{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:30:12Z","timestamp":1791894612378,"version":"4.3.4"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the National Key R&D Program of China","award":["2018YFA0901500"],"award-info":[{"award-number":["2018YFA0901500"]}]},{"name":"the National Key R&D Program of China","award":["2018YFA0901500"],"award-info":[{"award-number":["2018YFA0901500"]}]},{"name":"the National Key R&D Program of China","award":["2018YFA0901500"],"award-info":[{"award-number":["2018YFA0901500"]}]},{"name":"the National Key R&D Program of China","award":["2018YFA0901500"],"award-info":[{"award-number":["2018YFA0901500"]}]},{"name":"the National Key R&D Program of China","award":["2018YFA0901500"],"award-info":[{"award-number":["2018YFA0901500"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Genomics"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Pichia pastoris<\/jats:italic>\n                      (\n                      <jats:italic>Komagataella phaffii<\/jats:italic>\n                      ) is a model organism widely used for the recombinant expression of eukaryotic proteins, and it can metabolize methanol as its sole carbon and energy source. Methanol is oxidized to formaldehyde by alcohol oxidase (AOX). In the dissimilation pathway, formaldehyde is oxidized to CO\n                      <jats:sub>2<\/jats:sub>\n                      by formaldehyde dehydrogenase (FLD), S-hydroxymethyl glutathione hydrolase (FGH) and formate dehydrogenase (FDH).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The transcriptome and metabolome of\n                      <jats:italic>P. pastoris<\/jats:italic>\n                      were determined under methanol cultivation when its dissimilation pathway cut off. Firstly,\n                      <jats:italic>\u0394fld<\/jats:italic>\n                      and\n                      <jats:italic>\u0394fgh<\/jats:italic>\n                      were significantly different compared to the wild type (GS115), with a 60.98% and 23.66% reduction in biomass, respectively. The differential metabolites between GS115 and\n                      <jats:italic>\u0394fld<\/jats:italic>\n                      were mainly enriched in ABC transporters, amino acid biosynthesis, and protein digestion and absorption. Secondly, comparative transcriptome between knockout and wild type strains showed that oxidative phosphorylation, glycolysis and the TCA cycle were downregulated, while alcohol metabolism, proteasomes, autophagy and peroxisomes were upregulated. Interestingly, the down-regulation of the oxidative phosphorylation pathway was positively correlated with the gene order of dissimilation pathway knockdown. In addition, there were significant differences in amino acid metabolism and glutathione redox cycling that raised our concerns about formaldehyde sorption in cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This is the first time that integrity of dissimilation pathway analysis based on transcriptomics and metabolomics was carried out in\n                      <jats:italic>Pichia pastoris<\/jats:italic>\n                      . The blockage of dissimilation pathway significantly down-regulates the level of oxidative phosphorylation and weakens the methanol assimilation pathway to the point where deficiencies in energy supply and carbon fixation result in inefficient biomass accumulation and genetic replication. In addition, transcriptional upregulation of the proteasome and autophagy may be a stress response to resolve formaldehyde-induced DNA\u2013protein crosslinking.