JP2020531039A - シアリル化オリゴ糖を精製する工程 - Google Patents
シアリル化オリゴ糖を精製する工程 Download PDFInfo
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- JP2020531039A JP2020531039A JP2020512564A JP2020512564A JP2020531039A JP 2020531039 A JP2020531039 A JP 2020531039A JP 2020512564 A JP2020512564 A JP 2020512564A JP 2020512564 A JP2020512564 A JP 2020512564A JP 2020531039 A JP2020531039 A JP 2020531039A
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- JP
- Japan
- Prior art keywords
- sialylated
- oligosaccharide
- lactose
- fermentation broth
- oligosaccharides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
Description
i)発酵ブロスからバイオマスを分離するステップと、
ii)発酵ブロスから陽イオンを除去するステップと、
iii)発酵ブロスから陰イオン性不純物を除去するステップと、
iv)精製されるシアリル化オリゴ糖よりも分子量が小さい化合物を除去するステップと
を含む。
a)>100g/L、好ましくは>200g/L、より好ましくは>300g/Lの濃度まで、及び/又は
b)<80℃、好ましくは<50℃、より好ましくは20℃〜50℃、さらにより好ましくは30℃〜45℃、最も好ましくは35℃〜45℃の温度で(特に真空蒸発若しくは逆浸透に該当)、及び/又は
c)<80℃、好ましくは<50℃、より好ましくは4℃〜40℃の温度で(特にナノ濾過に該当)
濃縮する。
<組換え微生物を用いた3’−シアリルラクトースの発酵>
ビブリオ(Vibrio)sp.JT−FAJ−16由来の3’−シアリルトランスフェラーゼ遺伝子のゲノム組込みを含む、組換え3’−シアリルラクトース合成大腸菌株(E.coli BL21(DE3)ΔlacZ)を用いた3’−シアリルラクトースの流加発酵。大腸菌(E.coli)由来のグルコサミン−6−リン酸シンターゼをコードするCMP−シアル酸遺伝子GlmSの生合成を増強するため、シネコシスティス種(Synechocystis sp.)由来のN−アセチルグルコサミン2−エピメラーゼSlr1975、サッカロマイセス・セレビシエ(Saccharomyces cerevisiae)由来のグルコサミン6−リン酸N−アセチルトランスフェラーゼGna1、大腸菌由来のホスホエノールピルビン酸シンターゼPpsA、N−アセチルノイラミン酸シンターゼNeuB及びCMP−シアル酸シンテターゼNeuA(後者2つはカンピロバクター・ジェジュニ(Campylobacter jejuni)由来)を、大腸菌(E.coli)BL21(DE3)宿主中に染色体的に組み込んだ。さらに、大腸菌(E.coli)由来のラクトースパーミアーゼをコードする遺伝子LacYと、大腸菌(E.coli)W由来の遺伝子cscB(スクロースパーミアーゼ)、cscK(フルクトキナーゼ)、cscA(スクロースヒドロラーゼ)及びcscR(転写制御因子)とを、BL21ゲノムに組み込んだ。組み込まれた遺伝子の転写は、テトラサイクリンプロモーターPtet、PT5プロモーターのいずれかの構成的プロモーターから開始される。遺伝子galE(UDP−グルコース−4−エピメラーゼ)、galT(ガラクトース−1−リン酸ウリジリルトランスフェラーゼ)、galK(ガラクトキナーゼ)及びgalM(ガラクトース−1−エピメラーゼ)からなる機能性ガルオペロンを、大腸菌(E.coli)K12からBL21株のゲノムに導入した。N−アセチルグルコサミン−6−リン酸デアセチラーゼ(NagA)、グルコサミン−6−リン酸デアミナーゼ(NagB)及びN−アセチルグルコサミン特異的PTSタンパク質IIABC(NagE)をコードする、N−アセチルグルコサミン6−リン酸遺伝子の分解を防止するために、これらの遺伝子を染色体から欠失させた。加えて、マンノース、グルコース、グルコサミン及びN−アセチルグルコサミン向けの大腸菌(E.coli)PTS系の糖トランスポーターをコードするオペロンmanXYZを欠失させ、N−アセチルノイラミン酸リアーゼ、N−アセチルマンノサミンキナーゼ、N−アセチルマンノサミンキナーゼ−6−リン酸エピメラーゼ、シアル酸トランスポーターをそれぞれコードする遺伝子nanA、nanK、nanE、nanTも欠失させた。N−アセチルガラクトサミン−6−リン酸デアセチラーゼ(AgaA)をコードする遺伝子も欠失させた。
