Abstract
The yeast Candida utilis is used as a food additive and as a host for heterologous gene expression to produce various metabolites and proteins. Reliable protocols for intracellular production of recombinant proteins are available for C. utilis and have now been expanded to secrete proteins into the growth medium or to achieve surface display by linkage to a cell wall protein. A recombinant C. utilis strain was recently shown to induce oral tolerance in a mouse model of multiple sclerosis suggesting future applications in autoimmune therapy. Whole genome sequencing of C. utilis and its presumed parent Cyberlindnera (Pichia) jadinii demonstrated different ploidy but high sequence identity, consistent with identical recombinant technologies for both yeasts. C. jadinii was recently described as an antagonist to the important human fungal pathogen Candida albicans suggesting its use as a probiotic agent. The review summarizes the status of recombinant protein production in C. utilis, as well as current and future biotechnological and medical applications of C. utilis and C. jadinii.
Similar content being viewed by others
References
Bekatorou A, Psaríanos C, Koutinas AA (2006) Production of food grade yeasts. Food Technol Biotechnol 44:407–415
Belcarz A, Ginalska G, Lobarzewski J, Penel C (2002) The novel non-glycosylated invertase from Candida utilis (the properties and the conditions of production and purification). Biochim Biophys Acta 1594:40–53
Boňková H, Osadská M, Krahulec J, Lišková V, Stuchlík S, Turňa J (2014) Upstream regulatory regions controlling the expression of the Candida utilis maltase gene. J Biotechnol 189:136–142
Boze H, Moulin G, Galzy P (1992) Production of food and fodder yeasts. Crit Rev Biotechnol 12:65–86
Buerth C, Heilmann CJ, Klis FM, de Koster CG, Ernst JF, Tielker D (2011) Growth-dependent secretome of Candida utilis. Microbiology 157:2493–2503
Buerth C, Mausberg AK, Heininger MK, Hartung HP, Kieseier BC, Ernst JF (2016) Oral tolerance induction in experimental autoimmune encephalomyelitis with Candida utilis expressing the immunogenic MOG35-55 peptide. PLoS One 5:e0155082
Chan HT, Daniell H (2015) Plant-made oral vaccines against human infectious diseases—are we there yet? Plant Biotechnol J 13:1056–1070
De Jesus M, Rodriguez AE, Yagita H, Ostroff GR, Mantis NJ (2015) Sampling of Candida albicans and Candida tropicalis by Langerin-positive dendritic cells in mouse Peyer’s patches. Immunol Lett 168:64–72
Delic M, Valli M, Graf AB, Pfeffer M, Mattanovich D, Gasser B (2013) The secretory pathway: exploring yeast diversity. FEMS Microbiol Rev 37:872–914
Dworschack RG, Wickerham LJ (1961) Production of extracellular and total invertase by Candida utilis, Saccharomyces cerevisiae, and other yeasts. Appl Microbiol 9:291–294
Eisenhaber B, Schneider G, Wildpaner M, Eisenhaber F (2004) A sensitive predictor for potential GPI lipid modification sites in fungal protein sequences and its application to genome-wide studies for Aspergillus nidulans, Candida albicans, Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe. J Mol Biol 337:243–253
Enloe B, Diamond A, Mitchell AP (2000) A single-transformation gene function test in diploid Candida albicans. J Bacteriol 182:5730–5736
Feng T, Elson CO (2011) Adaptive immunity in the host-microbiota dialog. Mucosal Immunol 4:15–21