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12864-022-08592-8","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T17:23:03Z","timestamp":1652376183000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Comparative transcriptome and metabolome analyses reveal the methanol dissimilation pathway of Pichia pastoris"],"prefix":"10.1186","volume":"23","author":[{"given":"Yi-fan","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiashuo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengguang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"8592_CR1","doi-asserted-by":"publisher","first-page":"607028","DOI":"10.3389\/fmicb.2020.607028","volume":"11","author":"L Bernauer","year":"2021","unstructured":"Bernauer L, Radkohl A, Lehmayer LGK, Emmerstorfer-Augustin A. Komagataella phaffii as Emerging Model Organism in Fundamental Research. Front Microbiol. 2021;11:607028. https:\/\/doi.org\/10.3389\/fmicb.2020.607028.","journal-title":"Front Microbiol"},{"issue":"9","key":"8592_CR2","doi-asserted-by":"publisher","first-page":"5867","DOI":"10.1002\/jcp.29583","volume":"235","author":"M Karbalaei","year":"2020","unstructured":"Karbalaei M, Rezaee SA, Farsiani H. Pichia pastoris: A highly successful expression system for optimal synthesis of heterologous proteins. J Cell Physiol. 2020;235(9):5867\u201381. https:\/\/doi.org\/10.1002\/jcp.29583.","journal-title":"J Cell Physiol"},{"key":"8592_CR3","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bjm.2018.03.010","volume":"49","author":"AB Zepeda","year":"2018","unstructured":"Zepeda AB, Pessoa A, Far\u00edas JG. Carbon metabolism influenced for promoters and temperature used in the heterologous protein production using Pichia pastoris yeast. Braz J Microbiol. 2018;49:119\u201327. https:\/\/doi.org\/10.1016\/j.bjm.2018.03.010.","journal-title":"Braz J Microbiol"},{"issue":"6","key":"8592_CR4","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1002\/tcr.20056","volume":"5","author":"H Yurimoto","year":"2005","unstructured":"Yurimoto H, Kato N, Sakai Y. Assimilation, dissimilation, and detoxification of formaldehyde, a central metabolic intermediate of methylotrophic metabolism. Chem Rec. 2005;5(6):367\u201375. https:\/\/doi.org\/10.1002\/tcr.20056.","journal-title":"Chem Rec"},{"issue":"4","key":"8592_CR5","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1093\/genetics\/151.4.1379","volume":"151","author":"MA Johnson","year":"1999","unstructured":"Johnson MA, Waterham HR, Ksheminska GP, Fayura LR, Cereghino JL, Stasyk OV, Veenhuis M, Kulachkovsky AR, Sibirny AA, Cregg JM. Positive Selection of Novel Peroxisome Biogenesis-Defective Mutants of the Yeast Pichia pastoris. Genetics. 1999;151(4):1379\u201391. https:\/\/doi.org\/10.1093\/genetics\/151.4.1379.","journal-title":"Genetics"},{"issue":"4","key":"8592_CR6","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s00203-002-0450-2","volume":"178","author":"J Vorholt","year":"2002","unstructured":"Vorholt J. Cofactor-dependent pathways of formaldehyde oxidation in methylotrophic bacteria. Arch Microbiol. 2002;178(4):239\u201349. https:\/\/doi.org\/10.1007\/s00203-002-0450-2.","journal-title":"Arch Microbiol"},{"issue":"1","key":"8592_CR7","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1475-2859-5-39","volume":"5","author":"FS Hartner","year":"2006","unstructured":"Hartner FS, Glieder A. Regulation of methanol utilisation pathway genes in yeasts. Microb Cell Fact. 2006;5(1):39. https:\/\/doi.org\/10.1186\/1475-2859-5-39.","journal-title":"Microb Cell Fact"},{"key":"8592_CR8","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.3762\/bjoc.11.190","volume":"11","author":"M Geier","year":"2015","unstructured":"Geier M, Brandner C, Strohmeier GA, Hall M, Hartner FS, Glieder A. Engineering Pichia pastoris for improved NADH regeneration: A novel chassis strain for whole-cell catalysis. Beilstein J Org Chem. 2015;11:1741\u20138. https:\/\/doi.org\/10.3762\/bjoc.11.190.","journal-title":"Beilstein J Org Chem"},{"issue":"1","key":"8592_CR9","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ymben.2009.08.006","volume":"12","author":"K