Division of Biofunctional Chemistry
The Chemical Society of Japan

Vol. 32, No. 3 (2017. 12. 21)

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6jOɾοʥǻ˳ϨPØ3ŖHK5jEłƊΎ̎ 3 ǕRÃ̿ʆÓś$3399 ĶŖˉRoqmˌĩLchς8K5jEƠϑ 5 Ǖ˖Rǝʼ͒êśRÀʒPȆΔ-E=^?%^E${±¸¶|mρai
P,Eh$ɛˮO:ĭ͹m-EF3^=EɨÒƐƠĨ͡ʃɾRƻǄƤχĉ˖P0˿˜=»8^?%ěÕý1) '˖ˉˁʃĶƠ($ƈ˙̇ʂ·̆åô¹ ̴͟$ºďėˈ$2005
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7

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MRϧP͌ϹǻŊǶƃmƺČ=E°¢²ĶĤm˘-i%±x¶ϑĘ2ͤ˫ΥP·Ε;jiM$θȫįɬPfHKͤ˫Υ»Rʖɴǻo¨ϖʋƃ2ŊǶƃMŊǶ=$´¸2÷А;ji%9Rϳ$ŊǶMŘɐP±x¶ϑã2ęhϹ;jiEa$ͤ˫ΥɢɧRʥǻmõHE^^R°¢±¶|2Ő͊L,i%Ϧ˩ĚɞR LD ĶƠS°¢±¶|PȽĻɐϧ1gȽɇmͱ?
i9M2ΎЉL,HE2$əθLSɆƞRͤ˫Υ|cəbξ-˖ç˲ÑǻŊǶPĸȿ?iŊǶξǛLŖ͉ēŻǻͤ˫Υ°¢±¶|
2Ő͊POhII,i%ɢ̒LS$
9.=EЙξ°¢±¶|mŐ͊P=E±x¶ȠŚǻ N-acyl-N-alkyl
sulfonamide (LDNASA)ĶƠR΅̧OŊǶξǛΑ$OgWPCR³¶°|ZRƿϦPI-K̨Õ?i%¢Œ jDnWÍÈ¬: Ligand-directed (LD) chemistryœ. jDnWÍÈ NASA ¬,ÇĶ¿ĭ

 LD ĶƠPω˘Ő͊OŊǶƃM=KS9j^LP²(Ts)$o²q¨¸²(AI)$´«8s²¢¶t¸(BB)ON2Ͳė;jK-i(ŵ 1)%[3] =1=»ιRf.P$9jgSŊǶξǛ2σ5ŊǶįːbä-Ea$÷АǫRo±}¸¯¶2ųϺO}¸bƏ&,HE%C9L̓̚SЙξ

1IЙįːO°¢±¶|m˱Ƞ=K£Ŷ˳ŖȋPŏ51g˘-gjK3EʖϽƝĤL,iN-acyl-N-alkyl sulfonamide (NASA) P˵˱=$9jmŊǶƃM=E LDNASA ĶƠRϦ˩PŌh̪nF%[4]^@ FKBP12 m«²ͤ˫ΥM=K NASA ž°¢²ĶĤ 1 mͽͺ·Ŗȋ=$΂З̞ēPK°¢²ĶŊ

ǶmͨHE(ŵ 2a,b)%MALDI-TOF-MS ͷɪR̬ɬ$1 S FKBP12 ml@1 15 min L 98%°¢²Ķ?i

9M2l1HE%^E°¢²Ķϑãͷɪ1g$9RŊǶS±x¶̬Ŗ¦}θĀR Lys ʋƃˊˢˬPρͨ=$ƢƦOo¨̬ŖmÕ=K´¸2÷А;ji9M2Ɍg1MOHE% ̰-K$9j^LPǤ˸̕ƪLϦ˩=E 4 ̐ЌR LD ĶƠ(Ts, AI, BB, NASA)RŊǶξǛmfhƦϙ
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ΥRʾǛ2Ǟ 2 Lͫ;j$Ͳ17RξǛƦȽ kapp SǞ 3 PǬ.%fHK$ˢOi°¢²ĶĤʾǛPƶ?

i kapp mƨЗˬPʖaK´=$Ǟ 3 m˘-Kp¶|ͷɪ?i9ML$°¢²Ķ

´R

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ξǛͷɪLS NASA M Ts S FKBP12 °¢±¶|$NASA$AI$BB S eDHFR °¢±¶|Lʑΰ=E%
O0$CjDjR°¢²ĶĤSφŇPɾοəωĶ2O;jEbRmì˘=E%ŊǶξǛͷɪR̬ɬm
ŵ 2d P˾?%^@ FKBP12 °¢±¶|R̬ɬ1g$NASA M Ts RŊǶξǛ°ª¸¸mʑΰ?i