<組換え微生物を用いた6’−シアリルラクトースsHMOの発酵>
6’−シアリルラクトースを合成する菌株は、シアリルトランスフェラーゼにかかわらず、3’−シアリルラクトース産生株と同様の遺伝子的特徴を有する。6’−シアリルラクトースを産生するため、α−2,6−シアリルトランスフェラーゼをコードするフォトバクテリウム・レイオグナチ(Photobacterium leiognathi)JT−SHIZ−119由来のplsT6遺伝子を大腸菌(E.coli)BL21(DE3)ゲノムに導入した。
<発酵ブロスからの6’−シアリルラクトース及び3’−シアリルラクトースの精製>
ワインディング・モジュール・フィルタ(0.05μm分画)(CUT membrane technology、エルクラート、ドイツ)、クロスフローフィルタ(150kDa分画)(Microdyn−Nadir、ヴィースバーデン、ドイツ)を連続的に用いることにより、限外濾過により発酵培地からバイオマスを分離した。20g L−1を超えるシアリル化オリゴ糖を含有した約1m3の無細胞発酵培地が得られた。
<広角X線パワー(power)回折(XDR)による噴霧乾燥シアリルラクトースの分析>
広角X線粉末回折(XRD)を用いて、凍結乾燥した生成物の形態を調査した。銅アノード(45kV、40mA、波長0.154nmでKα1放出)及びPIXcel3D検出器を備えたX線回折計Empyrean(Panalytical、アルメロ、オランダ)を使用した。5〜45°2θの角度範囲、ステップサイズ0.04°2θ、カウント時間は1ステップ当たり100秒として、噴霧乾燥サンプル約100mgを反射モードで分析した。
<示差走査熱量測定(DSC)による噴霧乾燥シアリルラクトースの分析>
Mettler Toledo 821e(Mettler Toledo、ギーセン、ドイツ)による示差走査熱量測定(DSC)を用いて、噴霧乾燥生成物の熱事象を測定した(ガラス転移温度(Tg)、その後の発熱事象及び吸熱事象)。
Claims (23)
- 微生物発酵又はインビトロ生体触媒作用で産生されたシアリル化オリゴ糖を精製する方法であって、前記方法は、
i)発酵ブロスからバイオマスを分離するステップと、
ii)前記発酵ブロス又は反応混合物から陽イオンを除去するステップと、
iii)前記発酵ブロス又は反応混合物から陰イオン性不純物を除去するステップと、
iv)前記発酵ブロス又は反応混合物から精製される前記シアリル化オリゴ糖よりも分子量が小さい化合物を除去するステップと
を含む、方法。 - v)前記シアリル化オリゴ糖の濃度を上昇させるステップと、
vi)所望でないオリゴ糖を除去するステップと、
vii)着色物質を除去するステップと、
viii)エンドトキシンを除去するステップと、
ix)滅菌するステップと、
x)前記シアリル化オリゴ糖を噴霧乾燥又は結晶化するステップと
からなる群より選ばれる1つ以上のステップをさらに含む、請求項1に記載の方法。 - 前記シアリル化オリゴ糖が、シアリル化ヒトミルクオリゴ糖であり、好ましくは、3’−SL、6’−SL、LST−a、LST−b、LST−c、3−F−SL、DS−LNT及びF−LST−bからなる群より選ばれる、請求項1又は2に記載の方法。
- 前記発酵ブロスからのバイオマスの除去が、前記発酵ブロスに対する限外濾過、好ましくは、500kDa以上の分子量を有する前記バイオマス及び化合物を前記発酵ブロスから除去する限外濾過、より好ましくは、150kDa以上の分子量を有する前記バイオマス及び化合物を前記発酵ブロスから除去する限外濾過、最も好ましくは、100kDa以上の分子量を有する前記バイオマス及び化合物を前記発酵ブロスから除去する限外濾過を行うことにより実施される、請求項1〜3のいずれか一項に記載の方法。
- 前記発酵ブロスからの陽イオンの除去が、陽イオン交換クロマトグラフィーにより実施される、請求項1〜4のいずれか一項に記載の方法。
- 前記発酵ブロスからの陰イオン性不純物の除去が、陰イオン交換クロマトグラフィーにより実施される、請求項1〜5のいずれか一項に記載の方法。
- 前記精製されるシアリル化オリゴ糖よりも分子量が小さい化合物の除去が、クロスフロー濾過により実施される、請求項1〜6のいずれか一項に記載の方法。
- 前記精製されるシアリル化オリゴ糖の濃度が、ナノ濾過又は溶媒の蒸発により上昇する、請求項1〜7のいずれか一項に記載の方法。
- 着色物質の除去が、所望の前記シアリル化オリゴ糖を含有する前記発酵ブロス/溶液を活性炭で処理することにより実施される、請求項1〜8のいずれか一項に記載の方法。
