                         SEQUENCE LISTING

<110>  Pfizer Inc
       Bagley, Scott W
       Griffith, David A
       Kung, Daniel W.-S.
 
<120>  N2-Pyrazolospiroketone Acetyl-CoA Carboxylase Inhibitors

<130>  PC33983

<150>  61/259,831
<151>  2009-11-10

<160>  2     

<170>  PatentIn version 3.5

<210>  1
<211>  2356
<212>  PRT
<213>  Homo sapiens

<400>  1

Met Ala His His His His His His Asp Glu Val Asp Asp Glu Pro Ser 
1               5                   10                  15      


Pro Leu Ala Gln Pro Leu Glu Leu Asn Gln His Ser Arg Phe Ile Ile 
            20                  25                  30          


Gly Ser Val Ser Glu Asp Asn Ser Glu Asp Glu Ile Ser Asn Leu Val 
        35                  40                  45              


Lys Leu Asp Leu Leu Glu Lys Glu Gly Ser Leu Ser Pro Ala Ser Val 
    50                  55                  60                  


Gly Ser Asp Thr Leu Ser Asp Leu Gly Ile Ser Ser Leu Gln Asp Gly 
65                  70                  75                  80  


Leu Ala Leu His Ile Arg Ser Ser Met Ser Gly Leu His Leu Val Lys 
                85                  90                  95      


Gln Gly Arg Asp Arg Lys Lys Ile Asp Ser Gln Arg Asp Phe Thr Val 
            100                 105                 110         


Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Lys Val Ile 
        115                 120                 125             


Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Cys Met 
    130                 135                 140                 


Arg Ser Ile Arg Arg Trp Ser Tyr Glu Met Phe Arg Asn Glu Arg Ala 
145                 150                 155                 160 


Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn Ala 
                165                 170                 175     


Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val Pro Gly Gly Pro 
            180                 185                 190         


Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Leu Asp Ile Ala Lys 
        195                 200                 205             


Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser Glu 
    210                 215                 220                 


Asn Pro Lys Leu Pro Glu Leu Leu Leu Lys Asn Gly Ile Ala Phe Met 
225                 230                 235                 240 


Gly Pro Pro Ser Gln Ala Met Trp Ala Leu Gly Asp Lys Ile Ala Ser 
                245                 250                 255     


Ser Ile Val Ala Gln Thr Ala Gly Ile Pro Thr Leu Pro Trp Ser Gly 
            260                 265                 270         


Ser Gly Leu Arg Val Asp Trp Gln Glu Asn Asp Phe Ser Lys Arg Ile 
        275                 280                 285             


Leu Asn Val Pro Gln Glu Leu Tyr Glu Lys Gly Tyr Val Lys Asp Val 
    290                 295                 300                 


Asp Asp Gly Leu Gln Ala Ala Glu Glu Val Gly Tyr Pro Val Met Ile 
305                 310                 315                 320 


Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Lys Val Asn Asn 
                325                 330                 335     


Ala Asp Asp Phe Pro Asn Leu Phe Arg Gln Val Gln Ala Glu Val Pro 
            340                 345                 350         


Gly Ser Pro Ile Phe Val Met Arg Leu Ala Lys Gln Ser Arg His Leu 
        355                 360                 365             


Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn Ala Ile Ser Leu Phe 
    370                 375                 380                 


Gly Arg Asp Cys Ser Val Gln Arg Arg His Gln Lys Ile Ile Glu Glu 
385                 390                 395                 400 


Ala Pro Ala Thr Ile Ala Thr Pro Ala Val Phe Glu His Met Glu Gln 
                405                 410                 415     


Cys Ala Val Lys Leu Ala Lys Met Val Gly Tyr Val Ser Ala Gly Thr 
            420                 425                 430         


Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe Tyr Phe Leu Glu Leu 
        435                 440                 445             


Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Val Ala Asp 
    450                 455                 460                 


Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Ile Pro Leu 
465                 470                 475                 480 


Tyr Arg Ile Lys Asp Ile Arg Met Met Tyr Gly Val Ser Pro Trp Gly 
                485                 490                 495     


Asp Ser Pro Ile Asp Phe Glu Asp Ser Ala His Val Pro Cys Pro Arg 
            500                 505                 510         


Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp Glu Gly 
        515                 520                 525             


Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg Ser Asn 
    530                 535                 540                 


Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly Leu His 
545                 550                 555                 560 


Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe Ser Trp Gly Glu Asn 
                565                 570                 575     


Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu Leu Ser 
            580                 585                 590         


Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Ile Lys Leu Leu 
        595                 600                 605             


Glu Thr Glu Ser Phe Gln Met Asn Arg Ile Asp Thr Gly Trp Leu Asp 
    610                 615                 620                 


Arg Leu Ile Ala Glu Lys Val Gln Ala Glu Arg Pro Asp Thr Met Leu 
625                 630                 635                 640 


