JP5851401B2 - 安定な補酵素による酵素の安定化 - Google Patents
安定な補酵素による酵素の安定化 Download PDFInfo
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- JP5851401B2 JP5851401B2 JP2012525165A JP2012525165A JP5851401B2 JP 5851401 B2 JP5851401 B2 JP 5851401B2 JP 2012525165 A JP2012525165 A JP 2012525165A JP 2012525165 A JP2012525165 A JP 2012525165A JP 5851401 B2 JP5851401 B2 JP 5851401B2
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- 108090000340 Transaminases Proteins 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- XAZMYOQLNVTRPS-UHFFFAOYSA-L disodium;2-[[4-[2-(1,3-benzothiazol-2-yl)-3-[4-[4-[3-(1,3-benzothiazol-2-yl)-5-[4-[bis(2-sulfonatoethyl)carbamoyl]phenyl]tetrazol-3-ium-2-yl]-3-methoxyphenyl]-2-methoxyphenyl]tetrazol-2-ium-5-yl]benzoyl]-(2-sulfonatoethyl)amino]ethanesulfonate Chemical compound [Na+].[Na+].COC1=CC(C=2C=C(OC)C(=CC=2)N2[N+](=NC(=N2)C=2C=CC(=CC=2)C(=O)N(CCS([O-])(=O)=O)CCS([O-])(=O)=O)C=2SC3=CC=CC=C3N=2)=CC=C1N([N+](=N1)C=2SC3=CC=CC=C3N=2)N=C1C1=CC=C(C(=O)N(CCS([O-])(=O)=O)CCS([O-])(=O)=O)C=C1 XAZMYOQLNVTRPS-UHFFFAOYSA-L 0.000 description 1
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- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
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- 150000002988 phenazines Chemical class 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 230000007017 scission Effects 0.000 description 1
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- 230000009870 specific binding Effects 0.000 description 1
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Description
A=アデニンまたはその類似体、
T=それぞれ独立してO、S、
U=それぞれ独立してOH、SH、BH3 -、BCNH2 -、
V=それぞれ独立してOHまたはリン酸基、または2つの基が環状リン酸エステル基を形成する、
W=COOR、CON(R)2、COR、CSN(R)2、R=それぞれ独立してHまたはC1〜C2−アルキル、
X1、X2=それぞれ独立してO、CH2、CHCH3、C(CH3)2、NH、NCH3、
Y=NH、S、O、CH2、
Z=直鎖状または環状有機残基、
ただし、Zおよびピリジン残基は、グリコシル結合により連結されない
またはその塩、もしくは必要に応じて還元型
から選択される。
R4=それぞれ独立してH、F、Cl、CH3、
R5=CR4 2、
R5'およびR5''との間が単結合である場合、R5'=O、S、NH、NC1〜C2−アルキル、CR4 2、CHOH、CHOCH3、および、R5''=CR4 2、CHOH、CHOCH3、
R5'およびR5''との間が二重結合である場合、R5'=R5''=CR4、ならびに
R6、R6'=それぞれ独立してCHまたはCCH3
が好ましい。
このようなテストストリップは、安定化された酵素を、セルロース、プラスティックなどの吸収材料または/および膨潤性材料上に固定された形態で含む。
カルバNAD(図1A)またはNADをグルコース特異的GlucDHに添加した。これらの処方を、いずれの場合もPokalon foils(Lonza)に塗布し、乾燥後、温かく湿気のある条件下(32℃、相対空気湿度85%)で保管した。その後、反応速度および関数曲線(function curve)を定期的に測定した。平行して、各測定時間でcNAD/NAD分析および酵素の残存活性の測定を行った。
