JP2006314321A - 脂肪酸不飽和化酵素ファミリーのメンバーであるfad4、fad5、fad5−2およびfad6、ならびにそれらの使用方法 - Google Patents
脂肪酸不飽和化酵素ファミリーのメンバーであるfad4、fad5、fad5−2およびfad6、ならびにそれらの使用方法 Download PDFInfo
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- JP2006314321A JP2006314321A JP2006151242A JP2006151242A JP2006314321A JP 2006314321 A JP2006314321 A JP 2006314321A JP 2006151242 A JP2006151242 A JP 2006151242A JP 2006151242 A JP2006151242 A JP 2006151242A JP 2006314321 A JP2006314321 A JP 2006314321A
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Abstract
【解決手段】不飽和化酵素の核酸分子を含む組換え発現ベクター、発現ベクターが導入された宿主細胞。脂肪種子作物であるアマ(Linum sp.)やカラシナ(Brassica sp.)の形質転換体では、不飽和化の進行した新規な脂肪酸組成物の生成が確認できた。不飽和脂肪酸組成としては、GLA18:3(6,9,12)、SDA18:4(6,9,12,15)、AA20:4(5,8,11,14)、EPA20:5(5,8,11,14,17)、DPA22:5(4,7,10,13,16)及びDHA22:6(4,7,10,13,16,19)などが挙げられる。
【選択図】なし
Description
本出願は、2000年9月28日に提出された米国特許仮出願第60/236,303号、および2001年6月12日に提出された米国特許仮出願第60/297,562号に対する優先権を主張するものであり、それらのすべての内容は全体が参照として本明細書に組み入れられる。それらに引用されたすべての参考文献のすべての内容も明示的に参照として組み入れられ、本出願の一部であることを意図している。
脂肪酸は長鎖炭化水素側基を有するカルボン酸であり、多くの生物プロセスに根本的な役割を果たしている。脂肪酸は自然下で遊離していることは稀であり、実際には脂質の主成分としてエステル化されている。脂質/脂肪酸はエネルギー源であり(例えば、β酸化)、生物的または生化学的な情報を処理するために不可欠な細胞膜と一体化した構成要素でもある。
脂肪酸の生合成は植物および微生物の主な活動である。しかし、ヒトが必須脂肪酸、例えば、長鎖多価不飽和脂肪酸(LCPUFA)を合成する能力は限られている。バイオテクノロジーは長い間、植物および微生物における脂肪酸産生プロセスを操作するための効率的な手法と考えられてきた。これはコスト効果が高く再生可能であり、ほとんど副作用を伴わない。そこで、特殊な脂肪酸および医薬用ポリペプチドを含むさまざまな化合物の、植物、動物および微生物細胞の操作による生産を目的として、膨大な産業的取り組みがなされている。このため、バイオテクノロジーは、不飽和脂肪酸、特にLCPUFAを、これらの脂肪酸から最大の治療的価値が得られるような安全でコスト効果の高い様式で生産するために興味深い経路である。
本発明は、少なくとも一部には、本明細書において「不飽和化酵素(desaturases)」または「不飽和化酵素(desaturase)」核酸分子およびタンパク質分子(例えば、Fad4、Fad5、Fad5-2およびFad6)と互換的に称する、新規な脂肪酸不飽和化酵素ファミリーのメンバーの発見に基づく。これらの新規分子は脂肪酸不飽和化酵素ファミリーに属し、LCPUFAを産生する生物、例えば、ヤブレツボカビ(Thraustochytrium)、ピティウム・イレギュラレ(Pythium irregulare)、スキゾキトリウム(Schizochytrium)およびクリテコジニウム(Crythecodinium)において発現される。