Schroer","year":"2010","unstructured":"Schroer K, Peter Luef K, Stefan Hartner F, Glieder A, Pscheidt B. Engineering the Pichia pastoris methanol oxidation pathway for improved NADH regeneration during whole-cell biotransformation. Metab Eng. 2010;12(1):8\u201317. https:\/\/doi.org\/10.1016\/j.ymben.2009.08.006.","journal-title":"Metab Eng"},{"issue":"1","key":"8592_CR10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1080\/13102818.2020.1837012","volume":"35","author":"T Liu","year":"2020","unstructured":"Liu T, Liu B, Zhou H, Zhang J. Knockout of the DAS gene increases S-adenosylmethionine production in Komagataella phaffii. Biotechnol Biotechnol Equip. 2020;35(1):29\u201336. https:\/\/doi.org\/10.1080\/13102818.2020.1837012.","journal-title":"Biotechnol Biotechnol Equip"},{"issue":"2","key":"8592_CR11","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1002\/bit.22543","volume":"105","author":"E \u00c7elik","year":"2010","unstructured":"\u00c7elik E, \u00c7al\u0131k P, Oliver SG. Metabolic flux analysis for recombinant protein production byPichia pastorisusing dual carbon sources: Effects of methanol feeding rate. Biotechnol Bioeng. 2010;105(2):317\u201329. https:\/\/doi.org\/10.1002\/bit.22543.","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"8592_CR12","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/1475-2859-11-103","volume":"11","author":"AL Vanz","year":"2012","unstructured":"Vanz AL, L\u00fcnsdorf H, Adnan A, Nimtz M, Gurramkonda C, Khanna N, Rinas U. Physiological response of Pichia pastoris GS115 to methanol-induced high level production of the Hepatitis B surface antigen: catabolic adaptation, stress responses, and autophagic processes. Microb Cell Fact. 2012;11(1):103. https:\/\/doi.org\/10.1186\/1475-2859-11-103.","journal-title":"Microb Cell Fact"},{"key":"8592_CR13","doi-asserted-by":"publisher","unstructured":"Jord\u00e0, J., Suarez, C., Carnicer, M., ten Pierick, A., Heijnen, J. J., van Gulik, W., Ferrer, P., Albiol, J., & Wahl, A. Glucose-methanol co-utilization in Pichia pastoris studied by metabolomics and instationary 13C flux analysis. BMC Syst Biol. 2013;7(1). https:\/\/doi.org\/10.1186\/1752-0509-7-17.","DOI":"10.1186\/1752-0509-7-17"},{"key":"8592_CR14","doi-asserted-by":"publisher","unstructured":"Vartiainen, E., Blomberg, P., Ilm\u00e9n, M., Andberg, M., Toivari, M., & Penttil\u00e4, M. Evaluation of synthetic formaldehyde and methanol assimilation pathways in Yarrowia lipolytica. Fungal Biol Biotechnol, 2019;6(1). https:\/\/doi.org\/10.1186\/s40694-019-0090-9.","DOI":"10.1186\/s40694-019-0090-9"},{"issue":"1","key":"8592_CR15","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1002\/bit.27575","volume":"118","author":"F Guo","year":"2020","unstructured":"Guo F, Dai Z, Peng W, Zhang S, Zhou J, Ma J, Dong W, Xin F, Zhang W, Jiang M. Metabolic engineering of Pichia pastoris for malic acid production from methanol. Biotechnol Bioeng. 2020;118(1):357\u201371. https:\/\/doi.org\/10.1002\/bit.27575.","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"8592_CR16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/s0378-1119(98)00315-1","volume":"216","author":"S Shen","year":"1998","unstructured":"Shen S, Sulter G, Jeffries TW, Cregg JM. A strong nitrogen source-regulated promoter for controlled expression of foreign genes in the yeast Pichia pastoris. Gene. 1998;216(1):93\u2013102. https:\/\/doi.org\/10.1016\/s0378-1119(98)00315-1.","journal-title":"Gene"},{"issue":"5","key":"8592_CR17","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.jbiosc.2016.03.022","volume":"122","author":"K Wakayama","year":"2016","unstructured":"Wakayama K, Yamaguchi S, Takeuchi A, Mizumura T, Ozawa S, Tomizuka N, Hayakawa T, Nakagawa T. Regulation of intracellular formaldehyde toxicity during methanol metabolism of the methylotrophic yeast Pichia methanolica. J Biosci Bioeng. 