M$Kd SÌIRŊǶƃϧL\]Ř̛L,iRPƶ=$NASA R kL S Ts Pʑ[K 635 ùƐ31HE%
eDHFR Pƶ?i°¢±¶|LbŘɿP$Kd S°¢²ĶĤ:MPψ-S\MnNO-RPƶ=$NASA°¢²ĶĤRξǛƦȽ kL S AI Pʑ[$2241 ùƐ35$BB Pʑ[Kb$38 ùƐ3-9M2Ɍg1M

OHE%ǭgjE°ª¸¸1gÌʅŊǶξǛƦȽ(kL/Kd)m̝ė=EM9

k$NASA ž°¢²ĶĤS FKBP12$eDHFR RNGgPƶ=Kb$̤ 104M-1s-1 M͟=5Ɛ3Oþm˾=ERP

ƶ=K$LD ĶƠR̙¹¿ÙL,i Ts
c AI SȽĻ M-1s-1 ̎Ǜ$əθϦ˩;j

E BB Lb 102 M-1s-1 v¸¸L,HE%Ú»R̬ɬ1g$LDNASA ĶƠSǬɧ
R LD ĶƠfhbƐ3OŊǶξǛƦȽmɛ?i9M2ƦϙˬP˾;jE%;gPɢɹͻPfHK×Rͤ˫Υ°¢±¶|ʟMR˲ȫˬOʑΰ2Ő͊MOh$
LDNASA ĶƠRŊǶξǛS$˖ç˲ÑǻŊǶRÂLəbξǛƦȽRƐ3-$
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ji SNAP-tag ©Pĸȿ?i9

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ĶƠRÌʅŊǶξǛƦȽ(kL/Kd)S˘-

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MALDI-TOF MS Ħß (c) LD ¬,ÇĶ¿À (d)  LD¬,Ķ¿]igpQp

9mì˘=EƆŖ$CR Kd þPïƞ=KŊǶξǛ2ä¼?i9Mm˼·=K-i%9RËƨS$ĘƝ·ΕmДİĩM?iĶƠŊǶRξǛP͵Ťǻ2˲ȫϨ¾?i9MmɌ˼P˾?MMbP$ωęO±x¶ϋȕRȠʀm¾/iϗͱO˶ͲMOHE%
Ŕ. jDnWÍÈ NASA ¬, Bio-orthogonality »ιRf.P in vitro P07iɹͻ1g LDNASA ĶƠ2ĆjEŊǶξǛmɛ?i9M2˾;jE2$̧̢͉ZRƿϦP,EHKSʀˬͤ˫ΥPƶ?iϋȕǻc˖ç˲Ñǻ/ωŖǻb^EϗͱMOi%C9LʅP˖̧͉ēP0-KēŻǻ FKBP12
R°¢²Ķmͨ-$LDNASA ĶƠRʀˬϋȕǻm΁ð=E%
C2C12 ̧͉RƂБʭÂP 1 mʰī=q¶y­¢¸ǫ$rt¶´p¶|PfHKv¶÷А¶{Υmɹ
ė=E%CR̬ɬ$ŊǶϦƘ 10 Ęǫ1g 12 kDa ØθPR_

v¶Ķ FKBP12 P˳Ǥ?iŁ¹R¶2ͲgjE(ŵ 3)%^E$ŊǶϦƘУɐϧLR°¢²Ķːm̝ė=EM9k$̧
͉ēŻǻ FKBP12 R 77%2°¢²Ķ;jK-i9M2Ɍg1
MOHE%O0$ǬɧR Ts ž°¢²ĶĤm˘-KŘɦÝL°¢²ĶmͨHEƆŖLS$ŊǶ2σ-Ea°¢²Ķ|²¢Ŕ Ėĝ FKBP12 icjnG

Sč5ɹė;jO1HE%Ú»R9M1g$NASA ž°¢²ĶĤŞ͉ēRf.OƔϸ̢P0-Kb$ηξ·ЙįːO°¢²Ķ2ρͨ=$˖ç˲ÑǻbɻaKЙ-9M2ƨ΀;jE%
ŕ. NASA Ç¤<cpN($J\lnVWiSG
 Ǭɧ$LD °¢²ĶĤSͤ˫ΥP´¸ĘƝmƺČ?if.Pͽͺ;jK-E2$±x¶ϑãmͤ˫ΥPƺČ?if.Pͽͺ?jT$CRĶŖˉS½ŐλϬƬĤM=Kʃ͊?iMÊȃ;ji(ŵ 4a)%
C9L̓̚gS$NASA mŊǶƃМwarheadНM=EɃͳ½ŐλϬƬĤRϦ˩PŌh̪nF%ɢ˸̕L
S$ʀˬͤ˫ΥM=K Heat shock protein 90(Hsp90)mϋȕ=E%Hsp90 Sͤ˫ΥRu¸²p¶|móρ?iĘƝ¬£´¶M=K˶gjiͤ˫ΥL,i2$CRʥǻSx¶̧͉R˖ƞ·ƈʌPǳЅL,iEa$θǕLSɛɝOĨ͡¸~M=Kʡ˱mϷaKi%Ȍ&S^@ Hsp90 ±x¶R PU-H71 m

