毕赤酵母的非甲醇诱导系统研究进展
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摘要
毕赤酵母是一种能以甲醇为唯一碳源生长的甲基营养型酵母,常用作表达外源蛋白的细胞工厂。目前毕赤酵母常用的高效启动子AOX1(P_(AOX1))是一个严格的底物依赖型启动子,受甲醇的严格诱导,受葡萄糖、甘油、乙醇等非甲醇碳源抑制。但是甲醇有毒、易燃、易爆的特性使得其在食用、医用产品生产等领域受到很大的限制。本文将主要从P_(AOX1)机制改造、新型启动子和非甲醇诱导物研发的角度阐述毕赤酵母非甲醇诱导的研究进展。
Komagataella phaffii(K. phaffii) is a methyltrophic yeast that can grow with methanol as the sole carbon source to express heterologous proteins. At present, the efficient promoter AOX1(P_(AOX1)), commonly used in K. phaffii, is a strict substrate-dependent promoter, which is strictly induced by methanol and inhibited by non-methanol carbon sources such as glucose, glycerin, ethanol and so on. However, the toxic, flammable and explosive characteristics of methanol restrict the production of edible, medical products and other fields. In this paper, the research progress of non-methanol induction in K. phaffii was introduced from the point of view of P_(AOX1) mechanism modification, new promoter and non-methanol inducer development.
Komagataella phaffii(K. phaffii) is a methyltrophic yeast that can grow with methanol as the sole carbon source to express heterologous proteins. At present, the efficient promoter AOX1(P_(AOX1)), commonly used in K. phaffii, is a strict substrate-dependent promoter, which is strictly induced by methanol and inhibited by non-methanol carbon sources such as glucose, glycerin, ethanol and so on. However, the toxic, flammable and explosive characteristics of methanol restrict the production of edible, medical products and other fields. In this paper, the research progress of non-methanol induction in K. phaffii was introduced from the point of view of P_(AOX1) mechanism modification, new promoter and non-methanol inducer development.
引文
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[3] KURTZMAN C P.Description of Komagataella phaffii sp.nov.and the transfer of Pichia pseudopastoris to the methylotrophic yeast genus Komagataella[J].Int J Syst Evol Microbiol,2005,55(Pt 2):973-976.
[4] NAUMOV G I,NAUMOVA E S,TYURIN O V,et al.Komagataella kurtzmanii sp.nov.,a new sibling species of Komagataella (Pichia) pastoris based on multigene sequence analysis [J].Antonie Van Leeuwenhoek,2013,104(3):339-347.
[5] CELIK E,CALIK P.Production of recombinant proteins by yeast cells[J].Biotechnology Advances,2012,30(5):1108-1118.
[6] 张建国,黄勋娟,刘菲,等.毕赤酵母过氧化物酶体吞噬的研究进展[J].微生物学通报,2014,41(8):1684-1691.
[7] POTVIN G,AHMAD A,ZHANG Z.Bioprocess engineering aspects of heterologous protein production in Pichia pastoris:A review[J].Biochemical Engineering Journal,2012,64:91-105.
[8] ALAM?E T,LIIV L.Glucose repression of maltase and methanol-oxidizing enzymes in the methylotrophic yeast Hansenula polymorpha:Isolation and study of regulatory mutants [J].Folia Microbio,1998,43(5):443-452.
[9] INAN M.Studies on the alcohol oxidase (AOX1) promoter of Pichia pastoris [J].Pediatric Research,2000,41(4):62-62.
[10] HARTNER F S,RUTH C,LANGENEGGER D,et al.Promoter library designed for fine-tuned gene expression in Pichia pastoris [J].Nucleic Acids Research,2008,36(12):45-50.
[11] RUTH C,ZUELLIG T,MELLITZER A,et al.Variable production windows for porcine trypsinogen employing synthetic inducible promoter variants in Pichia pastoris[J].Syst Synth Biol,2010,4(3):181-191.
[12] XUAN Y,ZHOU X,ZHANG W,et al.An upstream activation sequence controls the expression of AOX1 gene in Pichia pastoris[J].FEMS yeast research,2009,9(8):1271-1282.