本発明の1つの局面は、不飽和化酵素タンパク質またはその生物活性断片をコードする単離された核酸分子、さらには不飽和化酵素をコードする核酸分子(例えば、不飽和化酵素mRNA)を同定するためのハイブリダイゼーションプローブとして用いるのに十分な核酸断片、および不飽和化酵素核酸分子の増幅または変異のためのPCRプライマーとして用いられる断片に関する。本発明で用いる「核酸分子」という用語は、DNA分子(例えばcDNAまたはゲノムDNA)およびRNA分子(例えばmRNA)、ならびにヌクレオチド類似体を用いて作製されたDNAまたはRNA類似体を含むものとする。核酸分子は一本鎖でも二本鎖でもよいが、好ましくは二本鎖DNAである。
本発明の1つの局面は、単離されたまたは組換え型の不飽和化酵素タンパク質およびポリペプチド、ならびにそれらの生物活性部分に関する。1つの態様では、標準的なタンパク質精製法を用いる適切な精製方式により、細胞または組織源から天然型の不飽和化酵素タンパク質を単離することができる。もう1つの態様では、組換えDNA法によって不飽和化酵素タンパク質が産生される。組換え体の発現の代わりに、標準的なペプチド合成法を用いて不飽和化酵素タンパク質またはポリペプチドを化学合成することもできる。
本発明は、不飽和脂肪酸、例えば、DHA(ドコサヘキサエン酸、22:6(n-6))、DPA(ドコサペンタエン酸、22:5(n-6))、AA(アラキドン酸、20:4(n-6))およびEPA(エイコサペンタエン酸、20:5(n-3))などのLCPUFAを生産する、新たな改善された方法を提供する。
本発明はさらに、本明細書に記載の遺伝子産物、好ましくはFad4、Fad5、Fad5-2およびFad6遺伝子産物をコードする核酸配列を含む、組換えベクターを提供する。組換えベクターという用語には、天然型のベクターまたはプラスミドに含まれるものよりも多い、少ないまたは異なる核酸配列を含むように変更、改変または操作されたベクター(例えば、プラスミド)が含まれる。1つの態様において、組換えベクターは、調節配列と機能的に結合した、少なくとも1つの脂肪酸不飽和化酵素をコードする核酸配列を含む。「調節配列と機能的に結合した」という語句は、(例えば、ベクターを宿主細胞内に導入した場合に)関心対象のヌクレオチド配列が、そのヌクレオチド配列の発現(例えば、増強した、増大した、構成的な、基礎的な、減弱した、低下した、または抑制した発現)、好ましくはヌクレオチド配列によってコードされる遺伝子産物の発現を可能とする様式で結合していることを意味する。ベクターの例は本明細書でさらに詳細に述べるほか、例えば、フラスコッティ(Frascotti)ら、米国特許第5,721,137号にも記載されており、その内容は参照として本明細書に組み入れられる。
本発明の1つの特に好ましい態様は、不飽和脂肪酸、例えばDHAを生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が著しく高収量で産生される条件下で培養することを含む方法である。「高収量生産法」、例えば、希望する化合物の生産のための(例えば、不飽和脂肪酸の生産のための)高収量生産法という用語には、同等の生産法に関する通常のレベルよりも高いまたは上のレベルで希望する化合物の生産が得られる方法が含まれる。高収量生産法により、著しい高収量で希望する化合物の生産が得られることが好ましい。「著しい高収量」という用語には、同等の生産法に関する通常のレベルよりも十分に高いまたは上の、例えば、希望する産物の商業生産(例えば、商業的に実現可能なコストでの産物の生産)のために十分なレベルの高さである、生産または収量のレベルが含まれる。1つの態様において、本発明は、不飽和脂肪酸を生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が2g/Lを上回るレベルで産生される条件下で培養することを含む方法を特徴とする。もう1つの態様において、本発明は、不飽和脂肪酸を生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が10g/Lを上回るレベルで産生される条件下で培養することを含む方法を特徴とする。もう1つの態様において、本発明は、不飽和脂肪酸を生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が20g/Lを上回るレベルで産生される条件下で培養することを含む方法を特徴とする。