分子调控一直是大家的关注点,并取得了长足的进展,为雷帕霉素高产菌株的分子育种及新活性衍生物的挖掘奠定了良好的基础。本文将主要总结雷帕霉素生物合成基因簇、生物合成途径及其分子调控机制方面的研究进展,并将就该重要抗生素的发现及其衍生物的功能、高产菌株育种等方面的研究进行简单回顾。
Rapamycin is a 31-membered macrocyclic antibiotic, produced by actinomycetes, such as Streptomyces rapamycinicus, Actinoplanes sp. N902-109 and Streptomyces iranensis. It exhibits various biological and pharmacological activities, including antifungal, immuno-suppressive, antitumor, neuroprotective and antiaging activities. The biosynthetic pathway of rapamycin has been clearly elucidated, in which the core macrolactone ring is synthesized by a hybrid type I PKS/NRPS. The rapamycin biosynthetic gene cluster has been cloned, which is 107.3 kb long and contains 21 structural genes and five regulatory genes. Because rapamycin and its analogs are clinically important, rapamycin biosynthesis and its regulation have attracted many attentions and made great progress, which laid a good foundation for the construction of high-yield strains and for the discovery of novel bioactive rapalogs. Here, we review recent progress of rapamycin biosynthesis and regulation, as well as the structures and functions of rapamycin and its derivatives. We also present the strategies used for strain improvement of Streptomyces rapamycinicus.
Rapamycin is a 31-membered macrocyclic antibiotic, produced by actinomycetes, such as Streptomyces rapamycinicus, Actinoplanes sp. N902-109 and Streptomyces iranensis. It exhibits various biological and pharmacological activities, including antifungal, immuno-suppressive, antitumor, neuroprotective and antiaging activities. The biosynthetic pathway of rapamycin has been clearly elucidated, in which the core macrolactone ring is synthesized by a hybrid type I PKS/NRPS. The rapamycin biosynthetic gene cluster has been cloned, which is 107.3 kb long and contains 21 structural genes and five regulatory genes. Because rapamycin and its analogs are clinically important, rapamycin biosynthesis and its regulation have attracted many attentions and made great progress, which laid a good foundation for the construction of high-yield strains and for the discovery of novel bioactive rapalogs. Here, we review recent progress of rapamycin biosynthesis and regulation, as well as the structures and functions of rapamycin and its derivatives. We also present the strategies used for strain improvement of Streptomyces rapamycinicus.
引文
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[18]Wong G K,Griffith S,Kojima I,et al.Antifungal activities of rapamycin and its derivatives,prolylrapamycin,32-desmethylrapamycin,and 32-desmethoxyrapamycin[J].JAntibiot,1998,51(5):487-491.
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[20]High K P,Washburn R G.Invasive aspergillosis in mice immunosuppressed with cyclosporin A,tacrolimus(FK506),or sirolimus(rapamycin)[J].J Infect Dis,1997,175(1):222-225.
[21]Gregory C R,Huie P,Billingham M E,et al.Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury.Its effect on cellular,growth factor,and cytokine responses in injured vessels[J].Transplantation,1993,55(6):1409-1418.
[22]Meiser B M,Billingham M E,Morris R E.Effects of cyclosporin,FK506,and rapamycin on graft-vessel disease[J].Lancet,1991,338(8778):1297-1298.
[23]Tsai M K,Chueh S C,Hu R H,et al.Effect of sirolimus in combination with low-dose cyclosporine and steroids on acute renal allograft rejection[J].J Formos Med Assoc,2003,102(2):91-96.
[24]Bae-Jump V L,Zhou C X,Boggess J F,et al.Synergistic effect of rapamycin and cisplatin in endometrial cancer cells[J].Cancer,2009,115(17):3887-3896.
[25]Shafer A,Zhou C X,Gehrig P A,et al.Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis[J].Int J Cancer,2010,126(5):1144-1154.
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[27]Argyriou P,Economopoulou P,Papageorgiou S.The role of mTOR inhibitors for the treatment of B-cell lymphomas[J].Advan Hematol,2012,2012(2012):1-13.
[28]Pan T H,Kondo S,Zhu W,et al.Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement[J].Neurobiol Dis,2008,32(1):16-25.
[29]Malagelada C,Jin Z H,et al.Rapamycin protects against neuron death in vitro and in vivo models of parkinson's disease[J].J Neurosci,2010,30(3):1166-1175.
[30]Tateda S,Kanno H,Ozawa H,et al.Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury[J].J Orthopaed Res,2017,35(1):93-103.
[31]Burke S E,Kuntz R E,Schwartz L B.Zotarolimus(ABT-578)eluting stent[J].Advan Drug Deliv Rev,2006,58(3):437-446.
[32]Harrison D E,Strong R,Sharp Z D,et al.Rapamycin fed late in life extends lifespan in genetically heterogeneous mice[J].Nature,2009,460(7253):392-395.
[33]Konig A,Schwecke T,Molnar I,et al.The pipecolate incorporating enzyme for the biosynthesis of the immunosuppressant rapamycin-Nucleotide sequence analysis,disruption and heterologous expression of rapPfrom Streptomyces hygroscopicus[J].Eur J Biochem,1997,247(2):526-534.
[34]Sattely E S,Fischbach M A,Walsh C T.Total biosynthesis:In vitro reconstitution of polyketide and nonribosomal peptide pathways[J].Cheminform,2008,39(46):757-793.
[35]Gregory M A,Hong H,Lill R E,et al.Rapamycin biosynthesis:Elucidation of gene product function[J].Organ Biomol Chem,2006,4(19):3565-2568.
[36]Wlodek A,Kendrew S G,Coates N J,et al.Diversity oriented biosynthesis via accelerated evolution of modular gene clusters[J].Nat Commun,2017,8(1):1206.
[37]Gatto G J,Boyne M T,Kelleher N L,et al.Biosynthesis of pipecolic acid by RapL,a lysine cyclodeaminase encoded in the rapamycin gene cluster[J].J Am Chem Soc,2006,128(11):3838-3847.
[38]Huang H,Ren S X,Yang S,et al.Comparative analysis of rapamycin biosynthesis clusters between Actinoplanes sp.N902-109 and Streptomyces hygroscopicus ATCC29253[J].Chin J Nat Med,2015,13(2):90-98.
[39]Molnar I,Aparicio J F,Haydock S F,et al.Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus:Analysis of genes flanking the polyketide synthase[J].Gene,1996,169(1):1-7.
[40]Park S R,Yoo Y J,Ban Y H.Biosynthesis of rapamycin and its regulation:past achievements and recent progress[J].JAntibiot(Tokyo),2010,63(8):434-441.
[41]Mo S,Kim D H,Lee J H,et al.Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues[J].J Am Chem Soc,2011,133(4):976-985.
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