[13] LIN-CEREGHINO G P,GODFREY L,BERNARD J,et al.Mxr1p,a key regulator of the methanol utilization pathway and peroxisomal genes in Pichia pastoris [J].Molecular and cellular biology,2006,26(3):883-897.
[14] KRANTHI B V,KUMAR R,KUMAR N V,et al.Identification of key DNA elements involved in promoter recognition by Mxr1p,a master regulator of methanol utilization pathway in Pichia pastoris[J].Biochim Biophys Acta,2009,1789(6-8):460-468.
[15] WANG X L,WANG Q,WANG J J,et al.Mit1 transcription factor mediates methanol signaling and regulates the alcohol oxidase 1 (AOX1) promoter in Pichia pastoris [J].Journal of Biological Chemistry,2016,291(12):6245-6261.
[16] STALEY C A,HUANG A,NATTESTAD M,et al.Analysis of the 5′ untranslated region (5′ UTR) of the alcohol oxidase 1 (AOX1) gene in recombinant protein expression in Pichia pastoris [J].Gene,2012,496(2):118-127.
[17] JOHNSON M,WATERHAM H,GP,FAYURA L,et al.Positive selection of novel peroxisome biogenesis-defective mutants of the yeast Pichia pastoris [J].Genetics,1999,151(4):1379-1391.
[18] CIRIACY M.Genetics of alcohol dehydrogenase in Saccharomyces cerevisiae:I.Isolation and genetic analysis of adh mutants [J].Mutation Research/Fundamental & Molecular Mechanisms of Mutagenesis,1975,29(3):315-325.
[19] SIMON M,ADAM G,RAPATZ W,et al.The Saccharomyces cerevisiae ADR1 gene is a positive regulator of transcription of genes encoding peroxisomal proteins [J].Molecular & Cellular Biology,1991,11(2):699.
[20] TACHIBANA C,YOO J Y,TAGNE J B,et al.Combined global localization analysis and transcriptome data identify genes that are directly coregulated by Adr1 and Cat8 [J].Molecular & Cellular Biology,2005,25(6):2138-2146.
[21] PARUA P K,RYAN P M,TRANG K,et al.Pichia pastoris 14-3-3 regulates transcriptional activity of the methanol inducible transcription factor Mxr1 by direct interaction [J].Molecular Microbiology,2012,85(2):282-298.
[22] SAHU U,KRISHNA RAO K,RANGARAJAN P N.Trm1p,a Zn(II)2Cys6-type transcription factor,is essential for the transcriptional activation of genes of methanol utilization pathway,in Pichia pastoris[J].Biochem Biophys Res Commun,2014,451(1):158-164.
[23] TAKAGI S,TSUTSUMI N,TERUI Y,et al.Method for methanol independent induction from methanol inducible promoters in Pichia:United States Patent 8143023 [P].2012.
[24] LEAO-HELDER A N,KRIKKEN A M,VAN DER KLEI I J,et al.Transcriptional down-regulation of peroxisome numbers affects selective peroxisome degradation in Hansenula polymorpha[J].J Biol Chem,2003,278(42):40749-40756.
[25] VALLINI V,BERARDI E,STRABBIOLI R.Mutations affecting the expression of the MOX gene encoding peroxisomal methanol oxidase in Hansenula polymorpha [J].Current Genetics,2000,38(4):163-170.
[26] PARK S H,KOH S S,CHUN J H,et al.Nrg1 is a transcriptional repressor for glucose repression of STA1 gene expression in Saccharomyces cerevisiae[J].Molcellbiol,1999,19(3):2044.
[27] BERKEY C D,VYAS V K,CARLSON M.Nrg1 and Nrg2 transcriptional repressors are differently regulated in response to carbon source [J].Eukaryotic Cell,2004,3(2):311-317.
[28] LEE S B,KANG H S,KIM T S.Nrg1 functions as a global transcriptional repressor of glucose-repressed genes through its direct binding to the specific promoter regions[J].Biochem Biophys Res Commun,2013,439(4):501-505.
[29] WANG X L,CAI M H,SHI L,et al.PpNrg1 is a transcriptional repressor for glucose and glycerol repression of AOX1 promoter in methylotrophic yeast Pichia pastoris [J].Biotechnol Lett,2016,38(2):291-298.
