足達 哲也 - 日本農芸化学会

 33 17 GPR120 GLP-1 !"#
YZ[\!S"]^_U`KaKbcde
$%&'()*+,
fLghHij@ klmHno456 GPR120
<pq&'>r%7=>?& r7s&'kl
mt\u[\vwxyST: (GLP-1) MN<OP
*+r%7z{|H&3)A GLP-1 }~klmt\u
-./0
G- (GPCR)
E b FGH€&KL8MN7OP;‚%
!"#$%&'()*+,-'./
&'KRT%ƒD+ „…†‡ˆ‰%&'Š‹Œ
01 23456789:%; GPCR <=>?*
H()*+'>A …†‡ŽŠ‹ŒH‘}’“”
+'@'>A BCD E b FGHIJ&KL8MN
•‡–/ —˜™š›œ7ž&'>Ÿ %}¡
7OP;Q (GPR40)1) 45FGHIJ&RSTM
'>A ¢r£ klmH¤¥4567¦§;
N7OP;Q (GPR41)2) <UV*+'>A WX
r%H¨¡' GLP-1 MN<©ª;|«|7¬­
1 1 d®L¯°±456¦§H.- GLP-1 MNˆ
A: a-LA ¦§²³H.- GLP-1 MNˆA ῎῎P´0.01 vs Vehicle.
B῍D: a6 (OA), a-LA .¨µ Vehicle (PEG400) ¦§H.- GLP-1 (B), Insulin (C) MNR¶\.¨µ·¸¹yST
¹\ySTº!» (DPPIV) “ˆ (D)A ῎῎P´0.01 vs Vehicle, ¼¼P´0.01 vs OA.
ῌ 5 ῌ
!"#$%
&'()*+,-./0123 a-45 $2
ῌ῏ῐ῍
8 C57BL/6J (a-LA) 6,./012789$2 (OA) : ;<=
῎ 2 >?@ABCDEFGH
A: a-LA IJKL>?BCMNOP Q GLP-1 QR (a), (c) >STQ4$2D ERK QR (b), (d) 3@ABCUV
WX (c), (d) (a), (b) YZ[\ ]^ GLP-1 QR>STQ4$2D ERK QR_`a b! : 100 mm.
B: c GLP-1 _`a>? GLP-1 >ST4$2D ERK _`aIde ῎῎Pf0.01 vs Vehicle, ggPf0.01 vs OA.
῎ 3 2 hijklmn>?>? a-LA IijkopO:
GLP-1 (A, D) q$r4$ (B, E) >STsit (C, F) uv C3H/He wxr (A῍C) ijk NSY wxr (D῍F) ῎῎Pf0.01
vs Vehicle, ggPf0.01 vs OA.
ῌ 6 ῌ
(vehicle) 400 !Cl"!'G
6/ ERK STLm<N BO
100 ml/min 100 nmol/g body weight 2E <!& HI a-LA !"& 2 =>?
15 NSY 3A*!'& $n#oLMN BO 3E
!
"#$%& $ GLP-1 '()
*
+
, -./0123
4%& 5
HI^CF6 a-LA !" GLP-1
GLP-1 '(5
6/ ERK 57!89:%;
Lpq<N& PN!$;)
*
LKr
<! 2 =>?@ NSY 3A* BC 40
aLde<N -& 2 =!'1 a-LA DE & F6!& $!'G
!"$#oLMN %s&'(F6
GLP-1 '()
*
+,
./0IQL& GLP-1 KPHt
uv!wrx)CLde<N4) y 1F6'
HI a-LA !; Vehicle !
J! GLP-1 KLMN BO 1A, BE& PQ
(P*z/{+|^}~,'(-.!€G
/I‚!ƒ„KM
1 OA '(R1MN; <
!& )
*
STUMN& PQ1 OA '(
… !& 0ƒ„†%r!@"& ƒ„‡1ˆ‰"
-Š‹2Œ3/hƒ„‡1Ž!‘S’-r
Vehicle 1MN; BO 1CE -&
GLP-1 VWX@YZ[YZ[\] IV
1) Itoh Y. et al., Nature, 422, 173῎176 (2003).
2) Xiong Y. et al., Proc. Natl. Acad. Sci. USA, 101, 1045῎50
(2004).
3) Hirasawa A. et al., Nat. Med., 11, 90῎94 (2005).