2016;122(5):545\u20139. https:\/\/doi.org\/10.1016\/j.jbiosc.2016.03.022.","journal-title":"J Biosci Bioeng"},{"key":"8592_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotochem.2020.112701","volume":"400","author":"W Yuan","year":"2020","unstructured":"Yuan W, zhong, X., Han, Q., Jiang, Y., Shen, J., & Wang, B. A novel formaldehyde fluorescent probe based on 1, 8-naphthalimide derivative and its application in living cell. J Photochem Photobiol, A. 2020;400: 112701. https:\/\/doi.org\/10.1016\/j.jphotochem.2020.112701.","journal-title":"J Photochem Photobiol, A"},{"key":"8592_CR19","doi-asserted-by":"publisher","unstructured":"Nakamura, J., Holley, D. W., Kawamoto, T., & Bultman, S. J. (2020). The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL\/6 mice. Genes Environ. 2020;42(1). https:\/\/doi.org\/10.1186\/s41021-020-00160-4.","DOI":"10.1186\/s41021-020-00160-4"},{"key":"8592_CR20","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3389\/fgene.2016.00200","volume":"7","author":"M North","year":"2016","unstructured":"North M, Gayt\u00e1n BD, Romero C, De La Rosa VY, Loguinov A, Smith MT, Zhang L, Vulpe CD. Functional Toxicogenomic Profiling Expands Insight into Modulators of Formaldehyde Toxicity in Yeast. Front Genet. 2016;7:200. https:\/\/doi.org\/10.3389\/fgene.2016.00200.","journal-title":"Front Genet"},{"issue":"3","key":"8592_CR21","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s00294-020-01057-z","volume":"66","author":"V Anandarajan","year":"2020","unstructured":"Anandarajan V, Noguchi C, Oleksak J, Grothusen G, Terlecky D, Noguchi E. Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe. Curr Genet. 2020;66(3):593\u2013605. https:\/\/doi.org\/10.1007\/s00294-020-01057-z.","journal-title":"Curr Genet"},{"issue":"1","key":"8592_CR22","doi-asserted-by":"publisher","first-page":"16545","DOI":"10.1038\/s41598-020-73376-7","volume":"10","author":"JC Gonzalez-Rivera","year":"2020","unstructured":"Gonzalez-Rivera JC, Sherman MW, Wang DS, Chuvalo-Abraham JCL, Hildebrandt Ruiz L, Contreras LM. RNA oxidation in chromatin modification and DNA-damage response following exposure to formaldehyde. Sci Rep. 2020;10(1):16545. https:\/\/doi.org\/10.1038\/s41598-020-73376-7.","journal-title":"Sci Rep"},{"issue":"4","key":"8592_CR23","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.cell.2020.07.010","volume":"182","author":"FY-H Chen","year":"2020","unstructured":"Chen FY-H, Jung H-W, Tsuei C-Y, Liao JC. Converting Escherichia coli to a Synthetic Methylotroph Growing Solely on Methanol. Cell. 2020;182(4):933-946.e14. https:\/\/doi.org\/10.1016\/j.cell.2020.07.010.","journal-title":"Cell"},{"issue":"6","key":"8592_CR24","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1007\/s12010-009-8684-y","volume":"160","author":"D Yasokawa","year":"2009","unstructured":"Yasokawa D, Murata S, Iwahashi Y, Kitagawa E, Nakagawa R, Hashido T, Iwahashi H. Toxicity of Methanol and Formaldehyde Towards Saccharomyces cerevisiae as Assessed by DNA Microarray Analysis. Appl Biochem Biotechnol. 2009;160(6):1685\u201398. https:\/\/doi.org\/10.1007\/s12010-009-8684-y.","journal-title":"Appl Biochem Biotechnol"},{"key":"8592_CR25","doi-asserted-by":"publisher","unstructured":"Jord\u00e0, J., Jouhten, P., C\u00e1mara, E., Maaheimo, H., Albiol, J., & Ferrer, P. (2012). Metabolic flux profiling of recombinant protein secreting Pichia pastoris growing on glucose:methanol mixtures. Microb Cell Fac. 2012;11(1). https:\/\/doi.org\/10.1186\/1475-2859-11-57.","DOI":"10.1186\/1475-2859-11-57"},{"key":"8592_CR26","doi-asserted-by":"publisher","first-page":"107467","DOI":"10.1016\/j.biotechadv.2019.107467","volume":"39","author":"T Zhu","year":"2020","unstructured":"Zhu T, Zhao T, Bankefa OE, Li Y. Engineering unnatural methylotrophic