Gly Val Val Cys Gly Ala Leu His Val Ala Asp Val Ser Leu Arg Asn 
                645                 650                 655     


Ser Val Ser Asn Phe Leu His Ser Leu Glu Arg Gly Gln Val Leu Pro 
            660                 665                 670         


Ala His Thr Leu Leu Asn Thr Val Asp Val Glu Leu Ile Tyr Glu Gly 
        675                 680                 685             


Val Lys Tyr Val Leu Lys Val Thr Arg Gln Ser Pro Asn Ser Tyr Val 
    690                 695                 700                 


Val Ile Met Asn Gly Ser Cys Val Glu Val Asp Val His Arg Leu Ser 
705                 710                 715                 720 


Asp Gly Gly Leu Leu Leu Ser Tyr Asp Gly Ser Ser Tyr Thr Thr Tyr 
                725                 730                 735     


Met Lys Glu Glu Val Asp Arg Tyr Arg Ile Thr Ile Gly Asn Lys Thr 
            740                 745                 750         


Cys Val Phe Glu Lys Glu Asn Asp Pro Ser Val Met Arg Ser Pro Ser 
        755                 760                 765             


Ala Gly Lys Leu Ile Gln Tyr Ile Val Glu Asp Gly Gly His Val Phe 
    770                 775                 780                 


Ala Gly Gln Cys Tyr Ala Glu Ile Glu Val Met Lys Met Val Met Thr 
785                 790                 795                 800 


Leu Thr Ala Val Glu Ser Gly Cys Ile His Tyr Val Lys Arg Pro Gly 
                805                 810                 815     


Ala Ala Leu Asp Pro Gly Cys Val Leu Ala Lys Met Gln Leu Asp Asn 
            820                 825                 830         


Pro Ser Lys Val Gln Gln Ala Glu Leu His Thr Gly Ser Leu Pro Arg 
        835                 840                 845             


Ile Gln Ser Thr Ala Leu Arg Gly Glu Lys Leu His Arg Val Phe His 
    850                 855                 860                 


Tyr Val Leu Asp Asn Leu Val Asn Val Met Asn Gly Tyr Cys Leu Pro 
865                 870                 875                 880 


Asp Pro Phe Phe Ser Ser Lys Val Lys Asp Trp Val Glu Arg Leu Met 
                885                 890                 895     


Lys Thr Leu Arg Asp Pro Ser Leu Pro Leu Leu Glu Leu Gln Asp Ile 
            900                 905                 910         


Met Thr Ser Val Ser Gly Arg Ile Pro Pro Asn Val Glu Lys Ser Ile 
        915                 920                 925             


Lys Lys Glu Met Ala Gln Tyr Ala Ser Asn Ile Thr Ser Val Leu Cys 
    930                 935                 940                 


Gln Phe Pro Ser Gln Gln Ile Ala Asn Ile Leu Asp Ser His Ala Ala 
945                 950                 955                 960 


Thr Leu Asn Arg Lys Ser Glu Arg Glu Val Phe Phe Met Asn Thr Gln 
                965                 970                 975     


Ser Ile Val Gln Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly His 
            980                 985                 990         


Met Lys Ala Val Val Met Asp Leu  Leu Arg Gln Tyr Leu  Arg Val Glu 
        995                 1000                 1005             


Thr Gln  Phe Gln Asn Gly His  Tyr Asp Lys Cys Val  Phe Ala Leu 
    1010                 1015                 1020             


Arg Glu  Glu Asn Lys Ser Asp  Met Asn Thr Val Leu  Asn Tyr Ile 
    1025                 1030                 1035             


Phe Ser  His Ala Gln Val Thr  Lys Lys Asn Leu Leu  Val Thr Met 
    1040                 1045                 1050             


Leu Ile  Asp Gln Leu Cys Gly  Arg Asp Pro Thr Leu  Thr Asp Glu 
    1055                 1060                 1065             


Leu Leu  Asn Ile Leu Thr Glu  Leu Thr Gln Leu Ser  Lys Thr Thr 
    1070                 1075                 1080             


Asn Ala  Lys Val Ala Leu Arg  Ala Arg Gln Val Leu  Ile Ala Ser 
    1085                 1090                 1095             


His Leu  Pro Ser Tyr Glu Leu  Arg His Asn Gln Val  Glu Ser Ile 
    1100                 1105                 1110             


Phe Leu  Ser Ala Ile Asp Met  Tyr Gly His Gln Phe  Cys Ile Glu 
    1115                 1120                 1125             


Asn Leu  Gln Lys Leu Ile Leu  Ser Glu Thr Ser Ile  Phe Asp Val 
    1130                 1135                 1140             