4) Adachi T. et al., Biochem Biophys Res. Commun., 340,
332῎337 (2006).
(DPPIV) ^C_`LMN;a (1D),
a-LA !$ GLP-1 bST1& GLP-1
V_`!U1c& K@aLd
e<N -8fg/hVi!"& a-LA GLP1 jKQ!k& H fg5 GLP-1
ῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌ
N'"& ¢:|+•;›£@ 8š
!"#$%
›| r/{+!1¤¥¦§+rUU¨
c <©1¤¥¦§ª& )
«¦¬­
4“”5•h–h|+–h— 67˜™
§'(& ®­§& ¯°±­§!²=& ³
´µ+¶/{+@b·3)
& *¸A¦*
8š›1œœ9žŸ +| raL¡
& ¹«*
|{º»>¼?hV@%;
& 1 )
«¦¬­'(¹«*
/h´µ
῍ 7 ῍
‚+u+…,'B†‡S ll<b L+…-HQ#$n;K'q%
n cˆK†
FjK‰.
Š/RDEC m$n;K"`$%'%‹Œ
'Ž01Š/H!ImH*`pK'q
SI; i1Ž0{|w2‘-OxyD
HA’5 ll<
3xy; K/01/23FjU“”
K •jK‰.Š/
‘–q /01/23F;< Streptomyces sp. TP-A0274 /01/23Fj})~8
/0 15 —})~p`'2) m˜™ •jK45'Š/})~ staO,
2 SI\]^I
staD, staP, staC 4 l;< m$` 4 l})~
6})~7š›‘p`89#$ 3 z˜'
1)
1
k!;
;< K252c H;<
Hœ9; n FjžŸ:;<53(5’
!"#$% &
'(
H StaO 6;¡ ¢¡
)*+,-./01/234 DNA 5
£:' ¤K ¥";<8.oVB
2678,9:;<=>?@A'BC
'% StaD ¦Kzb
¢¡£:
DE%F-.GHIJK L KM
2 =~H?(3u1 “¢3¡ (CPA)
N:'BOPHQ#$R;< SI
¦ i
A5§ P 450 Š/;< StaP H
6 T
UHMHV: W
CPA 2 —
¨8© aryl῍aryl ?(3
X .YZ[X \]^H_J
u1Kzq>¨ i$K?ª CPA ¢
`$ab LcdHe% fg;
¨K@« % 2 —¬¡AB¡am'˜
hJ% 2 iFjk!Kl%
“­®*A¯+,;< StaC ¬¡AB¡°
m$n;oVB"`$%'pqH r# st
K8±²CK@«¡/³~´µD¶ %·
u($ %!v&u(w
'xyKz
¸`$%3) mz˜K £:?(3u1
bFj{|'(H})~=>;*`pK'q m
Kƒ„¹¤|Eºl=~F 120 kDa »GŠ/;
$`jKzq€+53‚Fj%ƒ„
< StaD H n i°>¨AB¡1KH¼
e%
3 Streptomyces sp. TP-A0274 /01/23Fjk!
ῌ 8 ῌ
ῑ 500 kDa mna 4 ῐ@oGD%5
67"89 p StaD ijGSq8Z
rsD()*/,B,E)%rs(t)
@ue8Zv)AWw(J)x" yz{
|()}~/%&F CPA :€‚
%3ƒ"8 „… 4†9 8 ‡ˆ‰% Š
StaD G‹Œ"#mŽ῎6m
‘ ’“ῑ CPA :3%Y7F StaD ”GD%567%'89 $
^• Kcat/Kuncat 101.2 „250 mM IPA x– ) D
F CPA :3$< StaD xŽl7Fa—
%˜489
Š™š›ΐ&F StaD :œžŸ Z%
—89 ¡¢"8&
()*+,-./,:;3
StaD ῍£m ‹Œ"
#9 ¤¥ _` StaD :3 CPA ()*
4 ·¸ StaD & CPA 23Sq
¡rsD IPA ‘‚48 ·¸
StaD (60 nM) x³ 30¹ 30 Y()}~/³
CPA B/ HPLC ‚—9 8
StaD f#m CPA “ῑº»¼49
+,-./,ue P450StaP ῏@\
¦Ÿ 3ƒ"89 StaP I§ž P450 G
x o76¨©rsªO
«—¬— rs()*/,+­J)K®+,234
P450 ῍
¯%&F ()*+,-./,0123%
ῒ ῔!"#$
°6# P450 %±VW/
%&'#()*+,-./,01234%
D%567"85)9 ²³ StaD ῏@
\¦Ÿ X#m™šZ ^[\X#´
567%'89
µ567"8%¶f#9
CPA StaD 4)
References
()*+,-./,:;3$<=>?@A
BC) (CPA) D9 CPA ()*/,B,E)
&F:3GHStaD ῌIEJKL():;3MN
OD VioB PQRSTU6VW/G
D9 VioB X#EJKL();3῍
GIXD%"7Y7'#7'88Z
StaD &
[\ CPA :37]5
D'89 ^ _` abcdef StaD 1)
2)