さらにもう1つの態様において、本発明は、不飽和脂肪酸を生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が30g/Lを上回るレベルで産生される条件下で培養することを含む方法を特徴とする。さらにもう1つの態様において、本発明は、不飽和脂肪酸を生産するための高収量生産法であって、操作された植物または微生物を、不飽和脂肪酸が40g/Lを上回るレベルで産生される条件下で培養することを含む方法を特徴とする。
本発明の不飽和化酵素核酸分子、タンパク質およびそれらの断片は、組成物に組み入れることが可能な不飽和脂肪酸を生産するために用いることができる。本発明の組成物には、例えば、動物飼料として用いるための組成物、機能性食品(例えば、栄養補助食品)として用いるための組成物、および投与のために適した薬学的組成物が含まれる。
材料:ヤブレツボカビ属ATCC 21685およびピティウム・イレギュラレは、アメリカンタイプカルチャーコレクション(American type culture collection)(12301 Parklawn Drive、Rockville、Maryland、20852 USA)から購入し、培地中(Weete, J.D.ら(1997)Lipids 32:839〜845)にて24℃で7日間増殖させた。これに続いて、バイオマスを遠心処理によって回収し、RNAの単離に用いた。
以上の材料から、キュウ(Qiu)およびエリクソン(Erickson)(Qiu, X.およびEriekson, L.(1994)Plant Mol. Biol. Repr. 12:209〜214)に従って全RNAを単離した。cDNAライブラリーを全RNAから構築した。第1鎖cDNAはギブコ社(Gibco-BRL)のスーパースクリプトII(superscript II)逆転写酵素によって合成した。第2鎖cDNAはストラタジーン(Stratagene)社のDNAポリメラーゼIによって合成した。サイズ分画の後に、1kbを上回るcDNA挿入物をλ Uni-Zap XRベクター(Stratagene)中に連結した。続いて、この組換えDNAをギガパックIIIゴールド(Gigapack III gold) パッケージング抽出物(Stratagene)を用いてパッケージ化し、NZYプレートに播いた。この結果得られたライブラリーは5×106種の独立したクローンを示した。cDNAライブラリーのスクリーニングは標準的な方法(Sambrook, J、Fritseh, E.F.、Maniatis, T.(1989)「分子クローニング:実験マニュアル(Molecular Cloning - A laboratory manual)」(Cold Spring Harbor、New York、USA)に従って行った。
スーパースクリプトII(superscript II)逆転写酵素(Gibco-BRL)によって全RNAから一本鎖cDNAを合成し、2つの縮重プライマー(順方向プライマー:
および逆方向プライマー:
)を用いるPCR反応のためのテンプレートとして用いた。PCR増幅は、94℃ 1分間、55℃ 1.5分間および72℃ 2分間を35サイクルを行った後の72℃ 10分間の伸長段階からなる。800bp〜1000bpの増幅産物をアガロースゲルから単離し、キット(Qiaex IIゲル精製、Qiagen)によって精製した後にTAクローニングベクターpCR(登録商標)2.1(Invitrogen)中にクローニングした。続いて、クローニングした挿入物の配列を、プリズム・ダイデオキシ・ターミネーター・サイクルシークエンシング・システム(PRISM DyeDeoxy Terminator Cycle Sequencing System)(Perkin Elmer/Applied Biosysterns)によって決定した。