Leu Pro  Asn Phe Phe Tyr His  Ser Asn Gln Val Val  Arg Met Ala 
    1145                 1150                 1155             


Ala Leu  Glu Val Tyr Val Arg  Arg Ala Tyr Ile Ala  Tyr Glu Leu 
    1160                 1165                 1170             


Asn Ser  Val Gln His Arg Gln  Leu Lys Asp Asn Thr  Cys Val Val 
    1175                 1180                 1185             


Glu Phe  Gln Phe Met Leu Pro  Thr Ser His Pro Asn  Arg Gly Asn 
    1190                 1195                 1200             


Ile Pro  Thr Leu Asn Arg Met  Ser Phe Ser Ser Asn  Leu Asn His 
    1205                 1210                 1215             


Tyr Gly  Met Thr His Val Ala  Ser Val Ser Asp Val  Leu Leu Asp 
    1220                 1225                 1230             


Asn Ser  Phe Thr Pro Pro Cys  Gln Arg Met Gly Gly  Met Val Ser 
    1235                 1240                 1245             


Phe Arg  Thr Phe Glu Asp Phe  Val Arg Ile Phe Asp  Glu Val Met 
    1250                 1255                 1260             


Gly Cys  Phe Ser Asp Ser Pro  Pro Gln Ser Pro Thr  Phe Pro Glu 
    1265                 1270                 1275             


Ala Gly  His Thr Ser Leu Tyr  Asp Glu Asp Lys Val  Pro Arg Asp 
    1280                 1285                 1290             


Glu Pro  Ile His Ile Leu Asn  Val Ala Ile Lys Thr  Asp Cys Asp 
    1295                 1300                 1305             


Ile Glu  Asp Asp Arg Leu Ala  Ala Met Phe Arg Glu  Phe Thr Gln 
    1310                 1315                 1320             


Gln Asn  Lys Ala Thr Leu Val  Asp His Gly Ile Arg  Arg Leu Thr 
    1325                 1330                 1335             


Phe Leu  Val Ala Gln Lys Asp  Phe Arg Lys Gln Val  Asn Tyr Glu 
    1340                 1345                 1350             


Val Asp  Arg Arg Phe His Arg  Glu Phe Pro Lys Phe  Phe Thr Phe 
    1355                 1360                 1365             


Arg Ala  Arg Asp Lys Phe Glu  Glu Asp Arg Ile Tyr  Arg His Leu 
    1370                 1375                 1380             


Glu Pro  Ala Leu Ala Phe Gln  Leu Glu Leu Asn Arg  Met Arg Asn 
    1385                 1390                 1395             


Phe Asp  Leu Thr Ala Ile Pro  Cys Ala Asn His Lys  Met His Leu 
    1400                 1405                 1410             


Tyr Leu  Gly Ala Ala Lys Val  Glu Val Gly Thr Glu  Val Thr Asp 
    1415                 1420                 1425             


Tyr Arg  Phe Phe Val Arg Ala  Ile Ile Arg His Ser  Asp Leu Val 
    1430                 1435                 1440             


Thr Lys  Glu Ala Ser Phe Glu  Tyr Leu Gln Asn Glu  Gly Glu Arg 
    1445                 1450                 1455             


Leu Leu  Leu Glu Ala Met Asp  Glu Leu Glu Val Ala  Phe Asn Asn 
    1460                 1465                 1470             


Thr Asn  Val Arg Thr Asp Cys  Asn His Ile Phe Leu  Asn Phe Val 
    1475                 1480                 1485             


Pro Thr  Val Ile Met Asp Pro  Ser Lys Ile Glu Glu  Ser Val Arg 
    1490                 1495                 1500             


Ser Met  Val Met Arg Tyr Gly  Ser Arg Leu Trp Lys  Leu Arg Val 
    1505                 1510                 1515             


Leu Gln  Ala Glu Leu Lys Ile  Asn Ile Arg Leu Thr  Pro Thr Gly 
    1520                 1525                 1530             


Lys Ala  Ile Pro Ile Arg Leu  Phe Leu Thr Asn Glu  Ser Gly Tyr 
    1535                 1540                 1545             


Tyr Leu  Asp Ile Ser Leu Tyr  Lys Glu Val Thr Asp  Ser Arg Thr 
    1550                 1555                 1560             


Ala Gln  Ile Met Phe Gln Ala  Tyr Gly Asp Lys Gln  Gly Pro Leu 
    1565                 1570                 1575             


His Gly  Met Leu Ile Asn Thr  Pro Tyr Val Thr Lys  Asp Leu Leu 
    1580                 1585                 1590             


Gln Ser  Lys Arg Phe Gln Ala  Gln Ser Leu Gly Thr  Thr Tyr Ile 
    1595                 1600                 1605             


Tyr Asp  Ile Pro Glu Met Phe  Arg Gln Ser Leu Ile  Lys Leu Trp 
    1610                 1615                 1620             