cell factories for methanol-based biomanufacturing: Challenges and opportunities. Biotechnol Adv. 2020;39:107467. https:\/\/doi.org\/10.1016\/j.biotechadv.2019.107467.","journal-title":"Biotechnol Adv"},{"issue":"6","key":"8592_CR27","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/nbt.1544","volume":"27","author":"K De Schutter","year":"2009","unstructured":"De Schutter K, Lin Y-C, Tiels P, Van Hecke A, Glinka S, Weber-Lehmann J, Rouz\u00e9 P, Van de Peer Y, Callewaert N. Genome sequence of the recombinant protein production host Pichia pastoris. Nat Biotechnol. 2009;27(6):561\u20136. https:\/\/doi.org\/10.1038\/nbt.1544.","journal-title":"Nat Biotechnol"},{"issue":"D1","key":"8592_CR28","doi-asserted-by":"publisher","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","volume":"49","author":"M Kanehisa","year":"2020","unstructured":"Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2020;49(D1):D545\u201351. https:\/\/doi.org\/10.1093\/nar\/gkaa970.","journal-title":"Nucleic Acids Res"},{"key":"8592_CR29","doi-asserted-by":"publisher","unstructured":"van Zutphen T., Baerends R. J., Susanna K. A., de Jong A., Kuipers O. P., Veenhuis M.,van der Klei, I. J. . Adaptation of Hansenula polymorpha to methanol: a transcriptome analysis. BMC Genomics. 2010;11(1). https:\/\/doi.org\/10.1186\/1471-2164-11-1.","DOI":"10.1186\/1471-2164-11-1"},{"issue":"5","key":"8592_CR30","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/yea.1110","volume":"21","author":"T Nakagawa","year":"2004","unstructured":"Nakagawa T, Ito T, Fujimura S, Chikui M, Mizumura T, Miyaji T, Yurimoto H, Kato N, Sakai Y, Tomizuka N. Molecular characterization of the glutathione-dependent formaldehyde dehydrogenase geneFLD1 from the methylotrophic yeastPichia methanolica. Yeast. 2004;21(5):445\u201353. https:\/\/doi.org\/10.1002\/yea.1110.","journal-title":"Yeast"},{"issue":"22","key":"8592_CR31","doi-asserted-by":"publisher","first-page":"5885","DOI":"10.1128\/jb.180.22.5885-5890.1998","volume":"180","author":"Y Sakai","year":"1998","unstructured":"Sakai Y, Nakagawa T, Shimase M, Kato N. Regulation and Physiological Role of the DAS1 Gene, Encoding Dihydroxyacetone Synthase, in the Methylotrophic Yeast Candida boidinii. J Bacteriol. 1998;180(22):5885\u201390. https:\/\/doi.org\/10.1128\/jb.180.22.5885-5890.1998.","journal-title":"J Bacteriol"},{"issue":"10","key":"8592_CR32","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.1021\/ja808048c","volume":"131","author":"K Lu","year":"2009","unstructured":"Lu K, Ye W, Gold A, Ball LM, Swenberg JA. Formation of S-[1-(N2-Deoxyguanosinyl)methyl]glutathione between Glutathione and DNA Induced by Formaldehyde. J Am Chem Soc. 2009;131(10):3414\u20135. https:\/\/doi.org\/10.1021\/ja808048c.","journal-title":"J Am Chem Soc"},{"key":"8592_CR33","doi-asserted-by":"publisher","unstructured":"Pietzke M, Burgos-Barragan G, Wit N, Tait-Mulder J, Sumpton D, Mackay G. M, Patel K. J, Vazquez A. Amino acid dependent formaldehyde metabolism in mammals. Communications Chem. 2020;3(1). https:\/\/doi.org\/10.1038\/s42004-020-0324-z.","DOI":"10.1038\/s42004-020-0324-z"},{"key":"8592_CR34","doi-asserted-by":"publisher","first-page":"103589","DOI":"10.1016\/j.fm.2020.103589","volume":"92","author":"M Torrellas","year":"2020","unstructured":"Torrellas M, Roz\u00e8s N, Aranda A, Matallana E. Basal catalase activity and high glutathione levels influence the performance of non-Saccharomyces active dry wine yeasts. Food Microbiol. 