JP6826567B2 - 酵母のタンパク質フォールディング機構(protein−folding machinery)改良によるジンセノサイド生産増大 - Google Patents
酵母のタンパク質フォールディング機構(protein−folding machinery)改良によるジンセノサイド生産増大 Download PDFInfo
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- JP6826567B2 JP6826567B2 JP2018149258A JP2018149258A JP6826567B2 JP 6826567 B2 JP6826567 B2 JP 6826567B2 JP 2018149258 A JP2018149258 A JP 2018149258A JP 2018149258 A JP2018149258 A JP 2018149258A JP 6826567 B2 JP6826567 B2 JP 6826567B2
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Description
本発明の酵母細胞は、サッカロマイセス・セレビシエ(Saccharomyces cerevisiae: S. cerevisiae)CEN.PK2−1D野生型菌株[(MATα ura3-52; trp1-289; leu2-3,112; his3△ 1; MAL2-8; SUC2), EUROSCARF accession number: 30000B]に、ジンセノサイド生合成代謝経路を導入し、ジンセノサイド生合成に必須の前駆体であるスクアレン(squalene)の生合成を増大させるためにメバロン酸代謝経路を強化することにより、プロトパナキサジオール(protopanaxadiol; PPD)を生産する酵母菌株を作製し、前記酵母菌株をPPD酵母変異株と命名した。
PPD酵母変異株において、タンパク質フォールディングに関与するタンパク質であるCPR5、PDI1又はERO1の過剰発現が前記酵母変異株の成長及びPPD生産能に関与するか否かを確認するために、前記CPR5、PDI1又はERO1の遺伝子が過剰発現した酵母変異株を作製した。まず、CPR5、PDI1又はERO1遺伝子の過剰発現を誘導するために、前記遺伝子のプロモーターを高発現構成的プロモーターであるPGK1プロモーターに置換するためのPGK1プロモーター置換ベクターを作製し、前記ベクターを用いて作製した置換カセットをPPD酵母変異株に形質導入することにより、CPR5、PDI1又はERO1過剰発現酵母変異株を作製した。
前述したように作製した形質転換酵母変異株を2%ブドウ糖含有最小培地(minimal URA drop-out media)50mlにOD600値が0.5になるように接種し、30にて250rpmで攪拌しながら144時間好気条件で培養した。培養中の細胞成長については、分光光度計(spectrophotometer)を用いてOD600値を測定した。培養中の細胞内代謝産物(squalene, 2, 3-oxidosqualene, Protopanaxadiol)については、HPLC(High performance liquid chromatography)を用いて分析を行った。
Claims (11)
- タンパク質フォールディング(protein-folding)関与タンパク質の発現レベルが内在性発現レベルより増加した、ジンセノサイド又はその前駆体生産用組換えジンセノサイド生産酵母であって、
前記タンパク質フォールディング関与タンパク質はシャペロンタンパク質であり、前記シャペロンタンパク質はCPR5及びERO1からなる群から選択される少なくとも1つであり、前記ジンセノサイドはダンマラン(dammarane)系サポニンである、酵母。 - 前記CPR5の遺伝子は配列番号1の塩基配列からなり、ERO1の遺伝子は配列番号3の塩基配列からなる、請求項1に記載の組換えジンセノサイド生産酵母。
- 前記酵母は、サッカロマイセス・セレビシエ(S. cerevisiae)、サッカロマイセス・バヤヌス(S. bayanus)、サッカロマイセス・ブラウディ(S. boulardii)、サッカロマイセス・ブルデリ(S. bulderi)、サッカロマイセス・カリオカヌス(S. cariocanus)、サッカロマイセス・カリオカス(S. cariocus)、サッカロマイセス・チェバリエリ(S. chevalieri)、サッカロマイセス・ダイレネンシス(S. dairenensis)、サッカロマイセス・エリプソイデウス(S. ellipsoideus)、サッカロマイセス・ユーバヤヌス(S. eubayanus)、サッカロマイセス・エキシグス(S. exiguus)、サッカロマイセス・フロレンチヌス(S. florentinus)、サッカロマイセス・クルイベリ(S. kluyveri)、サッカロマイセス・マティニアエ(S. martiniae)、サッカロマイセス・モナセンシス(S. monacensis)、サッカロマイセス・ノルベンシス(S. norbensis)、サッカロマイセス・パラドキサス(S. paradoxus)、サッカロマイセス・パストリアヌス(S. pastorianus)、サッカロマイセス・スペンセロラム(S. spencerorum)、サッカロマイセス・トゥリセンシス(S. turicensis)、サッカロマイセス・ユニスポラス(S. unisporus)、サッカロマイセス・ウバラム(S. uvarum)、及びサッカロマイセス・ゾナタス(S. zonatus)からなる群から選択される、請求項1又は2に記載の組換えジンセノサイド生産酵母。
- 前記酵母は、さらにジンセノサイド合成に関与する遺伝子の発現が内在性発現レベルより増加した、請求項1〜3のいずれか一項に記載の組換えジンセノサイド生産酵母。
- 前記遺伝子は、PgDDS(Panax ginseng, dammarenediol-II synthase)、PgPPDS(Panax ginseng cytochrome P450 CYP716A47)、PgCPR(Panax ginseng, NADPH-cytochrome P450 reductase)、tHMG1(S. cerevisiae HMG-CoA reductase)及びPgSE(Panax ginseng, squalene epoxidase)からなる群から選択される少なくとも1つの遺伝子である、請求項4に記載の組換えジンセノサイド生産酵母。
- 前記前駆体は、スクアレン又は2,3−オキシドスクアレンである、請求項1〜5のいずれか一項に記載の組換えジンセノサイド生産酵母。
- ジンセノサイド生産酵母菌株のタンパク質フォールディング(protein-folding)関与タンパク質の発現レベルを内在性発現レベルより増加させるステップを含む、ジンセノサイド生産能が向上した組換え酵母の製造方法であって、
前記タンパク質フォールディング関与タンパク質はシャペロンタンパク質であり、前記シャペロンタンパク質はCPR5及びERO1からなる群から選択される少なくとも1つである、製造方法。 - 前記ジンセノサイド生産酵母菌株は、PgDDS(Panax ginseng, dammarenediol-II synthase)、PgPPDS(Panax ginseng cytochrome P450 CYP716A47)、PgCPR(Panax ginseng, NADPH-cytochrome P450 reductase)、tHMG1(S. cerevisiae HMG-CoA reductase)及びPgSE(Panax ginseng, squalene epoxidase)からなる群から選択される少なくとも1つの遺伝子の発現レベルが内在性発現レベルより増加した、請求項7に記載の組換え酵母の製造方法。
- ジンセノサイド及びジンセノサイド前駆体生産酵母菌株のタンパク質フォールディング(protein-folding)関与タンパク質の発現レベルを内在性発現レベルより増加させるステップを含む、ジンセノサイド前駆体生産能が向上した組換えジンセノサイド及びジンセノサイド前駆体生産酵母の製造方法であって、
前記タンパク質フォールディング関与タンパク質はシャペロンタンパク質であり、前記シャペロンタンパク質はCPR5及びERO1からなる群から選択される少なくとも1つであり、前記ジンセノサイドはダンマラン(dammarane)系サポニンである、製造方法。 - 前記ジンセノサイド前駆体は、スクアレン及び2,3−オキシドスクアレンを含む、請求項9に記載の組換え酵母の製造方法。
- 請求項1〜6のいずれか一項に記載の組換えジンセノサイド生産酵母を培養するステップを含む、ジンセノサイド又はその前駆体の生産方法。
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