Glu Ser  Met Ser Thr Gln Ala  Phe Leu Pro Ser Pro  Pro Leu Pro 
    1625                 1630                 1635             


Ser Asp  Met Leu Thr Tyr Thr  Glu Leu Val Leu Asp  Asp Gln Gly 
    1640                 1645                 1650             


Gln Leu  Val His Met Asn Arg  Leu Pro Gly Gly Asn  Glu Ile Gly 
    1655                 1660                 1665             


Met Val  Ala Trp Lys Met Thr  Phe Lys Ser Pro Glu  Tyr Pro Glu 
    1670                 1675                 1680             


Gly Arg  Asp Ile Ile Val Ile  Gly Asn Asp Ile Thr  Tyr Arg Ile 
    1685                 1690                 1695             


Gly Ser  Phe Gly Pro Gln Glu  Asp Leu Leu Phe Leu  Arg Ala Ser 
    1700                 1705                 1710             


Glu Leu  Ala Arg Ala Glu Gly  Ile Pro Arg Ile Tyr  Val Ser Ala 
    1715                 1720                 1725             


Asn Ser  Gly Ala Arg Ile Gly  Leu Ala Glu Glu Ile  Arg His Met 
    1730                 1735                 1740             


Phe His  Val Ala Trp Val Asp  Pro Glu Asp Pro Tyr  Lys Gly Tyr 
    1745                 1750                 1755             


Arg Tyr  Leu Tyr Leu Thr Pro  Gln Asp Tyr Lys Arg  Val Ser Ala 
    1760                 1765                 1770             


Leu Asn  Ser Val His Cys Glu  His Val Glu Asp Glu  Gly Glu Ser 
    1775                 1780                 1785             


Arg Tyr  Lys Ile Thr Asp Ile  Ile Gly Lys Glu Glu  Gly Ile Gly 
    1790                 1795                 1800             


Pro Glu  Asn Leu Arg Gly Ser  Gly Met Ile Ala Gly  Glu Ser Ser 
    1805                 1810                 1815             


Leu Ala  Tyr Asn Glu Ile Ile  Thr Ile Ser Leu Val  Thr Cys Arg 
    1820                 1825                 1830             


Ala Ile  Gly Ile Gly Ala Tyr  Leu Val Arg Leu Gly  Gln Arg Thr 
    1835                 1840                 1845             


Ile Gln  Val Glu Asn Ser His  Leu Ile Leu Thr Gly  Ala Gly Ala 
    1850                 1855                 1860             


Leu Asn  Lys Val Leu Gly Arg  Glu Val Tyr Thr Ser  Asn Asn Gln 
    1865                 1870                 1875             


Leu Gly  Gly Ile Gln Ile Met  His Asn Asn Gly Val  Thr His Cys 
    1880                 1885                 1890             


Thr Val  Cys Asp Asp Phe Glu  Gly Val Phe Thr Val  Leu His Trp 
    1895                 1900                 1905             


Leu Ser  Tyr Met Pro Lys Ser  Val His Ser Ser Val  Pro Leu Leu 
    1910                 1915                 1920             


Asn Ser  Lys Asp Pro Ile Asp  Arg Ile Ile Glu Phe  Val Pro Thr 
    1925                 1930                 1935             


Lys Thr  Pro Tyr Asp Pro Arg  Trp Met Leu Ala Gly  Arg Pro His 
    1940                 1945                 1950             


Pro Thr  Gln Lys Gly Gln Trp  Leu Ser Gly Phe Phe  Asp Tyr Gly 
    1955                 1960                 1965             


Ser Phe  Ser Glu Ile Met Gln  Pro Trp Ala Gln Thr  Val Val Val 
    1970                 1975                 1980             


Gly Arg  Ala Arg Leu Gly Gly  Ile Pro Val Gly Val  Val Ala Val 
    1985                 1990                 1995             


Glu Thr  Arg Thr Val Glu Leu  Ser Ile Pro Ala Asp  Pro Ala Asn 
    2000                 2005                 2010             


Leu Asp  Ser Glu Ala Lys Ile  Ile Gln Gln Ala Gly  Gln Val Trp 
    2015                 2020                 2025             


Phe Pro  Asp Ser Ala Phe Lys  Thr Tyr Gln Ala Ile  Lys Asp Phe 
    2030                 2035                 2040             


Asn Arg  Glu Gly Leu Pro Leu  Met Val Phe Ala Asn  Trp Arg Gly 
    2045                 2050                 2055             


Phe Ser  Gly Gly Met Lys Asp  Met Tyr Asp Gln Val  Leu Lys Phe 
    2060                 2065                 2070             


Gly Ala  Tyr Ile Val Asp Gly  Leu Arg Glu Cys Cys  Gln Pro Val 
    2075                 2080                 2085             