ɛ?i NASA ž°¢²ĶĤ 2 mŖȋ=Мŵ 4bН$
9j2̧͉ēŻǻ Hsp90 mϋȕˬP°¢²ĶŐ͊L,i9Mm˼·=E%^E$LC-MSMS
ͷɪPfHĶ͉ē Hsp90 R°¢²ĶϑãS±x¶̬ŖqθĀPƞŻ?i Lys58 L,i9MmɌg1P=E(ŵ 4c)%9R˶ͲmƃP±¶w¸ɾοmŖ˔ˬPͽͺ=$NASAmŊǶƃM=Kɛ?i½ŐλϬƬĤ
PU-NASA mŖȋ=E(ŵ 4d)%΂З̞ÂL
PU-NASA M̡ͮ Hsp90 mʯŖ?iM$ŊǶϦƘ 1 ɐϧL PU-NASA 2УĘƝØī=E´{2 84%ŋːLǭgjE%̰-K$¢ ŕ (a)NASA + 6 9 q  ĵ Ņ ± N E p f(b)Hsp90 +³!9 LDNASA ick 2 (c)Hsp90,ickĻ{(Lys58) (d) PU-NASA ,«äķ(e) Hsp90 ,qĵŅ±+69Fi?=nVĢĈĲ
,q­®

10

PU-NASA Pfix¶̧͉RƈʌϬƬʥǻm΁ð=E%99LS$½ŐλˬO Hsp90 ϬƬįɬm΁ð=

c?5?iEa$ϬƬĤmĖ˔=Ȩ͉mʣʧ=$Ϥɐϧq¶y­¢¸=Eǫ(21~69 h)R˖ƞːm΁ð=E%CR̬ɬ$PU-NASA SŘʾǛRŐλˬϬƬĤ PU-H71 fhbǣ-ƈʌϬƬʥǻm˾=E%
9RƈʌϬƬRŅűm˼1aiEaP$Hsp90 R{°qo¶ͤ˫ΥR˩˒ϙmΏ[E%?iM$
PU-NASA mĖ̻=EɦÝLS$HER2, cRaf, Akt,±¶ϖĶ Akt M-HEx¶RƈʌPϨ¾?i{°qo¶ͤ˫Υ2͟=5ʱƼ?i9M2l1HE(ŵ 4e)%9jS Hsp90 R¬£´¶ʥǻ2ϤɐϧϬƬ;

ji9MPfHK9jg{°qo¶ͤ˫Υ2½ƢƦĶ=E̬ɬL,iM͂/gji%¹Ʉ$ŘɦÝP0-KŐλˬϬƬĤ PU-H71 S Hsp90 mϤɐϧϬƬ?i9M2L3O-Ea${°qo¶RʱƼS\MnNΧ9gO1HE%Ú»R̬ɬS$PU-NASA 2̧͉ē Hsp90 Pƶ?i½ŐλˬOϬƬʥǻm
ɛ?i9Mm˾=K0h$ NASA ŊǶƃ2³¶°|RŊǶƃM=Kω˘Ő͊L,i9M2
ƨ΀;jE%
Ŗ. ;8+ ÔŰȌ&S̢̭ˬOŊǶξǛͷɪPfHK LDNASA ĶƠ2~104 M-1s-1 M-.ɻaKƐ3OÌʅŊǶξǛƦȽm˾?9MmɌg1P=E%Ͳ͝M;j2GL,i2$ÌʅŊǶξǛƦȽRƐ3;S$̧͉ēLRͤ˫Υ°¢±¶|P0-KˊPϗͱOȄšmȟI%[1, 6] ͤ˫Υ°¢±¶|RŊǶξǛS$ÌʅŊǶξǛƦȽ$ͤ˫ΥʾǛ$÷А΂͡ʾǛRCjDjPïƞ?i%̧͉ēSĘƝ{°rp¶|ˋȇM
ŢTji\Nɿ&Oͤ˫Υ2ЙƱǛPƞŻ?i2$̧͉Иɵͤ˫Υmϰ7T$¹͓PŁ¹Rͤ˫ΥʾǛSȽ nM+Ƚ µM ̎ǛL,iМÂPS pM, fM ̎Ǜ=1˩˒=O-ͤ˫ΥbƞŻ?iFk.Н%̧͉ēLSʔʸǻc͎μφǻ2ͱűL$÷А΂͡RƨįʾǛmƈc?9MPSϮ˞2,iEa$ä˩˒ϙͤ˫ΥR°¢±¶|LS$Ɛ3OÌʅŊǶξǛƦȽm˾?ŊǶ2Ɩ^=-%í/T$ͤ˫ΥʾǛ=°¢²ĶĤʾǛ=1 µM M-.̧͉ēŊǶɦÝmȃƦ=EƆŖ$ÌʅŊǶξǛƦȽ2 1 M-1s-1 RŊǶLS 50%ŊǶρͨɐϧ t50%=277 h (10 ɇÚ»!)L,i2$104 M-1s-1 RŊǶLS t50%=1.6 min MOḩ͉ƨЗM=Kω
ęL,i9M2l1i%ƨϳPS΂͡R͎μφ´cĘͷONb,iRLͺ̝νhPS-1O-