Frieman MB, Cormack BP (2004) Multiple sequence signals determine the distribution of glycosylphosphatidylinositol proteins between the plasma membrane and cell wall in Saccharomyces cerevisiae. Microbiologica 150:3105–3114
Fujino S, Akiyama D, Akaboshi S, Fujita T, Watanabe Y, Tamai Y (2006) Purification and characterization of phospholipase B from Candida utilis. Biosci Biotechnol Biochem 70:377–386
Gellissen G, Kunze G, Gaillardin C, Cregg JM, Berardi E, Veenhuis M, van der Klei I (2005) New yeast expression platforms based on methylotrophic Hansenula polymorpha and Pichia pastoris and on dimorphic Arxula adeninivorans and Yarrowia lipolytica—a comparison. FEMS Yeast Res 5:1079–1096
Henneberg W (1926) Handbuch der Gärungsbakteriologie, 2. Aufl. Bd.2. Paul Parey, Berlin
Hong YR, Chen YL, Farh L, Yang WJ, Liao CH, Shiuan D (2006) Recombinant Candida utilis for the production of biotin. Appl Microbiol Biotechnol 71:211–221
Idiris A, Tohda H, Kumagai H, Takegawa K (2010) Engineering of protein secretion in yeast: strategies and impact on protein production. Appl Microbiol Biotechnol 86:403–417
Ikushima S, Fujii T, Kobayashi O (2009a) Efficient gene disruption in the high-ploidy yeast Candida utilis using the Cre-loxP system. Biosci Biotechnol Biochem 73:879–884
Ikushima S, Fujii T, Kobayashi O, Yoshida S, Yoshida A (2009b) Genetic engineering of Candida utilis yeast for efficient production of L-lactic acid. Biosci Biotechnol Biochem 73:1818–1824
Ikushima S, Minato T, Kondo K (2009c) Identification and application of novel autonomously replicating sequences (ARSs) for promoter-cloning and co-transformation in Candida utilis. Biosci Biotechnol Biochem 73:152–159
Inskeep GC, Wiley AJ, Holderby JM, Hughes LP (1951) Food yeast from sulfite liquor. Ind Eng Chem 43:1702–1711
Iwakiri R, Eguchi S, Noda Y, Adachi H, Yoda K (2005a) Isolation and structural analysis of efficient autonomously replicating sequences (ARSs) of the yeast Candida utilis. Yeast 22:1049–1060
Iwakiri R, Noda Y, Adachi H, Yoda K (2005b) Isolation of the YAP1 homologue of Candida utilis and its use as an efficient selection marker. Yeast 22:1079–1087
Iwakiri R, Noda Y, Adachi H, Yoda K (2006) Isolation and characterization of promoters suitable for a multidrug-resistant marker CuYAP1 in the yeast Candida utilis. Yeast 23:23–24
Khan TR, Daugulis AJ (2010) Application of solid-liquid TPPBs to the production of L-phenylacetylcarbinol from benzaldehyde using Candida utilis. Biotechnol Bioeng 107:633–641
Kogan G, Sandula J, Simkovicova V (1993) Glucomannan from Candida utilis. Struct Investig Folia Microbiol (Praha) 38:219–224
Kondo K, Saito T, Kajiwara S, Takagi M, Misawa N (1995) A transformation system for the yeast Candida utilis: use of a modified endogenous ribosomal protein gene as a drug-resistant marker and ribosomal DNA as an integration target for vector DNA. J Bacteriol 177:7171–7177
Kondo K, Miura Y, Sone H, Kobayashi K, Iijima H (1997) High-level expression of a sweet protein, monellin, in the food yeast Candida utilis. Nat Biotechnol 15:453–457
Kunigo M, Bürth C, Tielker D, Ernst JF (2013) Heterologous protein secretion by Candida utilis. Appl Microbiol Biotechnol 97:7357–7368
Kunigo M, Buerth C, Ernst JF (2015) Secreted xylanase XynA mediates utilization of xylan as sole carbon source in Candida utilis. Appl Microbiol Biotechnol 99:8055–8064
Kurtzman CP, Johnson CJ, Smiley MJ (1979) Determination of conspecificity of Candida utilis and Hansenula jadinii through DNA reassociation. Mycologia 11:844–847
