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      Development of synthetic biology tools to engineer Pichia pastoris as a chassis for the production of natural products

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          Abstract

          The methylotrophic yeast Pichia pastoris (a.k.a. Komagataella phaffii) is one of the most commonly used hosts for industrial production of recombinant proteins. As a non-conventional yeast, P. pastoris has unique biological characteristics and its expression system has been well developed. With the advances in synthetic biology, more efforts have been devoted to developing P. pastoris into a chassis for the production of various high-value compounds, such as natural products. This review begins with the introduction of synthetic biology tools for the engineering of P. pastoris, including vectors, promoters, and terminators for heterologous gene expression as well as Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated System (CRISPR/Cas) for genome editing. This review is then followed by examples of the production of value-added natural products in metabolically engineered P. pastoris strains. Finally, challenges and outlooks in developing P. pastoris as a synthetic biology chassis are prospected.

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          Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation.

          Luke A Gilbert, Max A Horlbeck, Britt Adamson … (2014)
          While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of transcript function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90%-99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ∼1,000-fold range. Using these rules, we construct genome-scale CRISPRi and CRISPRa libraries, each of which we validate with two pooled screens. Growth-based screens identify essential genes, tumor suppressors, and regulators of differentiation. Screens for sensitivity to a cholera-diphtheria toxin provide broad insights into the mechanisms of pathogen entry, retrotranslocation and toxicity. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Counting on natural products for drug design.

            Tiago Rodrigues, Daniel Reker, Petra Schneider … (2016)
            Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.
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              Genome sequence of the recombinant protein production host Pichia pastoris.

              Kristof De Schutter, Yao-Cheng Lin, Petra Tiels … (2009)
              The methylotrophic yeast Pichia pastoris is widely used for the production of proteins and as a model organism for studying peroxisomal biogenesis and methanol assimilation. P. pastoris strains capable of human-type N-glycosylation are now available, which increases the utility of this organism for biopharmaceutical production. Despite its biotechnological importance, relatively few genetic tools or engineered strains have been generated for P. pastoris. To facilitate progress in these areas, we present the 9.43 Mbp genomic sequence of the GS115 strain of P. pastoris. We also provide manually curated annotation for its 5,313 protein-coding genes.
              Article 0 comments Cited 169 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jiazhang Lian
                Journal
                Journal ID (nlm-ta): Synth Syst Biotechnol
                Journal ID (iso-abbrev): Synth Syst Biotechnol
                Title: Synthetic and Systems Biotechnology
                Publisher: KeAi Publishing
                ISSN (Electronic): 2405-805X
                Publication date PMC-release: 03 May 2021
                Publication date Collection: June 2021
                Publication date (Electronic): 03 May 2021
                Volume: 6
                Issue: 2
                Pages: 110-119
                Affiliations
                [a ]Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China
                [b ]Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 310027, China
                Author notes
                [∗ ]Corresponding author. Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China. jzlian@ 123456zju.edu.cn
                Article
                Publisher Item ID: S2405-805X(21)00024-7
                DOI: 10.1016/j.synbio.2021.04.005
                PMC ID: 8113645
                PubMed ID: 33997361
                SO-VID: db25fc93-ffd1-42c6-88e7-e7e0ca0c17e3
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 27 January 2021
                Date revision received : 13 March 2021
                Date accepted : 26 April 2021
                Categories
                Subject: Article

                Keywords: pichia pastoris,natural products,synthetic biology,crispr/cas9,heterologous gene expression
                Data availability:
                Keywords: pichia pastoris, natural products, synthetic biology, crispr/cas9, heterologous gene expression

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