Fad4、Fad5、Fad5-2およびFad6のオープンリーディングフレームを、プレシジョンプラス(Precision Plus)酵素(Stratagene)を用いるPCRによって増幅し、TAクローニングベクター(pCR(登録商標)2.1、Invitrogen)中にクローニングした。PCR産物が最初のcDNAと同一であることをシークエンシングによって確認した後に、断片をBarnHI-EcoRI二重消化によって遊離させ、酵母発現ベクターpYES2(Invitrogen)中の誘導性プロモーターGAL1の制御下に挿入した。
ヤブレツボカビ、ピティウム・イレギュラレおよび酵母細胞を採取し、蒸留水で2回洗った。続いて2mLメタノール性KOH(7.5%w/v KOH、95%メタノール中)を材料に添加し、12mlガラス培養試験管に密封した混合物を80℃に2時間加熱した。0.5mLの水を添加し、非鹸化性脂質を除去するために試料を2mLヘキサンで2回抽出した。続いて、残った水相を1mL 6N HClの添加によって酸性化し、2mLヘキサンで2回抽出した。ヘキサン相を一緒にして、窒素流の下で乾燥させた。2mLの3Nメタノール性HCl(SUPELCO、Supelco Park、Bellefonte、PA 16823-0048)を添加し、混合物を80℃で2時間加熱した。室温に冷ました後に、1mLの0.9%NaClを添加し、混合物を2mLヘキサンで2回抽出した。一緒にしたヘキサンを窒素流の下で蒸発させた。その結果得られた脂肪酸メチルエステル(FAME)を、コベロ(Covello)およびリード(Reed)(Covello, P.S.およびReed, D.W.(1996)Plant Physiol. 111:223〜226)に従って、GCおよびGC-MSにより分析した。
カラシナ(B. juncea)およびアマの5〜6日齢実生の胚軸を、種々のプロモーターの制御下にある完全長cDNAを有するバイナリーベクターの宿主であるアグロバクテリウム・ツメファシエンス(Agrobacterium tumefaciens)を接種するための体外培養組織として用いた。20日齢のトランスジェニック実生を外因性脂肪酸処理に用いた。実生を葉、茎および根の3つの部分に分けた。それぞれを切断して小片にし、24ウェルタイタープレートに入れた。各ウェルに2mLの0.05%基質ナトリウム塩(NuCheck Prep Inc.、Elysian、MN)を添加した。次にプレートをゆっくりと振盪しながら24℃で4時間インキュベートした。インキュベーションの後に、植物組織を水で3回洗って脂肪酸分析に用いた。
ヤブレツボカビおよびピティウム・イレギュラレは、DHA、AA、EPAおよびDPAなどのLCPUFAを産生する能力があることから、科学界で最近関心を集めている。図23および24はそれぞれヤブレツボカビ属およびピティウム・イレギュラレの7日培養物から単離した脂質の脂肪酸組成を示している。表に示した通り、これらの微生物は、n-3およびn-6系の両方の、18炭素Δ6脂肪酸(γ-リノレン酸およびステアリドン酸)から22炭素Δ4脂肪酸(DHAおよびDPA)までの広範囲にわたる多価不飽和脂肪酸を含む。これらの生物、特にヤブレツボカビ属は、DHAおよびDPAの生合成に必要な不飽和化酵素および伸長酵素のすべてのセットを含むように思われる。この菌株には、プレチャー(Precher)経路におけるDHAおよびDPAの合成の前駆物質と提唱されている24炭素多価不飽和脂肪酸が存在しない(Voss, A.ら(1991)J. Biol. Chem. 266:19995〜20000;Mohammed, B.S.ら(1997)Biochem. J. 326:425〜430)。ヤブレツボカビ属では、24炭素脂肪酸はDHAおよびDPAなどの22炭素Δ4脂肪酸のインビボ合成に関与しないと思われる。
ヤブレツボカビ属およびピティウム・イレギュラレにおいてLCFUFAの生合成に関与する不飽和化酵素をコードする遺伝子を同定するために、PCRを用いるクローニング法を適用した。前端不飽和化酵素中のcyt b5様ドメインのN末端伸長部分のヘム結合モチーフ、およびすべてのミクロソーム不飽和化酵素中の第3の保存的ヒスチジンモチーフをそれぞれ標的とするように2つの縮重プライマーを設計した。この設計の背景にある根拠は、ヤブレツボカビ属およびピティウム・イレギュラレにおけるEPAおよびDHAの生合成に関与する不飽和化酵素に、他の前端不飽和化酵素と類似した一次構造、すなわち不飽和化酵素中のcyt b5様ドメインのN末端伸長部分があるはずというものである。ヤブレツボカビ属およびピティウム・イレギュラレから、N末端にcyt b5様ドメインを含む融合タンパク質をコードする4つのcDNA断片が同定された。