Kurtzman R, Basehoar-Powers (2011) The yeasts—a taxonomic study, vol. 1, 5 edn. Elsevier, London, Burlington, San Diego
Lamichhane A, Azegamia T, Kiyonoa H (2014) The mucosal immune system for vaccine development. Vaccine 32:6711–6723
Lawford GR, Kligeman A, Williams T (1979) Production of high-quality edible protein from Candida yeast grown in continuous culture. Biotechnol Bioeng 21:1163–1173
Li Y, Wei G, Chen J (2004) Glutathione: a review on biotechnological production. Appl Microbiol Biotechnol 66:233–242
Lycke N (2012) Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol 12:592–605
Madzak C, Gaillardin C, Beckerich JM (2004) Heterologous protein expression and secretion in the non-conventional yeast Yarrowia lipolytica: a review. J Biotechnol 109:63–81
Mallet S, Weiss S, Jacques N, Leh-Louis V, Sacerdot C, Casaregola S (2012) Insights into the life cycle of yeasts from the CTG clade revealed by the analysis of the Millerozyma (Pichia) farinosa species complex. PLoS One 7:e35842
Minter DW (2009) Cyberlindnera, a replacement name for Lindnera Kurtzman et al., nom. illegit. Mycotaxon 110:473–476
Miura Y, Kondo K, Shimada H, Saito T, Nakamura K, Misawa N (1998a) Production of lycopene by the food yeast, Candida utilis that does not naturally synthesize carotenoid. Biotechnol Bioeng 58:306–308
Miura Y, Kondo K, Saito S, Shimada H, Fraser PD, Misawa N (1998b) Production of the carotenoids lycopene, β-carotene, and astaxanthin in the food yeast Candida utilis. Appl Environ Microbiol 64:1226–1229
Miura Y, Kettoku M, Kato M, Kobayashi K, Kondo K (1999) High level production of thermostable α-amylase from Sulfolobus solfataricus in high-cell density culture of the food yeast Candida utilis. J Mol Microbiol Biotechnol 1:129–134
Mukherjee PK, Chandra J, Retuerto M, Sikaroodi M, Brown RE, Jurevic R, Salata RA, Lederman MM, Gillevet PM, Ghannoum MA (2014) Oral mycobiome analysis of HIV-infected patients: identification of Pichia as an antagonist of opportunistic fungi. PLoS Pathog 10:e1003996
Müller G (2011) Novel applications for glycosylphosphatidylinositol-anchored proteins in pharmaceutical and industrial biotechnology. Mol Membr Biol 28:187–205
Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163
Rodriguez L, Chavez FP, Basabe L, Rivero T, Delgado JM (1998) Development of an integrative DNA transformation system for the yeast Candida utilis. FEMS Microbiol Lett 165:335–340
Ruszova E, Pavek S, Hajkova V, Jandova S, Velebny V, Papezikova I, Kubala L (2008) Photoprotective effects of glucomannan isolated from Candida utilis. Carbohydr Res 343:501–511
Rupp O, Brinkrolf K, Buerth C, Kunigo M, Schneider J, Jaenicke S, Goesmann A, Pühler A, Jaeger KE, Ernst JF (2015) The structure of the Cyberlindnera jadinii genome and its relation to Candida utilis analyzed by the occurrence of single nucleotide polymorphisms. J Biotechnol 211:20–30
Schmidt FR (2004) Recombinant expression systems in the pharmaceutical industry. Appl Microbiol Biotechnol 65:363–372
Shimada H, Kondo K, Fraser PD, Miura Y, Saito T, Misawa N (1998) Increased carotenoid production by the food yeast Candida utilis through metabolic engineering of the isoprenoid pathway. Appl Environ Microbiol 64:2676–2680
Slot JC, Hibbett DS (2007) Horizontal transfer of a nitrate assimilation gene cluster and ecological transitions in fungi: a phylogenetic study. PLoS One 10:e1097
Stoltenburg R, Klinner U, Ritzerfeld P, Zimmermann M, Emeis CC (1992) Genetic diversity of the yeast Candida utilis. Curr Genet 22:441–446