2020;92:103589. https:\/\/doi.org\/10.1016\/j.fm.2020.103589.","journal-title":"Food Microbiol"},{"issue":"4","key":"8592_CR35","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1128\/ec.00007-09","volume":"8","author":"T Yano","year":"2009","unstructured":"Yano T, Takigami E, Yurimoto H, Sakai Y. Yap1-Regulated Glutathione Redox System Curtails Accumulation of Formaldehyde and Reactive Oxygen Species in Methanol Metabolism of Pichia pastoris. Eukaryot Cell. 2009;8(4):540\u20139. https:\/\/doi.org\/10.1128\/ec.00007-09.","journal-title":"Eukaryot Cell"},{"issue":"8","key":"8592_CR36","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1099\/mic.0.26320-0","volume":"149","author":"H Yurimoto","year":"2003","unstructured":"Yurimoto H, Lee B, Yano T, Sakai Y, Kato N. Physiological role of S-formylglutathione hydrolase in C1 metabolism of the methylotrophic yeast Candida boidinii. Microbiology. 2003;149(8):1971\u20139. https:\/\/doi.org\/10.1099\/mic.0.26320-0.","journal-title":"Microbiology"},{"issue":"4","key":"8592_CR37","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1080\/713857189","volume":"13","author":"E Skrzydlewska","year":"2003","unstructured":"Skrzydlewska E. Toxicological and Metabolic Consequences of Methanol Poisoning. Toxicol Mech Methods. 2003;13(4):277\u201393. https:\/\/doi.org\/10.1080\/713857189.","journal-title":"Toxicol Mech Methods"},{"key":"8592_CR38","doi-asserted-by":"publisher","unstructured":"Ru\u00dfmayer, H., Buchetics, M., Gruber, C., Valli, M., Grillitsch, K., Modarres, G., Guerrasio, R., Klavins, K., Neubauer, S., Drexler, H., Steiger, M., Troyer, C., Al Chalabi, A., Krebiehl, G., Sonntag, D., Zellnig, G., Daum, G., Graf, A. B., Altmann, F., & Koellensperger, G. (2015). Systems-level organization of yeast methylotrophic lifestyle. BMC Biol. 2015;13(1). https:\/\/doi.org\/10.1186\/s12915-015-0186-5.","DOI":"10.1186\/s12915-015-0186-5"},{"issue":"9","key":"8592_CR39","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/nrm.2017.56","volume":"18","author":"J Stingele","year":"2017","unstructured":"Stingele J, Bellelli R, Boulton SJ. Mechanisms of DNA\u2013protein crosslink repair. Nat Rev Mol Cell Biol. 2017;18(9):563\u201373. https:\/\/doi.org\/10.1038\/nrm.2017.56.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"8592_CR40","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1093\/nar\/gkaa1224","volume":"49","author":"S Zhao","year":"2020","unstructured":"Zhao S, Kieser A, Li H-Y, Reinking HK, Weickert P, Euteneuer S, Yaneva D, Acampora A, G\u00f6tz M, Feederle R, Stingele J. A ubiquitin switch controls autocatalytic inactivation of the DNA\u2013protein crosslink repair protease SPRTN. Nucleic Acids Res. 2020;49(2):902\u201315. https:\/\/doi.org\/10.1093\/nar\/gkaa1224.","journal-title":"Nucleic Acids Res"},{"key":"8592_CR41","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fmolb.2019.00040","volume":"6","author":"RS Marshall","year":"2019","unstructured":"Marshall RS, Vierstra RD. Dynamic Regulation of the 26S Proteasome: From Synthesis to Degradation. Front Mol Biosci. 2019;6:40. https:\/\/doi.org\/10.3389\/fmolb.2019.00040.","journal-title":"Front Mol Biosci"},{"issue":"1","key":"8592_CR42","doi-asserted-by":"publisher","first-page":"12","DOI":"10.2183\/pjab.85.12","volume":"85","author":"K Tanaka","year":"2009","unstructured":"Tanaka K. The proteasome: Overview of structure and functions. Proceedings of the Japan Academy, Series B. 2009;85(1):12\u201336. https:\/\/doi.org\/10.2183\/pjab.85.12.","journal-title":"Proceedings of the Japan Academy, Series B"},{"issue":"10","key":"8592_CR43","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s11427-017-9183-4","volume":"60","author":"NL Klages-Mundt","year":"2017","unstructured":"Klages-Mundt NL, Li L. Formation and repair of DNA-protein crosslink damage. Science China Life Sciences. 