Fad4(519アミノ酸残基)
Blastp nr
Blastp nr
Blastp nr
Blastp nr
Fad4の機能を確かめるために、完全長cDNAを誘導性プロモーターの制御下で酵母Invsc2株にて発現させた。図7は、培地に22:5(7,10,13,16,19)を補充することにより、Fad4 cDNAを含む酵母細胞がベクター対照と比較して別の脂肪酸を有したことを示している。ピークの保持時間はDHA標準物質と同一であった。遊離脂肪酸のLC/MS分析により、負イオンエレクトロスプレー法でDHA標準物質と同一な脱プロトン化分子イオン(m/z=279)が生じたことが示された。さらに、FAMEのGC/MS分析により、ピークのスペクトルがDHA標準物質のものと同一であることも示された(図8)。これらの結果は、Fad4が、22:5(7,10,13,16,19)基質の4位に二重結合を導入してΔ4不飽和化脂肪酸DHA(22:6(4,7,10,13,16,19)を生成しうる、Δ4脂肪酸不飽和化酵素であることを示している。
ヤブレツボカビFad4が脂肪種子作物において機能するか否かを明らかにするために、構成性プロモーターの制御下にあるFad4を含む構築物によってカラシナの形質転換を行った。8種の独立したトランスジェニック植物が得られた。カラシナには利用しうるΔ4脂肪酸不飽和化酵素基質がない。このため、この植物におけるトランスジェニック酵素の活性を検討するためには、22:5(n-3)基質を外因的に供給する必要がある。この実験では、野生型およびトランスジェニック体の両方にドコサペンタエン酸ナトリウムの水溶液を与えた。外因的に供給した基質はいずれの種類の植物の根、茎および葉によっても直ちに取り込まれるが、DHAに変換されるのはトランスジェニック体のみであることが明らかになった。葉でのDHAの産生レベルは根および茎よりも高かった。葉では、外因性基質が全脂肪酸の10〜20%のレベルまで取り込まれ、Δ4不飽和化脂肪酸(22:6、n-3)が全脂肪酸の3〜6%の範囲として産生された(図16)。これらの結果は、ヤブレツボカビ由来のΔ4脂肪酸不飽和化酵素が脂肪種子作物において機能することを示している。
Fad5-2が脂肪種子作物で機能するか否か、およびその発現が成長および発育に影響を及ぼすか否かを明らかにするために、カラシナに対して、構成性プロモーター(タンデム型カリフラワーモザイクウイルス35Sプロモーター)の後ろにFad5-2 cDNAを含むバイナリーベクターによる形質転換を行った。6種の独立した一次トランスジェニック植物が得られ、異なる組織由来の脂質の脂肪酸プロファイルを決定した。図17は、T1系統の3週齢実生植物の脂肪酸組成を示している。野生型と比べて、すべてのトランスジェニック植物組織は4つの新たなピークを含む変化した脂肪酸プロファイルを有し、これらは4種の異なるΔ5非不飽和化ポリメチレン中断型脂肪酸(Δ5-UPIFA)、具体的にはタキソール(taxoleic)酸(18:2-5,9);エフェドレン(ephedrenic)酸(18:2-5,11);ピノレン(pinolenic)酸(18:3-5,9,12)およびコニフェロン酸(coniferonic acid)(18:4-5,9,12,15)と同定された。このように、カラシナは酵母と同様に、P.イレギュラレΔ5不飽和化酵素を機能的に発現し、内因性基質18:1-9;18:1-11;18:2-9,12および18:3-9,12,15を対応するΔ5不飽和化脂肪酸に変換することができる。根はΔ5-UPIFAの産生量が最も多く、全脂肪酸の20%を占め、これに続いて茎では6%、葉では5%であった(図17)。