[30] 张平.毕赤酵母HXT和MIG基因对于AOX1启动子的碳源阻遏功能[D].华东理工大学,2010.
[31] 亓飞.毕赤酵母AOX1启动子的阻遏因子PpMig1、PpMig2的亚细胞定位及基于RNA-Seq技术的毕赤酵母基因组重注释和比较转录组学初步研究[D].华东理工大学,2014.
[32] VOGL T,STURMBERGER L,FAULAND P C,et al.Methanol independent induction in Pichia pastoris by simple derepressed overexpression of single transcription factors[J].Biotechnol Bioeng,2018,115(4):1037-1050.
[33] OHSAWA S,YURIMOTO H,SAKAI Y.Novel function of Wsc proteins as a methanol-sensing machinery in the yeast Pichia pastoris[J].Mol Microbiol,2017,104(2):349-363.
[34] 周祥山,张元兴,王锦佳,等.消除甲醇诱导型启动子单一甲醇碳源依赖性的方法:CN102757976A[P].2012.
[35] WANG J,WANG X,SHI L,et al.Methanol-independent protein expression by AOX1 promoter with trans-acting elements engineering and glucose-glycerol-shift induction in Pichia pastoris [J].Sci Rep,2017,7:41850.
[36] SHEN W,XUE Y,LIU Y,et al.A novel methanol-free Pichia pastoris system for recombinant protein expression[J].Microb Cell Fact,2016,15(1):178.
[37] KUMARI A,GUPTA R.Novel strategy of using methyl esters as slow release methanol source during lipase expression by mut(+) Pichia pastoris X33[J].Plos One,2014,9(8):e104272.
[38] TYURIN O,KOZLOV D G.Novel inductor for the promoters of the methanol utilization pathway[J].International Journal of Heat & Mass Transfer,2013,66(11):324-333.
[39] 蓝娜娜,张薷月,苏然,等.非甲醇诱导重组毕赤酵母表达木聚糖酶的条件优化[J].食品与发酵工业,2018,44(3):8-14.
[40] TYURIN O V,KOZLOV D G.Deletion of the FLD gene in methylotrophic yeasts Komagataella phaffii and Komagataella kurtzmanii results in enhanced induction of the AOX1 promoter in response to either methanol or formate [J].Microbiology,2015,84(3):408-411.
[41] 亓飞,蔡孟浩,周祥山,等.基于RNA-Seq技术的毕赤酵母基因组重注释及新型强启动子的发现与序列分析[J].华东理工大学学报,2014,40(2):167-175.
[42] SHEN S,SULTER G,JEFFRIES T W,et al.A strong nitrogen source-regulated promoter for controlled expression of foreign genes in the yeast Pichia pastoris [J].Gene,1998,216(1):93-102.
[43] RESINA D,SERRANO A,VALERO F,et al.Expression of a Rhizopus oryzae lipase in Pichia pastoris under control of the nitrogen source-regulated formaldehyde dehydrogenase promoter[J].J Biotechnol,2004,109(1):103-113.
[44] RESINA D,COS O,FERRER P,et al.Developing high cell density fed-batch cultivation strategies for heterologous protein production in Pichia pastoris using the nitrogen source-regulated FLD1 Promoter[J].Biotechnol Bioeng,2010,91(6):760-767.
[45] 夏烨.抗VEGF与IL-10主动免疫对HPV感染肿瘤模型的作用及碳、氮源对酵母高密度发酵与不同启动子指导的HPV16 L1表达的影响 [D];北京协和医学院,2016.
[46] LEE H W,AHN J O,JUNG J K,et al.Auto-inducible sodium phosphate symporter promoter from Pichia pastoris and method for producing recombinant protein using it [M].US20100279345A1.2011.
[47] AHN J,HONG J,PARK M,et al.Phosphate-responsive promoter of a Pichia pastoris sodium phosphate symporter [J].Appl Environ Microbiol,2009,75(11):3528-3534.
[48] BOIDOL W,SIMONIS M,T?PERT M,et al.Recombinant plasmids with genes for the biosynthesis of alkaline phosphatase of Escherichia coli [J].Mol Gen Genet,1982,185(3):510-512.
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