2$įːˬOͤ˫Υ°¢±¶|mͨ.PSƼO5Mb 103~104 M-1s-1 v¸¸RÌʅŊǶξǛƦȽ2ǳ
ͱL,i%C.=EȄšLS$ɢ˸̕LϦ˩=E LDNASA ĶƠSf.c5ƨ˘ˬO³¢²Pĝχ=EēŻǻͤ˫Υ°¢±¶|ʟL,iM͹/iFk.% ɢ˸̕LS;gP$LDNASA ĶƠmǶ˘=K Hsp90 R½ŐλϬƬĤRϦ˩PȋĪ=E%˒ŻϦ˩;
jK-i½ŐλϬƬĤSʖɴǻRЙ-q¶ÿϡRv¸²mʀˬM=EbR2\MnNL,i
2$ÔŰϦ˩=E NASA ŊǶƃS Lys ÿϡRo¨¶Pƶ?i÷А2Ő͊L,i%9Rf.P Lys mʀˬM=E½ŐλϬƬĤSƅşí2ƼO5$ɢ˸̕ȋɬS Lys-targetable inhibitor PĜ˘Ő͊OŊǶƃR

ȜǢM-.Ͷˀ1gbϗͱL,i%[7] ÔǫS$q¶mȟEO-2EaP½ŐλϬƬȍˠRƶΚ
MOHK9O1HEͤ˫ΥPɢ̢mω˘=K-5MŘɐP$ƨϳP in vivo Lì/i³¢²^L brush up?i9Mm˱Ƞ=$˸̕mρaK-3E-M͂/K-i%ŗ. İĴ ɢ˸̕S$ÒϓƐƠǈƠ˸̊̕$ʩż ɵȼȧR˸̕ƪLͨOlj^=E%ʩż ȼȧRˆǲO:Ƞ
ƺPǲ1gȆΔ˜=»8^?%^Eɢ̒L̨Õ=EēƮS$»˙ ʎś$ǫ͢ Ɛαś$ɚВ ȘśmS>a$Ə5R˸̕Ŧ$Ơ˖;nRŀĩPfHKǭgjEȋɬL,h$9RƆmühKʮ5ȆΔ͐=^?%
Ř. ěÕý
[1] Lang, K. & Chin, J. W. Chem. Rev. 114, 4764–4806 (2014), [2] Tsukiji, S., Miyagawa, M., Takaoka, Y.,

Tamura, T. & Hamachi, I. Nat. Chem. Biol. 5, 341–343 (2009), [3] Amaike, K., Tamura, T. & Hamachi, I. Chem.

11

Commun. 53, 11972–11983 (2017) [4] Tamura, T. et al. J. Am. Chem. Soc. 139, 14181–14191 (2017), [5]Oliveira, B. L., Guo, Z. & Bernardes, G. J. L. Chem. Soc. Rev. 46, 4895–4950 (2017), [6] ͰǇ ϶Π$˙ɥɜġ$ʩż ɵ, ɛʃŖȋĶƠŀßΆ, 74, 521-531 (2016), [7] Pettinger, J,. Jones, K., Cheeseman, M.D.
Angew. Chem. Int. Ed., 56, 15200–15209 (2017)12ĊĐėx ē  ¡\?BŃĸ¬LneM@fįõıĀĖĝs,ñÈ?B@ď,ĵĉĥ<¯þ!9ģbmpa
śģbmpa,ÖĩĨîĊĐ8ÌÖöòśÝv¨¬¨¬ņġ¬ĕĊĐč ã÷©ĺ
1. -3+