アマ種子においてΔ5不飽和化脂肪酸を産生させるために、2つの種子特異的プロモーター、すなわち異種性のアブラナナピンプロモーターおよびアマ内因性プロモーターの制御下にあるFad5-2により、アマの形質転換を行った。図26に示す通り、ナピンプロモーターを含むトランスジェニック植物は、1種類のΔ5不飽和化脂肪酸、すなわちタキソール酸を種子において全脂肪酸の1%のレベルで産生した。一方、アマニ特異的プロモーターを含むトランスジェニック植物は3種類のΔ5不飽和化脂肪酸:タキソール酸、ピノレン酸およびコニフェロン酸を産生した。これらのうち、タキソール酸(18:2-5,9)の存在量が最も多く、選んだ系統(FN-10-1)における全脂肪酸の9%を占め、次いでコニフェロン酸およびピノレン酸の順であった。驚いたことに、トランスジェニック種子におけるΔ5不飽和化脂肪酸の蓄積は他の脂肪酸の組成、特にオレイン酸レベルに大きな影響を及ぼした。異なるプロモーターの制御下でFad5-2不飽和化酵素を発現する2種類のトランスジェニック植物のいずれにおいても、Δ5-UPIFAの蓄積に伴ってオレイン酸は著しく増加した。ナピン特異的およびアマ種子特異的プロモーターを有するトランスジェニック植物におけるオレイン酸の含有量はそれぞれ全脂肪酸の平均44.7%および24.3%に達し、これに対して非形質転換対照は17.4%であった。
アマ種子においてΔ6不飽和化脂肪酸を産生させるために、2つの品種のアマに対して、異種性種子特異的プロモーター(アブラナのナピンプロモーター)の制御下にあるFad6 cDNAを含む構築物による形質転換を行った。品種Iのアマ(Normandy種)は伝統的な産業用脂肪種子作物であり、これに対して品種II(Solin種)は、品種Iの化学的変異誘発に由来する食用脂肪種子作物である。合計12種のトランスジェニック植物を作製した。トランスジェニック体の大半は、保持時間がGLAおよびSDAのものに対応する2つの新規脂肪酸を示し、それらは全脂肪酸の0.1〜4.3%を占めた(図27)。ソリン(Solin)種のトランスジェニック体におけるGLAレベルはSDAのものよりも高かったが、ノルマンディー(Normandy)種のトランスジェニック体におけるGLAレベルはSDAのものよりも低かった。これは、ソリン種のアマニにおける主要な脂肪酸がリノール酸であり、ノルマンディー種の種子における主要な脂肪酸がリノレン酸であることから理解しうる。
カラシナ種子においてΔ6不飽和化脂肪酸を産生させるために、カラシナに対して、アマの形質転換に用いたのと同じ構築物、すなわち、アブラナのナピンプロモーターの制御下にFad6がある構築物による形質転換を行った。15種の独立したトランスジェニック植物が得られた。トランスジェニック種子の脂肪酸分析により、大部分のトランスジェニック体のガスクロマトグラムには、野生型対照と比べて3種の新たな脂肪酸が生じていることが示された(図20)。この3種の脂肪酸は18:2(6,9)および18:3(6,9,12)および18:4(6,9,12,15)と同定された。カラシナはアマと同様に、P.イレギュラレ由来のFad6を機能的に発現し、内因性基質18:1(9)、18:2(9,12)および18:3(6,9,12)の6位に二重結合を導入して、トランスジェニック種子において対応する3種のΔ6脂肪酸の産生をもたらすことが可能である。トランスジェニック種子で産生される3種の新たな脂肪酸のうち、最も存在量が多いのはGLAであり、トランスジェニック種子におけるレベルは全脂肪酸の30%〜38%である。次に存在量の多い成分はSDAであり、これは複数のトランスジェニックにおいて全脂肪酸の3〜10%を占めている(図21)。
当業者は、定型的な範囲の実験により、本明細書に記載された特定の態様の等価物を認識する、または確認しうると考えられる。このような等価物は特許請求の範囲に含まれるものとする。
Claims (44)
- 以下からなる群より選択される、単離された核酸分子:
(a)配列番号:1、配列番号:3、配列番号:5または配列番号:7に示したヌクレオチド配列を含む核酸分子;
(b)配列番号:2、配列番号:4、配列番号:6または配列番号:8に示したアミノ酸配列を含むポリペプチドをコードする核酸分子;および
(c)配列番号:2、配列番号:4、配列番号:6または配列番号:8に示したアミノ酸配列を含むポリペプチドの天然の対立遺伝子バリアントをコードする核酸分子。 - 以下からなる群より選択される、単離された核酸分子:
(a)配列番号:1、3、5、7のヌクレオチド配列またはそれらの相補物との同一性が少なくとも70%であるヌクレオチド配列を含む核酸分子;
(b)配列番号:1、3、5、7のヌクレオチド配列またはそれらの相補物を含む核酸の少なくとも30ヌクレオチドの断片を含む核酸分子;