Leu Val  Tyr Ile Pro Pro Gln  Ala Glu Leu Arg Gly  Gly Ser Trp 
    2090                 2095                 2100             


Val Val  Ile Asp Ser Ser Ile  Asn Pro Arg His Met  Glu Met Tyr 
    2105                 2110                 2115             


Ala Asp  Arg Glu Ser Arg Gly  Ser Val Leu Glu Pro  Glu Gly Thr 
    2120                 2125                 2130             


Val Glu  Ile Lys Phe Arg Arg  Lys Asp Leu Val Lys  Thr Met Arg 
    2135                 2140                 2145             


Arg Val  Asp Pro Val Tyr Ile  His Leu Ala Glu Arg  Leu Gly Thr 
    2150                 2155                 2160             


Pro Glu  Leu Ser Thr Ala Glu  Arg Lys Glu Leu Glu  Asn Lys Leu 
    2165                 2170                 2175             


Lys Glu  Arg Glu Glu Phe Leu  Ile Pro Ile Tyr His  Gln Val Ala 
    2180                 2185                 2190             


Val Gln  Phe Ala Asp Leu His  Asp Thr Pro Gly Arg  Met Gln Glu 
    2195                 2200                 2205             


Lys Gly  Val Ile Ser Asp Ile  Leu Asp Trp Lys Thr  Ser Arg Thr 
    2210                 2215                 2220             


Phe Phe  Tyr Trp Arg Leu Arg  Arg Leu Leu Leu Glu  Asp Leu Val 
    2225                 2230                 2235             


Lys Lys  Lys Ile His Asn Ala  Asn Pro Glu Leu Thr  Asp Gly Gln 
    2240                 2245                 2250             


Ile Gln  Ala Met Leu Arg Arg  Trp Phe Val Glu Val  Glu Gly Thr 
    2255                 2260                 2265             


Val Lys  Ala Tyr Val Trp Asp  Asn Asn Lys Asp Leu  Ala Glu Trp 
    2270                 2275                 2280             


Leu Glu  Lys Gln Leu Thr Glu  Glu Asp Gly Val His  Ser Val Ile 
    2285                 2290                 2295             


Glu Glu  Asn Ile Lys Cys Ile  Ser Arg Asp Tyr Val  Leu Lys Gln 
    2300                 2305                 2310             


Ile Arg  Ser Leu Val Gln Ala  Asn Pro Glu Val Ala  Met Asp Ser 
    2315                 2320                 2325             


Ile Ile  His Met Thr Gln His  Ile Ser Pro Thr Gln  Arg Ala Glu 
    2330                 2335                 2340             


Val Ile  Arg Ile Leu Ser Thr  Met Asp Ser Pro Ser  Thr 
    2345                 2350                 2355     


<210>  2
<211>  2458
<212>  PRT
<213>  Homo sapiens

<400>  2

Met Val Leu Leu Leu Cys Leu Ser Cys Leu Ile Phe Ser Cys Leu Thr 
1               5                   10                  15      


Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 
            20                  25                  30          


Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 
        35                  40                  45              


Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 
    50                  55                  60                  


His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 
65                  70                  75                  80  


Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 
                85                  90                  95      


Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 
            100                 105                 110         


Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 
        115                 120                 125             


Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 
    130                 135                 140                 


Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 
145                 150                 155                 160 


Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 
                165                 170                 175     


Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 
            180                 185                 190         


Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 
        195                 200                 205             


Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 
    210                 215                 220                 


His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 
225                 230                 235                 240 


Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly 
                245                 250                 255     


Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 
            260                 265                 270         


Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 
        275                 280                 285             


Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 
    290                 295                 300                 


Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 
305                 310                 315                 320 


Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 
                325                 330                 335     


Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly 
            340                 345                 350         


His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 
        355                 360                 365             


Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 
    370                 375                 380                 


Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 
385                 390                 395                 400 


Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 
                405                 410                 415     


Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 
            420                 425                 430         


Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 
        435                 440                 445             


Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 
    450                 455                 460                 


Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 
465                 470                 475                 480 


Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 
                485                 490                 495     


His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 
            500                 505                 510         


Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 
        515                 520                 525             


Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 
    530                 535                 540                 


Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 
545                 550                 555                 560 


Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 
                565                 570                 575     


His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 
            580                 585                 590         


Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 
        595                 600                 605             


Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 
    610                 615                 620                 


Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 
625                 630                 635                 640 


Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu 
                645                 650                 655     


Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 
            660                 665                 670         


Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 
        675                 680                 685             


Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 
    690                 695                 700                 


Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 
705                 710                 715                 720 


Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 
                725                 730                 735     


Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp 
            740                 745                 750         


Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 
        755                 760                 765             


Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 
    770                 775                 780                 


Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg 
785                 790                 795                 800 


Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 
                805                 810                 815     


Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 
            820                 825                 830         