 èąǕbĢP˖ţç2Έ˖=EM31g$qvrć̦S˖ţʥİP½ŐʄRǳЅć̦MOHE%C
jS$qvrŅƝRbIЙ-ŊǶǻ0fW$Mh.iƏɿOϖĶȽPΧű=EЙ-³{ʥǻPfi̧͉ē˕ƇRǉ_OiĞǮ2¹űL,iM͂/gjK-i%C=KθǕ$CRΙ1OĶƠˬˊǻmƃʶM=$ʥǻqvr̐МReactive Sulfur Species: RSSНM-.Ƀ=-w±¸2˖^jE%CR
Ʀ̾SΑɀc˸̓̕PfHK͗ǓˢOi9Mb,i2$ɢ̒LS Banargee g[1]c Slusarenko g[2]RΑɀ
P,i'˖ç˕Ƈ¼L$×R˖çēˉΥmϖĶO-=SϏć?iĩmȟIŜqvräĘƝĶŖˉ(Pý.9MM?i%9RƦ̾PƃJ5M$Ə5RŜqvrĶŖˉ29jP΄Ǥ?i%í/T$ŏ51g
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HK3EМǫιmň˅Н%
9Rf.P$Ə̐ƏɿOʥǻqvr̐2ƞŻ=$CjDj̧͉ē·˖çēLϗͱOǩħmȗHKi2$9jgS³{¤ªvM-.°¶RbMPÍ-2πİ=K-iMb͂/
gjK-i%í/Ţ͉ēLS$GSH PÙͫ;ji-5I1Rʥǻqvr̐2Ǝűǻ·ēűǻϖĶ³R̵ŤmȗHK0h$'ɐϧƋĶPá.ʥǻqvr̐RʾǛRƈʱ(M-.˒Κ2±o²q©
PΧ3K-iM͂/gjK-i%=E2HK$9Rf.Oʥǻqvr̐RƋİmŐʹĶ?i9M2$³{qv´¸RɃͷɌP̹2i%?OlG$ʥǻqvr̐MŐλˬPǶ̜?iˊǻmȟIͥĊ´¸2ʖagjK-i2$9RɦÝmʴE?ͥĊ´¸SɻaKƼO-R2˒ƨL,i%

C9Lɢ˸̕LS$CRūЉmĘƝͽͺRÿϿ1gͷʙ=$9j^LS½Ő͊L,HE˖̧͉ÂRʥǻqvr̐R±o²q©qª¸¶|mχȋ?i9Mm˱ˬM=E%
2. ģ  b m p a , Ö   U K ? n î , ċ đ LS$OBŐλˬͥĊ従来の”不不可逆性”蛍光プローブ´¸RϦ˩SƐ35ėσjK-iR1$CjmͥĊ´¸Ϧ˩RͶˀ1g̥ͷ5%ʥǻqvr̐mŐʹĶŐ͊
OͥĊ

無蛍光性

´¸S9j^LPȽƏƞŻ?i2[3]$CRƐľSʥǻqvr̐MͥĊ´¸R½Ő

λˬŊǶPfi˩ͥĊǻRˏǭ2Ƕ̜Ņ˔MO

蛍光性

脱離離基（消光団） cf.	
  Angew.	
  Chem.	
  Int.	
  Ed.	
  2005,	
  44,	
  2922.
新しく設計した” 可逆性”蛍光プローブ

HK-i%í/T$ʥǻqvr̐ÂRv¸²
ƃМ-SHНRЙ-ʖɴǻmĜ˘=$͌ϹǻR,iʬĊŲmͥĊŲP̬Ŗ;Ai9ML$ͥĊR
有⾊色・蛍光性

OFF/ON mĞǮŐ͊MOi2Мŵ 1 »Н$½ŐλˬO͌ϹŊǶd/$ƶΚˉΥRʾǛRƈʱm±

無⾊色・無蛍光性¢ 1
 ñ È? B@ ď+ Ç Ĕ! 9ģ b m pao²q©Pκ.9MSχȋL3O-%C913

L̓̚gS$¸~MͥĊ
Rć$ͥĊ´¸RǶ̜P)ĶƠˬǔͪǻЭŐλǻ*mØ¾?iM-.¶´¸RɃ=-ĘƝͽͺʟRϦȘmǴ=E%

LS$NRf.P=KͥĊ´¸PŐλǻmȟEAi1$C9Pŕ˸̓̕RˌĨǻ2˒ji%C

RȍˠM=KȌ&S$9j^LPˌ͏PϦ˩mρaK3EĘƝē˕Ķǔͪž´¸¨¶P˵˱=E[4]%9jS$´¸¨¶͕̦RʖϽƝǻmĜ˘=$͕̦ĘƝēP̐&Rʖɴǻƥ͊ƃmȟEAi9ML$
˖˔ˬ pH LRĘƝē˕ĶǔͪŊǶmƨ˒=EbRL,i%ɢ˸̕LSCR˩ȃmȜǢ=$v¸²ƃ
Rf.Oǣ-ʖɴ̐mɛ?iʥǻqvr̐Pfi)ĘƝϧ*ǔͪŊǶ2ƨ˒Ő͊L,iM͂/$ɃͳͥĊ´¸RϦ˩PŌh̪nFМŵ 1 ¼Н%Ú¼P$CRȋĪím̨Õ?i%