(c)配列番号:2、4、6または8のアミノ酸配列との同一性が少なくとも約50%であるアミノ酸配列を含むポリペプチドをコードする核酸分子;および
(d)配列番号:2、4、6または8のアミノ酸配列の少なくとも10個の連続したアミノ酸残基を含む断片である、配列番号:2、4、6または8のアミノ酸配列を含むポリペプチドの断片をコードする核酸分子。 - 請求項1または2記載の核酸分子の相補物とストリンジェントな条件下でハイブリダイズする、単離された核酸分子。
- 請求項1または2記載の核酸分子を含むベクター。
- 発現ベクターである、請求項4記載のベクター。
- 請求項5記載の発現ベクターをトランスフェクトした宿主細胞。
- 植物細胞、微生物細胞および動物細胞からなる群より選択される、請求項6記載の宿主細胞。
- 植物細胞が、アマ(アマ属(Linum sp.))、ナタネ(アブラナ属(Brassica sp.))、ダイズ(ダイズ属(Glycine and Soja sp.))、ヒマワリ(ヒマワリ属(Helianthus sp.))、ワタ(ワタ属(Gossypium sp.))、トウモロコシ(ズィー・メイス(Zea mays))、オリーブ(モクセイ科(Olea sp.))、ベニバナ(ベニバナ属(Carthamus sp.))、カカオ(テオブロマ・カカオ(Theobroma cacao))およびラッカセイ(ラッカセイ属(Arachis sp.))からなる群より選択される脂肪種子作物から得られる細胞である、請求項7記載の宿主細胞。
- 微生物細胞が、ヤブレツボカビ(Thraustochytrium)、ピティウム・イレギュラレ(Pythium irregulare)、スキゾキトリウム(Schizochytrium)およびクリテコジニウム(Crythecodinium)からなる群より選択される、請求項8記載の宿主細胞。
- ポリペプチドを産生させるために請求項6記載の宿主細胞を培養する段階を含む、ポリペプチドの生産方法。
- 以下からなる群より選択される、単離されたポリペプチド:
(a)配列番号:2、4、6または8の少なくとも10個の連続したアミノ酸を含む断片である、配列番号:2、4、6または8のアミノ酸配列を含むポリペプチドの断片;
(b)配列番号:1、3、5または7からなる核酸分子の相補物とストリンジェントな条件下でハイブリダイズする核酸分子によってコードされるポリペプチドである、配列番号:2、4、6または8のアミノ酸配列を含むポリペプチドの天然の対立遺伝子バリアント;
(c)配列番号:1、3、5または7のヌクレオチド配列を含む核酸との同一性が少なくとも70%であるヌクレオチド配列を含む核酸分子によってコードされるポリペプチド;および
(d)配列番号:2、4、6または8のアミノ酸配列との同一性が少なくとも60%であるアミノ酸配列を含むポリペプチド。 - 配列番号:2、4、6または8記載のアミノ酸配列を含む、請求項11記載の単離されたポリペプチド。
- 不飽和脂肪酸の生産方法であって、請求項1または2記載の単離された核酸分子による細胞のトランスフェクションおよび形質転換を行う段階、ならびに不飽和脂肪酸が産生される条件下で細胞を培養または栽培する段階を含む方法。
- 細胞が植物細胞、動物細胞および微生物細胞からなる群より選択される、請求項13記載の方法。
- 植物が脂肪種子作物から選択される、請求項14記載の方法。
- 脂肪種子作物が、アマ(アマ属)、ナタネ(アブラナ属)、ダイズ(ダイズ属(Glycine and Soja sp.))、ヒマワリ(ヒマワリ属)、ワタ(ワタ属)、トウモロコシ(Zea mays)、オリーブ(モクセイ科)、ベニバナ(ベニバナ属)、カカオ(Theobroma cacao)およびラッカセイ(ラッカセイ属)からなる群より選択される、請求項15記載の方法。
- 不飽和脂肪酸を回収する段階をさらに含む、請求項13記載の方法。
- 不飽和脂肪酸が、GLA 18:3(6,9,12)、SDA 18:4(6,9,12,15)、AA 20:4(5,8,11,14)、EPA 20:5(5,8,11,14,17)、DPA 22:5(4,7,10,13,16)およびDHA 22:6(4,7,10,13,16,19)からなる群より選択される、請求項13記載の方法。