Leu Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp 
        835                 840                 845             


Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 
    850                 855                 860                 


Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 
865                 870                 875                 880 


Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 
                885                 890                 895     


Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 
            900                 905                 910         


Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 
        915                 920                 925             


Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 
    930                 935                 940                 


Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 
945                 950                 955                 960 


Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 
                965                 970                 975     


Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 
            980                 985                 990         


His Gln Val Phe His Ser Val Leu  Glu Asn Leu Thr Asn  Val Met Ser 
        995                 1000                 1005             


Gly Phe  Cys Leu Pro Glu Pro  Val Phe Ser Ile Lys  Leu Lys Glu 
    1010                 1015                 1020             


Trp Val  Gln Lys Leu Met Met  Thr Leu Arg His Pro  Ser Leu Pro 
    1025                 1030                 1035             


Leu Leu  Glu Leu Gln Glu Ile  Met Thr Ser Val Ala  Gly Arg Ile 
    1040                 1045                 1050             


Pro Ala  Pro Val Glu Lys Ser  Val Arg Arg Val Met  Ala Gln Tyr 
    1055                 1060                 1065             


Ala Ser  Asn Ile Thr Ser Val  Leu Cys Gln Phe Pro  Ser Gln Gln 
    1070                 1075                 1080             


Ile Ala  Thr Ile Leu Asp Cys  His Ala Ala Thr Leu  Gln Arg Lys 
    1085                 1090                 1095             


Ala Asp  Arg Glu Val Phe Phe  Ile Asn Thr Gln Ser  Ile Val Gln 
    1100                 1105                 1110             


Leu Val  Gln Arg Tyr Arg Ser  Gly Ile Arg Gly Tyr  Met Lys Thr 
    1115                 1120                 1125             


Val Val  Leu Asp Leu Leu Arg  Arg Tyr Leu Arg Val  Glu His His 
    1130                 1135                 1140             


Phe Gln  Gln Ala His Tyr Asp  Lys Cys Val Ile Asn  Leu Arg Glu 
    1145                 1150                 1155             


Gln Phe  Lys Pro Asp Met Ser  Gln Val Leu Asp Cys  Ile Phe Ser 
    1160                 1165                 1170             


His Ala  Gln Val Ala Lys Lys  Asn Gln Leu Val Ile  Met Leu Ile 
    1175                 1180                 1185             


Asp Glu  Leu Cys Gly Pro Asp  Pro Ser Leu Ser Asp  Glu Leu Ile 
    1190                 1195                 1200             


Ser Ile  Leu Asn Glu Leu Thr  Gln Leu Ser Lys Ser  Glu His Cys 
    1205                 1210                 1215             


Lys Val  Ala Leu Arg Ala Arg  Gln Ile Leu Ile Ala  Ser His Leu 
    1220                 1225                 1230             


Pro Ser  Tyr Glu Leu Arg His  Asn Gln Val Glu Ser  Ile Phe Leu 
    1235                 1240                 1245             


Ser Ala  Ile Asp Met Tyr Gly  His Gln Phe Cys Pro  Glu Asn Leu 
    1250                 1255                 1260             


Lys Lys  Leu Ile Leu Ser Glu  Thr Thr Ile Phe Asp  Val Leu Pro 
    1265                 1270                 1275             


Thr Phe  Phe Tyr His Ala Asn  Lys Val Val Cys Met  Ala Ser Leu 
    1280                 1285                 1290             


Glu Val  Tyr Val Arg Arg Gly  Tyr Ile Ala Tyr Glu  Leu Asn Ser 
    1295                 1300                 1305             


Leu Gln  His Arg Gln Leu Pro  Asp Gly Thr Cys Val  Val Glu Phe 
    1310                 1315                 1320             


Gln Phe  Met Leu Pro Ser Ser  His Pro Asn Arg Met  Thr Val Pro 
    1325                 1330                 1335             


Ile Ser  Ile Thr Asn Pro Asp  Leu Leu Arg His Ser  Thr Glu Leu 
    1340                 1345                 1350             


Phe Met  Asp Ser Gly Phe Ser  Pro Leu Cys Gln Arg  Met Gly Ala 
    1355                 1360                 1365             


Met Val  Ala Phe Arg Arg Phe  Glu Asp Phe Thr Arg  Asn Phe Asp 
    1370                 1375                 1380             


Glu Val  Ile Ser Cys Phe Ala  Asn Val Pro Lys Asp  Thr Pro Leu 
    1385                 1390                 1395             


Phe Ser  Glu Ala Arg Thr Ser  Leu Tyr Ser Glu Asp  Asp Cys Lys 
    1400                 1405                 1410             


Ser Leu  Arg Glu Glu Pro Ile  His Ile Leu Asn Val  Ser Ile Gln 
    1415                 1420                 1425             