H. Onaka, Actinomycetol, 20, 62῎71 (2006).
H. Onaka, S. Taniguchi, Y. Igarashi and T. Furumai, J.
Antibiot (Tokyo), 55, 1063῎71 (2002).
3) H. Onaka, S. Taniguchi, Y. Igarashi and T. Furumai,
Biosci. Biotechnol. Biochem., 67, 127῎38 (2003).
4) S. Asamizu, Y. Kato, Y. Igarashi and H. Onaka, Tetrahedron Lett., 48, 2923῎2926 (2007).
5) M. Makino, H. Sugimoto, Y. Shiro, S. Asamizu, H. Onaka
and S. Nagano, Proc. Natl. Acad. Sci. USA, 104, 11591῎
11596 (2007).
gh" defijgh'89 ^kl StaD YO
ῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌ
῍ 9 ῍
15 ῌ!"#$%
&''()*+,
-.
!"#$%&'
( )*+,-./#$%&01( (#/2345.6 78(
#9.:;#/
+ <)*+=.>( ?@AB%C.DE F
GH
I6 <!JK
C.DF
GHI!
"LM#$NBO %&P'&(QRS
BTL:L ?)U(#*2V/6 (0(+,F
-. ,(//.8(#GHWX%
Y:6
NMR ! p 3 = c :¼ p 3 j z Ÿa 8 GM 1 r x
٤ Z[ \T0]^_&8 ?_&1`=
2aabc3.d#/6 \T0e
4f567Y:g ?='8K(# X 9c
¥~HI QCM . Ÿ8
q7Tn¦*. Y
:.]<VJLe4Y:6 (0(<HY 67L
cl)L mM NSY:"IL CSI-MS .Y mM N
h;.
i<j=Y=.>k(#/V/<8l:
Sr§(I6 <H QCM .Yes67.j6
6 ?mSn@ABC Gb3 DoRpq]/#
7tK<801 T*
7t!'›K6
\T08BCRpqrE X 9c:L<
lu{¨HIlV"#/Id 8©u1H6 „
j=8sV"I't.FuI<8l:"I6 <j=67
‰v01‰8 67῍67BC T*
7t!
=.GvwHV-.8(# NMR .L:L e
"# 1000 wl'dªL«;V 8l¬u6
4
\T0 NMR .YYxJ5yz6 ?<
K NMR .!"#67efx=.>(I6 Y _&1`{gI(I16=.
|B%(#
8 p3 †XqyEjzY]{ ­|1/®¯ =
.Jd<8l:L <HY}K=LL~"#
."#/IL GM1 DoBCx e1 2 K=.
("Ig %n€MN‚Vƒ01?_&.
g }o®^YV2 Trp ~oqDVƒY›
NJ<8lOV2V/6 ?<YZ[ „ …PGV†X
/€=.8<8L60"I6 e4
\T0?
qNSY67BC;.l‡K .Qˆ( ?=
}K=.L°[[h;.
±8¬~H#
_&2a.>( ?R‰.
\T0h;ŠS
/6 ²³ 15 –D8/J/†XqEL}K=.
F‹ <8.TŒ(I6
<8.310YyI \T0=_&2a
UVŽ5W‘1 ’“XY.!