- 不飽和脂肪酸の生産方法であって、少なくとも1つの不飽和化酵素標的分子を含む組成物を、請求項11または12記載の少なくとも1つの単離されたポリペプチドと、不飽和脂肪酸が生成される条件下で接触させる段階を含む方法。
- 不飽和脂肪酸を回収する段階をさらに含む、請求項19記載の方法。
- 不飽和脂肪酸が、GLA 18:3(6,9,12)、SDA 18:4(6,9,12,15)、AA 20:4(5,8,11,14)、EPA 20:5(5,8,11,14,17)、DPA 22:5(4,7,10,13,16)およびDHA 22:6(4,7,10,13,16,19)からなる群より選択される、請求項19記載の方法。
- 不飽和脂肪酸を産生しうる細胞の作製方法であって、脂肪酸アシル鎖における二重結合の形成を触媒する活性を有する不飽和化酵素をコードする核酸分子である、請求項1または2記載の核酸分子を該細胞に導入する段階を含む方法。
- 細胞が、植物細胞、動物細胞および微生物細胞からなる群より選択される、請求項22記載の方法。
- 植物細胞が脂肪種子植物由来の細胞である、請求項23記載の方法。
- 脂肪種子植物が、アマ(アマ属)、ナタネ(アブラナ属)、ダイズ(ダイズ属(Glycine and Soja sp.))、ヒマワリ(ヒマワリ属)、ワタ(ワタ属)、トウモロコシ(Zea mays)、オリーブ(モクセイ科)、ベニバナ(ベニバナ属)、カカオ(Theobroma cacao)およびラッカセイ(ラッカセイ属)である、請求項24記載の方法。
- 不飽和脂肪酸が、GLA 18:3(6,9,12)、SDA 18:4(6,9,12,15)、AA 20:4(5,8,11,14)、EPA 20:5(5,8,11,14,17)、DPA 22:5(4,7,10,13,16)およびDHA 22:6(4,7,10,13,16,19)からなる群より選択される、請求項22記載の方法。
- 不飽和脂肪酸の生産を調節するための方法であって、不飽和脂肪酸の産生の調節が起こるように請求項6記載の細胞を培養する段階を含む方法。
- 不飽和脂肪酸の産生が増強される、請求項27記載の方法。
- 不飽和脂肪酸が、GLA 18:3(6,9,12)、SDA 18:4(6,9,12,15)、AA 20:4(5,8,11,14)、EPA 20:5(5,8,11,14,17)、DPA 22:5(4,7,10,13,16)およびDHA 22:6(4,7,10,13,16,19)からなる群より選択される、請求項27記載の方法。
- 産生された不飽和脂肪酸を回収する段階をさらに含む、請求項27記載の方法。
- 不飽和脂肪酸の大規模生産のための方法であって、不飽和脂肪酸が産生されるように請求項6記載の細胞を培養する段階を含む方法。
- 不飽和脂肪酸の産生が増強される、請求項31記載の方法。
- 不飽和脂肪酸が、GLA 18:3(6,9,12)、SDA 18:4(6,9,12,15)、AA 20:4(5,8,11,14)、EPA 20:5(5,8,11,14,17)、DPA 22:5(4,7,10,13,16)およびDHA 22:6(4,7,10,13,16,19)からなる群より選択される、請求項31記載の方法。
- 産生された不飽和脂肪酸を回収する段階をさらに含む、請求項29記載の方法。
- 請求項11または12記載のポリペプチドを含む組成物。
- 請求項13記載の方法によって生産されたポリペプチドを含む組成物。
- 請求項19記載の方法によって生産されたポリペプチドを含む組成物。
- 請求項22記載の方法によって作製された細胞を含む組成物。
- 動物飼料中に用いられる、請求項35記載の組成物。
- 動物飼料中に用いられる、請求項36記載の組成物。
- 栄養補助食品として用いられる、請求項36記載の組成物。
- ヒトまたは動物の食事を補うための方法であって、請求項35記載の組成物を投与する段階を含む方法。
- 障害を有する患者の治療方法であって、患者が治療されるように請求項35記載の組成物を投与する段階を含む方法。
- 障害が、ストレス、糖尿病、癌、炎症性疾患および心血管疾患からなる群より選択される、請求項43記載の方法。
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