Cys Ala  Asp His Leu Glu Asp  Glu Ala Leu Val Pro  Ile Leu Arg 
    1430                 1435                 1440             


Thr Phe  Val Gln Ser Lys Lys  Asn Ile Leu Val Asp  Tyr Gly Leu 
    1445                 1450                 1455             


Arg Arg  Ile Thr Phe Leu Ile  Ala Gln Glu Lys Glu  Phe Pro Lys 
    1460                 1465                 1470             


Phe Phe  Thr Phe Arg Ala Arg  Asp Glu Phe Ala Glu  Asp Arg Ile 
    1475                 1480                 1485             


Tyr Arg  His Leu Glu Pro Ala  Leu Ala Phe Gln Leu  Glu Leu Asn 
    1490                 1495                 1500             


Arg Met  Arg Asn Phe Asp Leu  Thr Ala Val Pro Cys  Ala Asn His 
    1505                 1510                 1515             


Lys Met  His Leu Tyr Leu Gly  Ala Ala Lys Val Lys  Glu Gly Val 
    1520                 1525                 1530             


Glu Val  Thr Asp His Arg Phe  Phe Ile Arg Ala Ile  Ile Arg His 
    1535                 1540                 1545             


Ser Asp  Leu Ile Thr Lys Glu  Ala Ser Phe Glu Tyr  Leu Gln Asn 
    1550                 1555                 1560             


Glu Gly  Glu Arg Leu Leu Leu  Glu Ala Met Asp Glu  Leu Glu Val 
    1565                 1570                 1575             


Ala Phe  Asn Asn Thr Ser Val  Arg Thr Asp Cys Asn  His Ile Phe 
    1580                 1585                 1590             


Leu Asn  Phe Val Pro Thr Val  Ile Met Asp Pro Phe  Lys Ile Glu 
    1595                 1600                 1605             


Glu Ser  Val Arg Tyr Met Val  Met Arg Tyr Gly Ser  Arg Leu Trp 
    1610                 1615                 1620             


Lys Leu  Arg Val Leu Gln Ala  Glu Val Lys Ile Asn  Ile Arg Gln 
    1625                 1630                 1635             


Thr Thr  Thr Gly Ser Ala Val  Pro Ile Arg Leu Phe  Ile Thr Asn 
    1640                 1645                 1650             


Glu Ser  Gly Tyr Tyr Leu Asp  Ile Ser Leu Tyr Lys  Glu Val Thr 
    1655                 1660                 1665             


Asp Ser  Arg Ser Gly Asn Ile  Met Phe His Ser Phe  Gly Asn Lys 
    1670                 1675                 1680             


Gln Gly  Pro Gln His Gly Met  Leu Ile Asn Thr Pro  Tyr Val Thr 
    1685                 1690                 1695             


Lys Asp  Leu Leu Gln Ala Lys  Arg Phe Gln Ala Gln  Thr Leu Gly 
    1700                 1705                 1710             


Thr Thr  Tyr Ile Tyr Asp Phe  Pro Glu Met Phe Arg  Gln Ala Leu 
    1715                 1720                 1725             


Phe Lys  Leu Trp Gly Ser Pro  Asp Lys Tyr Pro Lys  Asp Ile Leu 
    1730                 1735                 1740             


Thr Tyr  Thr Glu Leu Val Leu  Asp Ser Gln Gly Gln  Leu Val Glu 
    1745                 1750                 1755             


Met Asn  Arg Leu Pro Gly Gly  Asn Glu Val Gly Met  Val Ala Phe 
    1760                 1765                 1770             


Lys Met  Arg Phe Lys Thr Gln  Glu Tyr Pro Glu Gly  Arg Asp Val 
    1775                 1780                 1785             


Ile Val  Ile Gly Asn Asp Ile  Thr Phe Arg Ile Gly  Ser Phe Gly 
    1790                 1795                 1800             


Pro Gly  Glu Asp Leu Leu Tyr  Leu Arg Ala Ser Glu  Met Ala Arg 
    1805                 1810                 1815             


Ala Glu  Gly Ile Pro Lys Ile  Tyr Val Ala Ala Asn  Ser Gly Ala 
    1820                 1825                 1830             


Arg Ile  Gly Met Ala Glu Glu  Ile Lys His Met Phe  His Val Ala 
    1835                 1840                 1845             


Trp Val  Asp Pro Glu Asp Pro  His Lys Gly Phe Lys  Tyr Leu Tyr 
    1850                 1855                 1860             


Leu Thr  Pro Gln Asp Tyr Thr  Arg Ile Ser Ser Leu  Asn Ser Val 
    1865                 1870                 1875             


His Cys  Lys His Ile Glu Glu  Gly Gly Glu Ser Arg  Tyr Met Ile 
    1880                 1885                 1890             