´d#‚µ¶VR‰8V8ƒ~H6 ²£ …D
"# ”R•DBC;.Z‡ 15 –D†XqE.Qˆ
o~BC=‹ .31088l =_&2a
( 3 [\]^_—K `ga˜b™(I6 +
G1/Š8SFY:6
Y ?=Ycš›/'d.Y 15 –D p3
† X q E (VWRLLAPPFSNRLLP) 8 GM 1 ” R • D
w£ +.„¥:Ig ·…c./I®y
(Galb1œ3GalNAcb1œ4(NeuAca2œ3)Galb1œ4Glcb1œ
†‡¸.ˆg(I¹‰.Š‹ºK†‡»Œ
1῎Cer) 67eff( 'ghc3.T(
Ž(a˜6
I6
ž CSI-MS . ŸWqXN”K0i6:
. !g p3 8 GM1 ”R•D¡j67Uk'l
).¢m(I6 ’“XY.Yno(I£¤yp/#
ῌ 10 ῌ
/0 12
1)
H. Shimizu, N. Fujitani, T. Ohta, N. Nagahori, Y. Komata, N. Miura, T. Matsubara, T. Sato, S.-I. Nishimura:
Glycoconjugate J., 22, 261 (2005).
2)
N. Fujitani, H. Shimizu, T. Matsubara, T. Ohta, Y. Komata, N. Miura, T. Sato, S.-I. Nishimura: Carbohydr. Res.,
Special Issue; Glycomimetics, 342, 1895 (2007).
*-5; <63=> Trp
6?@A=
B#$*-&%C(
9D@EFGH:*-5%IJK LMNO$( 15 $P$%H
15 :*-5 Q$( RS T6 7*U -
p3 GM1 !"#
2C/V *W X+, 2!"+
$
%&%'$( )& NMR ,Y#Z/$%(
GM1
[S &+, '(\])$3^_Q`*+
p3 *+,-.
( / p3 )0 12$
,abc+,-.d/e$Q_/(
34 *-5$% GM1 678 9 2 :
ῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌ
/
0fgh0c12cij3k412c5 H67l
!
m8S9nAo@
pqrq@ (OXT) )
s:
(OXTR) tuvrwt@Duvr-;$+,
xd.<=>.<?@&%
$( &+,-.ysAz
{BQ OXTR |C}~
D (Oxtr-/-) €vE.<Fm%21)( 9G
H‚ƒ
Oxtr-/-€v E=C2„IQ^
J1 (WT) €v…†K‡LMN%ˆ‰B
<1
2=C1)( &2 Š‹EŒ=>.< O
$PŽ$ EŒ OXTR %?@=}
ŒS¼ WT, Oxtr-/-Yk™€v £g„
J ªLS; ~« h¤¥iJ ªMPOA; m« Ž
c-Fos V˜WXbcuv(
&-Q$( )& &+,EŒ! =>
X‘Ž OXT/OXTR ’
Q^-2C/R
E.<$E=S/Œ “”.<Ž$
4
B
•
OXT/OXTR ’%Wb
C
Oxtr-/-&
A¨
c-Fos n©o
p% WT "
Qq=$r}%2 ªs 1«( & Š‹ Oxtr-/-
–
E.<Fm £g„J h¤¥iJ 3kW
T-.P&-RQ(
< Fm%¬­Q$&-®Q(
"#$%&'
73456 EŒIŒ€v%E=Y
2.
1.
(
)*+,-./ OXT/OXTR 01(
789%:; OXT/OXTR 01(2+,-
“”.<-/^ OXT/OXTR ’%L/4•
2+,-3456 E.<UM8 OXT/OXTR
-2C/R OXT c-Fos
’%L/4•-2C/R 3kW<
–T-.( 1S 7 ZR
— c-Fos
V˜WXbc–T-.( Y
k™€v (WT, Oxtr-/-)
š1S 1›3 Z
WT
t?V˜uv
C57BL/6J €v-E
=wxŒC2„IQ ¯y 34° ±y 85›90²
mt8!z{Q( ) S _` a-.4-bI
Œ€v- 5 ![ Œ K‡LMN_Ž$
Q OXT c-Fos
E.<UMœ-\ž( Œ€vY
|i_E=
}Q$€v-;$(
]^ZŸ 80
S_` a-.4-bIQ )¡ cd
$ c-Fos efG M¢-…†Q(
§-‹/&%m2 OXTR
M¢•V(
M¢-…†Q( µ@r¶A
E=„IQ€vŽ$ ¤¥~· c-Fos OXT
£g„J h¤¥iJE.<j¦gk=l
³´
t?uvn©o%>%¸/¹º%2
ªs 2«( & P=¹º»€·%¸/ OXT n
©o2=C( _ OXTR %M¢Q xd
῍ 11 ῍
/8! OXT CD1E93" OXT #
$4GB1. F Oxtr-/-G3
:1 c-Fos 17-3 HIIJK
JKLM
1GBB NL (OP!H
IIJGBMN1453 OQR1SP T /
.2
8!10 QR >12?3M451
3 C57BL/6J ",
H OXT ,¨ c-Fos ?F´µ)q@A ¶» "
(c-Fos) ¼A» ·¸‘ (OXT)
4GB1 UVW1XY
!STZ,HUVWMSTZX
Y1*B[H MY ZM[\
]^_`\]`^.3 KJa_
c-Fos M- `a1b2cd1efB STZgb!