ŏ<QpISV($ĵĉģbmpa
3. G k Q R B n Ŏ GSHŏ[5]|²v¶МGSHНS˖çēLʃ͊?iÙͫˬOȔϖĶˉΥR¹IL,h$̧͉ēP̤ 0.5-10 mMRЙ-ʾǛ̟ŴLŜ^jK-i%CRƐľS GSH ÂRv¸²ƃ2ϏćɾοМ-SHНmŌiϏćçM=KƞŻ=$̧͉ēL˖>E°w²ȋĘc͵ϽƝˉΥONRϖĶ³mʬŇ=Eh$Glutathione
S-transferase (GST)Pfiʐˉc͡ˉRȨėМGSH ȖŖНRϠˉΥM=Kă5ONϗͱOʃ͊mɛ=K-i%;gP2ņ͉P0-KS$CRЙ-ƈʌʥǻPЙʾǛR GSH 2ǳͱL,h$CRƏϙR GSH
2Ȕ2nĤСȺƸ̳ʝ˨̈́ǻmˏǭ=K-iMbƅş;jK-i%9Rf.P$GSH mŌhǌ5˸̕
S$ƃ˽̧͉˖ˉƠ1gĺ˨·Ĩ͡ĶƠM-HEǑǙ-ІƀP^E2HK-i%
C9L$ĢιRȍˠPƃJ-KĶƠǔͪžͥĊ´¸mͽͺ·Ϧ˩=EM9k$GSH ʰīǫ 1 ̋̎ǛLǔͪPχ?iM-.ɻaKξ-ŊǶξǛmɛ=$1IͷϹƦȽ Kd 2 3.0 mM MOi}q̦´¸¨¶Ќ2Ͳ-F;j$̧͉ē GSH ʾǛ̟ŴPŖ͐=EͥĊ´¸RϦ˩PȋĪ=E%;gP9R

Иɵm GSH ϾǶ̜ǻR°ª²´¸¨¶МTAMRAНP±¶w¸mÕ=K̬Ŗ;A$˖̧͉Â
R GSH ʾǛRƋĶPá-ͥĊʠϤ2?i FRET žͥĊɢͥĊ´¸mϦ˩=E%´¸m˘-i9ML$9j^LS½Ő͊FHEɿ&OǶ˘ƨЗ2Ő͊MOHE%í/T$ͥĊЊǯϣ¼Lêȋ=Eɹϙ̳m˘-i9ML$˖̧͉ēR GSH ʾǛm˲ȫˬPƦϙ?i9MbŐ͊
MOHE%;gP$2ņ͉ÂR GSH ʾǛŞ͉R̐ЌPfHKƐ35ˢOh$ϾǐPʾǛRЙ-2ņ͉2,i¹ɄL$-5I1R2ņ͉LSʆǐ̧͉M,^hƋlgO-³¢²R GSH ʾǛL,iM-.͑šʮ-˶Ͳ2Ͳė;jEМŵ 2Н%^E$ϖĶ³МφϖĶʔ̦НPƶ?i GSH ʾǛƋĶR̋ŁãLRϖĶϏćМGSH-GSSGН
q{²RŐλˬqª¸¶|PbȋĪ=E%CR GSH RϖĶϏćξǛm2ņ͉Mʆǐ̧͉Lʑΰ?
iM$2ņ͉Sʆǐ̧͉Pʑ[K$GSSG RϏ
ćʃɾМ|²v¶±
{¸Pfi GSSG
RϏćʃ͊Н2Ðρ=K
0h$2ņ͉LSƎˬ
³ZRϫǮʃɾ
2˩χ=K-i9Mm
˾Ũ?i̬ɬm˖̧͉ÂLĚaKͲė=E%¢ 2 (a) å  * ğ Ć ő é ¼ Ė ĝ , GSH ø ¿ < ą z C i p ¦ Ñ  $ ă  (b) " : # : , Ė ĝ , GSH ø ¿ , ® ľ Ę á Ŏ  ě Õ ý 5 6 8 Á ā ŏ

4. [ ? W m e j N k ` > W Ŏ R-SnSH ę ŏ < Q p I S V (  $  ĵ ĉ ģ  b m p a ʅP$q´¦±²p̽МR-SnSH ̽Нm¸~M=EͥĊ´¸RϦ˩P˵ȏ=E%9jgRĶŖˉS$qvrŅƝ2 2 IÚ»πOHK-iR2əƐRˊǰL,h$¶{ΥÂRq¶ʋƃМCysН$,i-Ş͉ΥPƞŻ?i GSH c Cys 2Ə˻Ķ;jE¦±²pçŘ̲L14

,i%9j^L$˖çēLRƞŻS˼·;jK-E2$CRƞŻϙc˖çLRǩħPI-KSɠͷɌ
R9M2Ə1HE%CR͈ɒRÂ$2014 ǕPΦʘg2ƅş=EΑɀ[6]2$Ǥ΄ĘϘRƐ3OρƿP̹
2HE%ĐçˬPS$Cys c GSH R¦±²pçМCys-SnSH, GSnSHНŞ͉ēP00fCȽ 10 µM
ƞŻ=$GSH fhbǣ-ȔϖĶê˘m˾?9Mc$˻Ķʔ̦RĢДçM=Kbʃ͊=.iM-.ƅş
m=K-i%=1=$9jgR˸̕S-@jb̧͉˺˹PfiĘɪ2ǳЅL,h$˖3E^^RȁƅSǭgjK-O-%C9L$ĢιRĘƝͽͺoqpo2 R-SnSH ̽RŐλˬŐʹĶPȜǢŐ͊1m˸
̕=E%=1=$Ϧ˩PǤEHKƐ3OϴƉPOHERS$̧͉ÂPƏϙPƞŻ?i GSH Pƶ?iϋȕǻRˏǭL,HE%R-SnSH ̽S GSH Pʑ[K̤ 1/1,000 ̎Ǜ=1ƞŻ=O-MÊȃ;jiEa$GSH Pƶ=K 10,000 ùÚ»Rϋȕǻ2ʖagji%9jS´¸ͽͺP0-KSɻaKЙ-¸²L,H