2017;60(10):1065\u201376. https:\/\/doi.org\/10.1007\/s11427-017-9183-4.","journal-title":"Science China Life Sciences"},{"issue":"7","key":"8592_CR44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181370","volume":"12","author":"C Jayachandran","year":"2017","unstructured":"Jayachandran C, Palanisamy Athiyaman B, Sankaranarayanan M. Cofactor engineering improved CALB production in Pichia pastoris through heterologous expression of NADH oxidase and adenylate kinase. PLoS ONE. 2017;12(7): e0181370. https:\/\/doi.org\/10.1371\/journal.pone.0181370.","journal-title":"PLoS ONE"},{"issue":"4","key":"8592_CR45","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1099\/mic.0.2006\/001404-0","volume":"153","author":"A Kern","year":"2007","unstructured":"Kern A, Hartner FS, Freigassner M, Spielhofer J, Rumpf C, Leitner L, Fr\u00f6hlich K-U, Glieder A. Pichia pastoris \u201cjust in time\u201d alternative respiration. Microbiol. 2007;153(4):1250\u201360. https:\/\/doi.org\/10.1099\/mic.0.2006\/001404-0.","journal-title":"Microbiol"},{"issue":"8","key":"8592_CR46","doi-asserted-by":"publisher","first-page":"863","DOI":"10.4161\/auto.7.8.15697","volume":"7","author":"T van Zutphen","year":"2011","unstructured":"van Zutphen T, Veenhuis M, van der Klei IJ. Damaged peroxisomes are subject to rapid autophagic degradation in the yeastHansenula polymorpha. Autophagy. 2011;7(8):863\u201372. https:\/\/doi.org\/10.4161\/auto.7.8.15697.","journal-title":"Autophagy"},{"key":"8592_CR47","doi-asserted-by":"publisher","first-page":"463","DOI":"10.3389\/fmicb.2020.00463","volume":"11","author":"C Zhang","year":"2020","unstructured":"Zhang C, Ma Y, Miao H, Tang X, Xu B, Wu Q, Mu Y, Huang Z. Transcriptomic Analysis of Pichia pastoris (Komagataella phaffii) GS115 During Heterologous Protein Production Using a High-Cell-Density Fed-Batch Cultivation Strategy. Front Microbiol. 2020;11:463. https:\/\/doi.org\/10.3389\/fmicb.2020.00463.","journal-title":"Front Microbiol"},{"issue":"8","key":"8592_CR48","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nrm4015","volume":"16","author":"J Stingele","year":"2015","unstructured":"Stingele J, Jentsch S. DNA\u2013protein crosslink repair. Nat Rev Mol Cell Biol. 2015;16(8):455\u201360. https:\/\/doi.org\/10.1038\/nrm4015.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"8592_CR49","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3390\/jof7020090","volume":"7","author":"MN Mota","year":"2021","unstructured":"Mota MN, Martins LC, S\u00e1-Correia I. The Identification of Genetic Determinants of Methanol Tolerance in Yeast Suggests Differences in Methanol and Ethanol Toxicity Mechanisms and Candidates for Improved Methanol Tolerance Engineering. J Fungi. 2021;7(2):90. https:\/\/doi.org\/10.3390\/jof7020090.","journal-title":"J Fungi"},{"issue":"6","key":"8592_CR50","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s11274-019-2654-5","volume":"35","author":"Y Gu","year":"2019","unstructured":"Gu Y, Gao J, Cao M, Dong C, Lian J, Huang L, Cai J, Xu Z. Construction of a series of episomal plasmids and their application in the development of an efficient CRISPR\/Cas9 system in Pichia pastoris. World J Microbiol Biotechnol. 2019;35(6):79. https:\/\/doi.org\/10.1007\/s11274-019-2654-5.","journal-title":"World J Microbiol Biotechnol"},{"issue":"7","key":"8592_CR51","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1093\/bioinformatics\/btu743","volume":"31","author":"Y Naito","year":"2014","unstructured":"Naito Y, Hino K, Bono H, Ui-Tei K. CRISPRdirect: software for designing CRISPR\/Cas guide RNA with reduced off-target sites. Bioinformatics. 2014;31(7):1120\u20133. https:\/\/doi.org\/10.1093\/bioinformatics\/btu743.","journal-title":"Bioinformatics"},{"issue":"1","key":"8592_CR52","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1186\/1471-2164-13-738","volume":"13","author":"S Liang","year":"2012","unstructured":"Liang S, Wang B, Pan L, Ye Y, He M, Han S, Zheng S, Wang X, Lin Y. Comprehensive structural annotation of Pichia pastoris transcriptome and the response to various carbon sources using deep paired-end RNA sequencing. BMC Genomics. 