PTSD 1*Bc NL !"
!*
GBdEMcd1eH fhi!
"+ OXT #$,- +./%
OXT #$%&'() gj,H OXT/OXTR Rhk1i
0&'
B T- 2jjkBlPMmnlnmo
npq+`0Zb
( )1*2 3
r8 fhi1sBT- hituo1v-
c-Fos 4 +56,
7
C3wxyz{p)qhitur|Ys}3C
-1. /8! 9:;<=%10
B
OXTR >121?3453 Oxtr-/-
@6A7B
189B
1)
C :;4 DE<E
OXT c-Fos =>?F@AGB1<H
Takayanagi, Y. et al.: Proc. Natl. Acad. Sci. U.S.A., 102,
16096῎16101 (2005).
ῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌῌ
1. #$% &'()
C‡ B-:‚:š›῎‘’“”'•1–œ—3
!"
0 lPM‰Š:‹'‰Z`00&MLy1˜
~t{udq`0vqv € ‚
B$k BM6x ™) g-ƒ<&š›œ#
: (1) 2 1’“”'•B- žžŸŸ1
9wxƒ! y„z( r…{†B
8 Lewis ¡¢•žž3£ž)‰1¤¥
ƒ| T xƒ}GB9w‡5~ˆ€
¦
9^_‚ƒ'*>† TiM
3 lPM‰Š:‹'—)40&M£¤' 5 1m£
Z 3 13-
¡§¡&¢1¨-
E U‰Z!Š[„‹!GiM 
¥%: 6 3 ©¦§Ž:¢1453 7 ,¨ 8 1 2 : 1
€9^_‚ƒ'!…ŒM!Ž(†‡ }s@M
ª@10- ©”ª_‚ƒ'—
ˆ1eH‰Z}‘ T
‰Z« ¬-­'®¯°‰£' (9) ›±
- U‰Zm’ ‰Z>12Gi- 9w“
<^'—‰Z« ¬-9bH-°-7,15-‰£'
”‡5~ˆ1•GB!‡F7–>†
(10) ‚²‰Zy1˜B$k
T
U 9w‰Š:‹'€9^_‚ƒ'—‰
Z1GiBŒ&%Ž3 ˜9w€9^
2. *+,%-!"
_‚ƒ'‰Š:‹'‰Zhi1 9w€9
^_‚ƒ'‰Z1GiB1™3
6y« ³± 11 ¬´­£Š%µ
(PLE) ®D¶¯:G]`- 90· e.e. ¸
¹°±²M 11 12 1 $k ! 6y«ºq(M 1 C 48 ³Ly
῍ 12 ῍
Scheme 1.
Scheme 2.
Scheme 3.
Synthesis of racemic diterpenes.
Preparation of the optically active intermediates.
Synthesis of cryptoquinone and 12-deoxyroyleanone.
ent-
(9) _ (1) & B-;_B_de῍fghiP6jklmn
T$ o&p&qrst1uvwxr^yz{
%!|} 12-@AB9CDE;F (15) &~€
3.
Cryptoquinone, 12-deoxyroyleannone ῌῒ῏ῑ
‚O6PQBF (16) &ƒ„
!"#$ %!&'"()*+,
…†‡
-#./012345#67897:
;<&=>'? 12-@AB9CDE;F (15) GHD
ῐ῎ῌΐ῍
I#1JKLMNL'O6PQBF
ˆ‰Š!‹#$ YZŒ_Ž
(16) &RST UVWXV$ YZVW[
&…0‘’{“” o”“&•–•
'\C]^;68_`a^ g-9OCbc]:
DIŒ_—˜DQ;EB9&™šz
ῌ 13 ῌ
!"#
$%& '()
*+,-./0123&
ῌ 14 ῌ