- エンドトキシンの除去が、所望の前記オリゴ糖を含有する溶液の、6kDaフィルタ又は3kDaフィルタによる濾過により実施される、請求項1〜9のいずれか一項に記載の方法。
- 溶液の滅菌が、0.2μmフィルタによる前記溶液の濾過により実施される、請求項1〜10のいずれか一項に記載の方法。
- SMBクロマトグラフィーのステップをさらに含む、請求項1〜11のいずれか一項に記載の方法。
- 電気透析のステップをさらに含む、請求項1〜12のいずれか一項に記載の方法。
- シアリル化オリゴ糖の調製物であって、前記シアリル化オリゴ糖が請求項1〜13のいずれか一項に記載の方法で精製された、調製物。
- 前記シアリル化オリゴ糖が、80重量%以上の純度で前記調製物中に存在する、請求項14に記載の調製物。
- 前記調製物が、流体又は粉末であり、好ましくは、粒子が非晶質又は結晶性の粒子である粉末である、請求項14又は15に記載の調製物。
- 栄養組成物、好ましくは乳児用調製粉乳を製造するための、請求項14〜16のいずれか一項に記載の調製物の使用。
- 少なくとも1種のシアリル化オリゴ糖を含む栄養組成物であって、前記少なくとも1種のシアリル化オリゴ糖が、微生物発酵又は生体触媒作用で産生されており、前記栄養組成物が、医薬製剤、栄養補助食品、乳飲料又は乳児用調製粉乳である、栄養組成物。
- 少なくとも5種のHMOを含む栄養組成物であって、前記少なくとも5種のHMOは、2’−フコシルラクトース、3−フコシルラクトース、ラクト−N−テトラオース、ラクト−N−ネオテトラオース、ラクト−N−フコペンタオースI、3’−シアリルラクトース及び6’−シアリルラクトースからなる群より選ばれる、栄養組成物。
- 少なくとも1種のシアリル化HMOと、少なくとも1種の中性HMOと、プロバイオティック微生物とを含む、請求項18又は19に記載の栄養組成物。
- 乾燥重量で>80%の純度を有し、かつ10重量%未満の水を有するシアリル化オリゴ糖から本質的になる、噴霧乾燥されGMOのない粉末。
- 3’−シアリルラクトースと、6’−シアリルラクトースと、3’−シアリルラクトース及び6’−シアリルラクトースの混合物と、からなる群より選ばれる、請求項21に記載の噴霧乾燥された粉末生成物。
- 前記噴霧乾燥された粉末が、3’−シアリルラクトースと、6’−シアリルラクトースと、1種以上の中性HMOとの混合物から本質的になり、前記1種以上の中性HMOが、2’−フコシルラクトースと、3−フコシルラクトースと、ラクト−N−テトラオースと、ラクト−N−ネオテトラオースと、ラクト−N−フコペンタオースIとからなる群より選ばれる、請求項22に記載の噴霧乾燥された粉末生成物。
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DE202017007249U1 (de) | 2016-03-07 | 2020-04-23 | Glycom A/S | Abtrennung von Oligosacchariden aus der Fermentationsbrühe |
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RU2020108730A (ru) | 2021-09-30 |
WO2019043029A1 (en) | 2019-03-07 |
CN117778496A (zh) | 2024-03-29 |
US20240199673A1 (en) | 2024-06-20 |
EP3676274A1 (en) | 2020-07-08 |
BR112020003502A2 (pt) | 2020-09-01 |
US20200308211A1 (en) | 2020-10-01 |
EP3450443A1 (en) | 2019-03-06 |
MX2020002263A (es) | 2020-07-20 |
AU2018322785B2 (en) | 2023-03-23 |
JP2023153971A (ja) | 2023-10-18 |
AU2023203977A1 (en) | 2023-07-13 |
US11912735B2 (en) | 2024-02-27 |
KR20200041370A (ko) | 2020-04-21 |
CN111094311A (zh) | 2020-05-01 |
JP7330171B2 (ja) | 2023-08-21 |
AU2018322785A1 (en) | 2020-02-27 |
PH12020550069A1 (en) | 2021-02-15 |
SG11202001296UA (en) | 2020-03-30 |
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