2012;13(1):738. https:\/\/doi.org\/10.1186\/1471-2164-13-738.","journal-title":"BMC Genomics"},{"issue":"3","key":"8592_CR53","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1134\/s0026261715030212","volume":"84","author":"OV Tyurin","year":"2015","unstructured":"Tyurin OV, Kozlov DG. 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. Microbiol. 2015;84(3):408\u201311. https:\/\/doi.org\/10.1134\/s0026261715030212.","journal-title":"Microbiol"},{"issue":"5","key":"8592_CR54","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/bioinformatics\/btn025","volume":"24","author":"R Li","year":"2008","unstructured":"Li R, Li Y, Kristiansen K, Wang J. SOAP: short oligonucleotide alignment program. Bioinformatics. 2008;24(5):713\u20134. https:\/\/doi.org\/10.1093\/bioinformatics\/btn025.","journal-title":"Bioinformatics"},{"issue":"4","key":"8592_CR55","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357\u201360. https:\/\/doi.org\/10.1038\/nmeth.3317.","journal-title":"Nat Methods"},{"issue":"4","key":"8592_CR56","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","volume":"9","author":"B Langmead","year":"2012","unstructured":"Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9(4):357\u20139. https:\/\/doi.org\/10.1038\/nmeth.1923.","journal-title":"Nat Methods"},{"key":"8592_CR57","doi-asserted-by":"publisher","unstructured":"Li B, Dewey, C. N.. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12(1). https:\/\/doi.org\/10.1186\/1471-2105-12-323.","DOI":"10.1186\/1471-2105-12-323"},{"key":"8592_CR58","doi-asserted-by":"publisher","unstructured":"Love M. I, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12). https:\/\/doi.org\/10.1186\/s13059-014-0550-8","DOI":"10.1186\/s13059-014-0550-8"},{"issue":"D1","key":"8592_CR59","doi-asserted-by":"publisher","first-page":"D642","DOI":"10.1093\/nar\/gkz859","volume":"48","author":"PT Monteiro","year":"2019","unstructured":"Monteiro PT, Oliveira J, Pais P, Antunes M, Palma M, Cavalheiro M, Galocha M, Godinho CP, Martins LC, Bourbon N, Mota MN, Ribeiro RA, Viana R, S\u00e1-Correia I, Teixeira MC. YEASTRACT+: a portal for cross-species comparative genomics of transcription regulation in yeasts. Nucleic Acids Res. 2019;48(D1):D642\u20139. https:\/\/doi.org\/10.1093\/nar\/gkz859.","journal-title":"Nucleic Acids Res"},{"key":"8592_CR60","doi-asserted-by":"publisher","unstructured":"Godinho, C. P., Palma, M., Oliveira, J., Mota, M. N., Antunes, M., Teixeira, M. C., Monteiro, P. T., & S\u00e1-Correia, I. (2021). The N.C.Yeastract and CommunityYeastract databases to study gene and genomic transcription regulation in non-conventional yeasts. FEMS Yeast Research, 21(6). https:\/\/doi.org\/10.1093\/femsyr\/foab045.","DOI":"10.1093\/femsyr\/foab045"},{"key":"8592_CR61","doi-asserted-by":"publisher","unstructured":"Shen, X., Gong, X., Cai, Y., Guo, Y., Tu, J., Li, H., Zhang, T., Wang, J., Xue, F., & Zhu, Z.-J. Normalization and integration of large-scale metabolomics data using support vector regression.Metabolomics, 2016;12(5). https:\/\/doi.org\/10.1007\/s11306-016-1026-5.","DOI":"10.1007\/s11306-016-1026-5"}],"container-title":["BMC Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12864-022-08592-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12864-022-08592-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12864-022-08592-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T17:23:28Z","timestamp":1652376208000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcgenomics.biomedcentral.com\/articles\/10.1186\/s12864-022-08592-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["8592"],"URL":"https:\/\/doi.org\/10.1186\/s12864-022-08592-8","relation":{},"ISSN":["1471-2164"],"issn-type":[{"value":"1471-2164","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,12]]},"assertion":[{"value":"3 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"366"}}