cNADまたはNADがアルコール脱水素酵素を含む検出溶液に添加された。これらの混合物を2〜8℃でおよび35℃で保管した。ついでアルコール脱水素酵素(ADH)の安定性を定期的に調べ、酵素の残存活性を測定した。
グルコースを測定するために、それぞれがグルコース脱水素酵素、NAD、メディエーターおよび、必要に応じて、光学的指示薬を含む種々のテストシステムが、光学的および電気化学的に測定された。
周辺光に対する安定性を測定するために、それぞれ、NADまたはカルバNADと併用して、グルコース脱水素酵素(GlucDH)、グルコース−6−リン酸脱水素酵素(G6PDH)およびグルコース脱水素酵素突然変異体2(GlucDH−mut2)から選択される酵素を含む、種々のテストシステムが国際公開第03/097859号に記載の方法にしたがって製造され、続いて血液試料が添加された。具体的には、テストシステムは、酵素および補酵素を含む光重合可能な液体組成物を支持体に塗布し、続いて、12〜15μmの厚さを有する試薬層を得るために組成物を400W、360nmの波長で10秒間光照射適用することにより製造された。検出は、数分間、蛍光法で行われた。
本明細書に記載される、診断用テストエレメントを製造するために使用され得る具体的な組成物の例が以下に明記される。
特に、ジアホラーゼ、カルバNAD、テトラゾリウム塩および乳酸を含む液体試薬が乳酸脱水素酵素の活性を測定するために使用された。25℃で溶液中に保管された検出試薬は、以下の成分を含んでいた:
3U/mL ジアホラーゼ (豚の心臓由来)
2mM カルバNADまたは0.2mM NAD
2mM テトラゾリウム塩 WST−3
50mM 乳酸ナトリウム
0.1M トリシン/HCl、pH 8.8
特に、グルコース脱水素酵素(GlucDH)、カルバNAD、ジアホラーゼ、ニトロソアニリンおよびリンモリブデン酸を含む組成物が血糖を測定するために使用された。テストストリップは、第一の処方をポリカーボネート箔にドクターブレード(層高 100μm)を使用して塗布し、第一層を乾燥し、第一層に第二の処方を塗布(ドクターブレードギャップ 30μm)し、そして第二層を乾燥することにより得られ、32℃で相対空気湿度30〜70%で保管された。第一層および第二層に使用された処方は、表3に示されている:
特に、グリセロール脱水素酵素、カルバNAD、ジアホラーゼおよびテトラゾリウム塩を含む組成物がトリグリセリドを測定するために使用された。テストストリップは、表4に記載される処方をポリカーボネート箔にドクターブレード(層高 80μm)を使用して塗布し、続いて乾燥することにより得られ、32℃で相対空気湿度30〜70%で保管された。
グルコース脱水素酵素およびジアホラーゼのカルバNADによる安定化を評価するために、多数のテストストリップが実施例5と同様に製造された。テストストリップの第一および第二層に使用された処方が表5に示されている。
種々の脱水素酵素の熱安定性に対するNADおよびカルバNADの影響を測定するために、第一工程において酵素(1mg/mL)が個々の測定緩衝液に対して4℃で20時間透析された。続いて3.8mMのNADまたはカルバNADが試料に添加され、そして、試料が4℃で保管された。
Claims (23)
- 酵素を長期間安定化する方法であって、前記酵素が安定化された補酵素の存在下で保管され、かつ、前記酵素として酵素番号EC1.1.1.2であるアルコール脱水素酵素、酵素番号EC1.1.1.49であるグルコース−6−リン酸脱水素酵素または酵素番号EC1.6.99.2であるジアホラーゼが使用されることを特徴とする方法であって、
前記安定化された補酵素が、
安定化されたニコチンアミドアデニンジヌクレオチド(NAD/NADH)化合物、
安定化されたニコチンアミドアデニンジヌクレオチドリン酸(NADP/NADPH)化合物、
式(I)の化合物
A=アデニンまたはその類似体、
T=それぞれ独立してO、S、
U=それぞれ独立してOH、SH、BH3 -、BCNH2 -、
V=それぞれ独立してOHまたはリン酸基、または2つの基が環状リン酸エステル基を形成する、
W=COOR、CON(R)2、COR、CSN(R)2、R=それぞれ独立してHまたはC1〜C2−アルキル、
X1、X2=それぞれ独立してO、CH2、CHCH3、C(CH3)2、NH、NCH3、
Y=NH、S、O、CH2、
Z=直鎖状または環状有機残基、
ただし、Zおよびピリジン残基は、グリコシル結合により連結されない
またはその塩、もしくは還元型
であり、
前記長期間の安定化が、前記酵素が前記安定化された補酵素の存在下で少なくとも2週間の期間保管された場合に、酵素活性の初期値を基準として50%未満の酵素活性の低下しかみられないことであることを特徴とする方法。 - カルバNADが安定化された補酵素として使用されることを特徴とする請求項1または2記載の方法。
- 安定化された酵素が、少なくとも4週間の期間保管されることを特徴とする請求項1〜3のいずれかに記載の方法。
- 安定化された酵素が、少なくとも8週間の期間保管されることを特徴とする請求項1〜3のいずれかに記載の方法。
- 安定化された酵素が、少なくとも20℃の温度で保管されることを特徴とする請求項1〜5のいずれかに記載の方法。
- 安定化された酵素が、少なくとも25℃の温度で保管されることを特徴とする請求項1〜5のいずれかに記載の方法。