Su GD, Huang DF, Han SY, Zheng SP, Lin Y (2010) Display of Candida antarctica lipase B on Pichia pastoris and its application to flavor ester synthesis. Appl Microbiol Biotechnol 86:1493–1501
Tamakawa H, Ikushima S, Yoshida S (2010a) Efficient production of L-lactic acid from xylose by a recombinant Candida utilis strain. J Biosci Bioeng 113:73–75
Tamakawa H, Ikushima S, Yoshida S (2010b) Ethanol production from xylose by a recombinant Candida utilis strain expressing protein-engineered xylose reductase and xylitol dehydrogenase. Biosci Biotechnol Biochem 75:1994–2000
Tamakawa H, Ikushima S, Yoshida S (2013a) Construction of a Candida utilis strain with ratio-optimized expression of xylose-metabolizing enzyme genes by cocktail multicopy integration method. J Biosci Bioeng 115:532–539
Tamakawa H, Mita T, Yokoyama A, Ikushima S, Yoshida S (2013b) Metabolic engineering of Candida utilis for isopropanol production. Appl Microbiol Biotechnol 97:6231–6239
Tanaka T, Yamada R, Ogino C, Kondo A (2012) Recent developments in yeast cell surface display toward extended applications in biotechnology. Appl Microbiol Biotechnol 95:577–591
Thévenot J, Cordonnier C, Rougeron A, Le Goff O, Nguyen HT, Denis S, Alric M, Livrelli V, Blanquet-Diot S (2015) Enterohemorrhagic Escherichia coli infection has donor-dependent effect on human gut microbiota and may be antagonized by probiotic yeast during interaction with Peyer’s patches. Appl Microbiol Biotechnol 99:9097–9110
Thompson AL, Johnson BT, Sempowski GD, Gunn MD, Hou B, DeFranco AL, Staats HF (2012) Maximal adjuvant activity of nasally delivered IL-1α requires adjuvant-responsive CD11c(+) cells and does not correlate with adjuvant-induced in vivo cytokine production. J Immunol 188:2834–2846
Tomita Y, Ikeo K, Tamakawa H, Gojobori T, Ikushima S (2012) Genome and transcriptome analysis of the food-yeast Candida utilis. PLoS One 7:e37226
Van Ooyen AJ, Dekker P, Huang M, Olsthoorn MM, Jacobs DI, Colussi PA, Taron CH (2006) Heterologous protein production in the yeast Kluyveromyces lactis. FEMS Yeast Res 6:381–392
Wang DH, Zhang JL, Dong YY, Wei GY, Qi B (2015) Glutathione is involved in physiological response of Candida utilis to acid stress. Appl Microbiol Biotechnol 99:10669–10679
Wei W, Hong-Lan Y, Huifang B, Daoyuan Z, Qi-Mu-Ge S, Wood AJ (2010) The effective expression of xylanase gene in Candida utilis by 18S rDNA targeted homologous recombination in pGLR9K. Mol Biol Rep 37:2615–2620
Yamada Y, Matsuda M, Mikata K (1995) The phylogenetic relationships of Pichia jadinii, formerly classified in the genus Hansenula, and related species based on the partial sequence of 18S and 26S ribosomal RNAs (Saccharomycetaceae). Biosci Biotechnol Biochem 59:518–520
Yanai T, Sato M (2001) Purification and characterization of a beta-D-xylosidase from Candida utilis IFO 0639. Biosci Biotechnol Biochem 65:527–533
Acknowledgments
The work in the laboratory of the authors was funded in part by the Cluster of Industrial Biotechnology NRW CLIB2021.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical statement
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Buerth, C., Tielker, D. & Ernst, J.F. Candida utilis and Cyberlindnera (Pichia) jadinii: yeast relatives with expanding applications. Appl Microbiol Biotechnol 100, 6981–6990 (2016). https://doi.org/10.1007/s00253-016-7700-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-016-7700-8