E2$΂ͨϞ΋Rɡ$GSH Pƶ=K 10,000 ùÚ»Rϋȕǻmɛ?iͥĊ´¸RϦ˩PȋĪ=E%´¸R GSH O-= R-SnSH ZRͷϹƦȽ Kd SCjDj Kd,GSH > 100 [mM], Kd,RSSH = 10 [µM]9RͥĊL,h$˖̧͉ÂLS GSH PǶ̜A@$1IəωOʾǛ̟ŴL R-SnSH R_PǶ̜?iͥĊ´¸

L,i9Mm˼·=E%
GSH´¸MŘɿP FRET žͥĊ

í/T$2 ̋03LRq©°´¸mϦ˩=$ɿ&O˖̧͉qª¸¶|mŐ͊M=E%qª¸¶|RȴĄPȋĪ=$ϖĶ³МφϖĶʔ̦НRΛ͙

Pfi R-SnSH ̽RƈʱRɿƝmŐʹĶ?i9MPȋĪ=E%^E$R-SnSH ʾǛRƦϙ0fW$̧͉
R̐ЌRψ-Pfi R-SnSH ʾǛRψ-mŐʹĶ?i9Mbχȋ=E%;gP$ĢιR GSH´¸Më˘?i9ML$˖̧͉ÂLR GSH M R-SnSH ʾǛR˳Ϩc$,iğʽPƶ?i GSH O-=S R-SnSH
RʾǛƋİRˌ̖ǻmΏɰ?i9MPȋĪ=E%9jgS-@jb¿˞ĚR̬ɬL,h$R-SnSH ̽R˖̧͉ÂLRʃ͊ͷɌPƐ35ư¾?ibRMɞǪ;ji%
5.  ; 8 +ʥǻqvr̐R}¨w²qv´¸SɇρɚʈRĴ-Lρƿ=K-iɃ=-ĘϘL,i¹ɄL$ͥĊ´¸Ϧ˩˸̕SǫjmŌHK-iR2˒ˋL,i%ɢ˸̕S$CRf.OĘϘʁɂž˸̕P

˖>Ez¬

mƐ35ſaiЀɃˬOȋɬL,iMɞǪ=K-i%^EŘɐP$ɢ˸̕SbRJ5hRĶƠRͶˀ1gbЀɃˬOρƿ2,h$ʖɴПʖϽƝǔͪŊǶm«¸M=EɃ=-ͥĊ´¸ͽͺʟM-.$ɿ&O˖çēƻĘƝRŐλˬŐʹĶmχȋ?iɃ=-oqpombEg?9M
2L3E%CjSV-KS$'Ƀ=-ĘƝͽͺʟ2Ƀ=-Ƕ˘mŐ͊P?i(M-.ĢíPůljO͖͜ˬ˸̕m͇`ƖíM=K$ǫRƏ5R˸̕PΝˎ?i9MmɞǪ=K-i%İĴ ɢ˸̕S$ɨÒƐƠƐƠϯ͡Ơ̢СĺƠ̢˸̊̕ ʪϘʢ˅ȼȧR˸̕ƪPKͨljEbRL?%
ɇЃfhƏƐOi:ȷȰ$ĭ͹mΣh^=EʪϘʢ˅ȼȧ0fW̄Θ˴ƝΓǎPȆΔm˜=»8^?%^E$ɛʃŖȋRėɧiͅЛ̊ĺRŗ˙ɋŒΓǎМɨÒƐƠĺƠϑНRǮŀĩmS>a$ʪϘ˸̕ƪRƏ5RɄ&R¦¸PǲfhȆΔ-E=^?%
ěÕý
[1]

T. V. Mishanina, M. Libiad, R. Banerjee, Nat. Chem. Biol. 2015, 11, 457-464.

[2]

M. C. H. Gruhlke, A. J. Slusarenko, Plant Phys. Biochem. 2012, 59, 98-107.

[3]a) X. Chen, Y. Zhou, X. Peng, J. Yoon, Chem. Soc. Rev. 2010, 39, 2120-2135; b) V. S. Lin, W. Chen, M. Xian, C.

[4]a) S. Kenmoku, Y. Urano, H. Kojima, T. Nagano, J. Am. Chem. Soc. 2007, 129, 7313-7318; b) M. Sakabe, D.