- 安定化された酵素が、少なくとも30℃の温度で保管されることを特徴とする請求項1〜5のいずれかに記載の方法。
- 安定化された酵素が、少なくとも50%の相対空気湿度または/および乾燥剤なしで保管されることを特徴とする請求項1〜8のいずれかに記載の方法。
- 安定化された酵素が、乾燥物としてまたは液相中で保管されることを特徴とする請求項1〜9のいずれかに記載の方法。
- 安定化された補酵素により安定化される酵素および前記安定化された補酵素からなる複合体であって、少なくとも2週間、少なくとも20℃の温度でまたは/および300nm以上の波長の光の存在下で保管された場合に、酵素活性の初期値を基準として50%未満の酵素活性の低下しかみられず、前記安定化された補酵素が、
安定化されたニコチンアミドアデニンジヌクレオチド(NAD/NADH)化合物、
安定化されたニコチンアミドアデニンジヌクレオチドリン酸(NADP/NADPH)化合物、
式(I)の化合物
A=アデニンまたはその類似体、
T=それぞれ独立してO、S、
U=それぞれ独立してOH、SH、BH3 -、BCNH2 -、
V=それぞれ独立してOHまたはリン酸基、または2つの基が環状リン酸エステル基を形成する、
W=COOR、CON(R)2、COR、CSN(R)2、R=それぞれ独立してHまたはC1〜C2−アルキル、
X1、X2=それぞれ独立してO、CH2、CHCH3、C(CH3)2、NH、NCH3、
Y=NH、S、O、CH2、
Z=直鎖状または環状有機残基、
ただし、Zおよびピリジン残基は、グリコシル結合により連結されない
またはその塩、もしくは還元型
であり、前記酵素が、酵素番号EC1.1.1.2であるアルコール脱水素酵素、酵素番号EC1.1.1.49であるグルコース−6−リン酸脱水素酵素または酵素番号EC1.6.99.2であるジアホラーゼであることを特徴とする複合体。 - 前記安定化された補酵素により安定化される酵素であって、少なくとも4週間保管されることを特徴とする請求項11記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、少なくとも8週間保管されることを特徴とする請求項11記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、少なくとも25℃の温度で保管されることを特徴とする請求項11〜13のいずれかに記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、少なくとも30℃の温度で保管されることを特徴とする請求項11〜13のいずれかに記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、高い空気湿度で、乾燥剤なしで保管されることを特徴とする請求項11〜15のいずれかに記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、酵素活性の初期値を基準として30%未満の酵素活性の低下しかみられないことを特徴とする請求項11〜16のいずれかに記載の複合体。
- 前記安定化された補酵素により安定化される酵素であって、酵素活性の初期値を基準として20%未満の酵素活性の低下しかみられないことを特徴とする請求項11〜16のいずれかに記載の複合体。
- 請求項11〜18のいずれかに記載の複合体を含む、分析物を測定するための検出試薬。
- 請求項11〜18のいずれかに記載の複合体または請求項19記載の検出試薬を含むことを特徴とするテストエレメント。
- 酵素を安定化する方法であって、前記酵素が天然の補酵素の存在下で保管され、前記酵素として、酵素番号EC1.1.1.1またはEC1.1.1.2であるアルコール脱水素酵素、酵素番号EC1.4.1.5であるL−アミノ酸脱水素酵素、酵素番号EC1.1.1.47であるグルコース脱水素酵素、酵素番号EC1.1.1.49であるグルコース−6−リン酸脱水素酵素、酵素番号EC1.1.1.6であるグリセロール脱水素酵素、酵素番号EC1.1.1.30である3−ヒドロキシ酪酸脱水素酵素、酵素番号EC1.1.1.27またはEC1.1.1.28である乳酸脱水素酵素および酵素番号EC1.1.1.37であるリンゴ酸脱水素酵素からなる群から選択される脱水素酵素、または、酵素番号EC1.6.99.2であるジアホラーゼが使用され、前記天然の補酵素として、天然のニコチンアミドアデニンジヌクレオチド(NAD/NADH)化合物または天然のニコチンアミドアデニンジヌクレオチドリン酸(NADP/NADPH)化合物が使用されることを特徴とする方法。
- 酵素番号EC1.1.1.1またはEC1.1.1.2であるアルコール脱水素酵素、酵素番号EC1.1.1.47であるグルコース脱水素酵素、酵素番号EC1.1.1.49であるグルコース−6−リン酸脱水素酵素または酵素番号EC1.6.99.2であるジアホラーゼが前記酵素として使用されることを特徴とする請求項21記載の方法。
- 安定化された酵素が300nm以上の波長の光の存在下で保管されることを特徴とする請求項1〜10および21〜22のいずれかに記載の方法。
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