J. Chang, Chem. Soc. Rev. 2015.
Asanuma, M. Kamiya, R. J. Iwatate, K. Hanaoka, T. Terai, T. Nagano, Y. Urano, J. Am. Chem. Soc. 2013, 135,15

409-414.
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K. Umezawa, M. Yoshida, M. Kamiya, T. Yamasoba, Y. Urano, Nat. Chem. 2017, 9, 279-286.
T. Ida, T. Sawa, H. Ihara, Y. Tsuchiya, Y. Watanabe, Y. Kumagai, M. Suematsu, H. Motohashi, S. Fujii, T.

Matsunaga, M. Yamamoto, K. Ono, N. O. Devarie-Baez, M. Xian, J. M. Fukuto, T. Akaike, Proc. Natl. Acad. Sci. U. S. A
2014, 111, 7606-7611.

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1. -

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h$Ł̧͉˖ˉRϷŲS͹lT'TgTgOøÓRϷŲ(L,h$ŗ͉́2Ř>ă3Мí/Tt²z¸˖˗cċ˥Ƕ̜$όàƝR̯ȑONНm?iRPƶ=$Ə̧͉˖ˉLŞ͉̐:MP¾/gjE
ǩħ2ˢOh$ˊƦRʃ͊PˊĶ=E̬ɬ$̧͉ϷŲčçM=K˖ƞ·Ɲơ̸ɱRįː2»Ɋ?iR
L,i%o©·¨S 1776 ǕP'ƲaiŷƭRͱűSÖËRĘɺP,i(M-.ÄɈRŷƲΑm
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ČjK-E9MPOi%9RƏ̧͉˖ˉR'Ęɺ(mŐ͊P?iR2̧͉̐:MPˢOiόàƝ˩˒¸¶L,h$~©ÂRNRόàƝmĜ˘?i1mʙƦ?itsp{RʃɾL,i%
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DNA »F7LO5 DNA MďP{³v¸©mǥȋ?i¶¶{Υ»LbЈ̸PΧ9i9

M2θǕɌg1POHK3E%ˊP¶RĶƠ÷АМ́;ǫ÷АНS DNA R÷АPʑ[KƏɿL,i9M1g$¶÷А2όàƝ˩˒¸¶mͳƦ?iM-.'¶¸ÛΌ(bȭŪ;jK-i%ɢ̒LS$¶¸ÛΌmɹ΀?iEaP¶{ΥĶƠŖȋʟ2ɛ˘L,i˔˚mι[Eǫ$Ȍ&R˸̕ȋɬM˒ŻŌh̪nL-i˸̕PI-K̨Õ?i%
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i 2%¶{ΥĶƠŖȋʟS$¹͓ˬ

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˱ˬ¶{Υm˩˒;AKŰŋ?iɄʟMSƐ35ˢOh$ĶƠˬPŖȋ=E£

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M C ɡ̗vt²Ŝɛ£mŊǶ;Ai NCLМNative Chemical LigationН7 m˘-E%NCL LS Cys 2ǳЅPOi2$Ƒ˃R

H2A S Cys ʋƃmȟEO-Ea$π̬ŊǶǫ'͌˻ŊǶ(MŢTji°w²ŊǶm˘-K Cys ʋƃm Ala ʋƃPƋȮ 8 ?i9MLqpOčϤ H2A mǭE%ǭgjE H2A m˘-K H2A-H2B q§¸c{³v¸©R΂З̞ēĔɾȋmͨ-$±¶¶ H2A Mʃ͊2Ř̛L,i9Mm˼·=EМŵ 2BН% ʅP˼̖=E²¸m˘-Ḱ;ǫ÷АČh H2A mŖȋ=$CRˉ˔ĶƠˬǻΥR΁ðmͨHE%
3 ̐ЌRˢOí;ǫ÷АМ±¶ϖĶ Ser$ª²Ķ Lys$o²Ķ LysН2ƺČ;jE H2A 0f
W 57 ˡ˱R Tyr 2±¶ϖĶ;jE H2A mêͮ=E%9jgR÷АČh H2A m˘-K{³v¸©

mĔɾȋ=$CRˆƢƦǻm΁ð=EM9k$3 ̐ЌR÷АmȟI H2A Sˁ÷А H2A MŘ̛RȢİm
˾=ERPƶ=$±¶ϖĶ Tyr mȟI
H2A SˆƢƦǻ2Ɛ35ä¼?i9

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69, 923-960. 3) Shimko, JC.; North, JA.; Bruns, AN.; Poirier, MG.; Ottesen, JJ. J. Mol. Biol. 2011 408, 187-204. 4) Siman, P.; Karthikeyan,

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2017Ǖ12ɚ21ɇ˩ͨËıƾЬ101-8307 ɨÒϓļÙ˙Ĺ̄˙Жʜő1-5, ɇɢĶƠß˖çʃ͊ϨπĶƠϑß
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