Thr Asp  Ile Ile Gly Lys Asp  Asp Gly Leu Gly Val  Glu Asn Leu 
    1895                 1900                 1905             


Arg Gly  Ser Gly Met Ile Ala  Gly Glu Ser Ser Leu  Ala Tyr Glu 
    1910                 1915                 1920             


Glu Ile  Val Thr Ile Ser Leu  Val Thr Cys Arg Ala  Ile Gly Ile 
    1925                 1930                 1935             


Gly Ala  Tyr Leu Val Arg Leu  Gly Gln Arg Val Ile  Gln Val Glu 
    1940                 1945                 1950             


Asn Ser  His Ile Ile Leu Thr  Gly Ala Ser Ala Leu  Asn Lys Val 
    1955                 1960                 1965             


Leu Gly  Arg Glu Val Tyr Thr  Ser Asn Asn Gln Leu  Gly Gly Val 
    1970                 1975                 1980             


Gln Ile  Met His Tyr Asn Gly  Val Ser His Ile Thr  Val Pro Asp 
    1985                 1990                 1995             


Asp Phe  Glu Gly Val Tyr Thr  Ile Leu Glu Trp Leu  Ser Tyr Met 
    2000                 2005                 2010             


Pro Lys  Asp Asn His Ser Pro  Val Pro Ile Ile Thr  Pro Thr Asp 
    2015                 2020                 2025             


Pro Ile  Asp Arg Glu Ile Glu  Phe Leu Pro Ser Arg  Ala Pro Tyr 
    2030                 2035                 2040             


Asp Pro  Arg Trp Met Leu Ala  Gly Arg Pro His Pro  Thr Leu Lys 
    2045                 2050                 2055             


Gly Thr  Trp Gln Ser Gly Phe  Phe Asp His Gly Ser  Phe Lys Glu 
    2060                 2065                 2070             


Ile Met  Ala Pro Trp Ala Gln  Thr Val Val Thr Gly  Arg Ala Arg 
    2075                 2080                 2085             


Leu Gly  Gly Ile Pro Val Gly  Val Ile Ala Val Glu  Thr Arg Thr 
    2090                 2095                 2100             


Val Glu  Val Ala Val Pro Ala  Asp Pro Ala Asn Leu  Asp Ser Glu 
    2105                 2110                 2115             


Ala Lys  Ile Ile Gln Gln Ala  Gly Gln Val Trp Phe  Pro Asp Ser 
    2120                 2125                 2130             


Ala Tyr  Lys Thr Ala Gln Ala  Ile Lys Asp Phe Asn  Arg Glu Lys 
    2135                 2140                 2145             


Leu Pro  Leu Met Ile Phe Ala  Asn Trp Arg Gly Phe  Ser Gly Gly 
    2150                 2155                 2160             


Met Lys  Asp Met Tyr Asp Gln  Val Leu Lys Phe Gly  Ala Tyr Ile 
    2165                 2170                 2175             


Val Asp  Gly Leu Arg Gln Tyr  Lys Gln Pro Ile Leu  Ile Tyr Ile 
    2180                 2185                 2190             


Pro Pro  Tyr Ala Glu Leu Arg  Gly Gly Ser Trp Val  Val Ile Asp 
    2195                 2200                 2205             


Ala Thr  Ile Asn Pro Leu Cys  Ile Glu Met Tyr Ala  Asp Lys Glu 
    2210                 2215                 2220             


Ser Arg  Gly Gly Val Leu Glu  Pro Glu Gly Thr Val  Glu Ile Lys 
    2225                 2230                 2235             


Phe Arg  Lys Lys Asp Leu Ile  Lys Ser Met Arg Arg  Ile Asp Pro 
    2240                 2245                 2250             


Ala Tyr  Lys Lys Leu Met Glu  Gln Leu Gly Glu Pro  Asp Leu Ser 
    2255                 2260                 2265             


Asp Lys  Asp Arg Lys Asp Leu  Glu Gly Arg Leu Lys  Ala Arg Glu 
    2270                 2275                 2280             


Asp Leu  Leu Leu Pro Ile Tyr  His Gln Val Ala Val  Gln Phe Ala 
    2285                 2290                 2295             


Asp Phe  His Asp Thr Pro Gly  Arg Met Leu Glu Lys  Gly Val Ile 
    2300                 2305                 2310             


Ser Asp  Ile Leu Glu Trp Lys  Thr Ala Arg Thr Phe  Leu Tyr Trp 
    2315                 2320                 2325             


Arg Leu  Arg Arg Leu Leu Leu  Glu Asp Gln Val Lys  Gln Glu Ile 
    2330                 2335                 2340             


Leu Gln  Ala Ser Gly Glu Leu  Ser His Val His Ile  Gln Ser Met 
    2345                 2350                 2355             


Leu Arg  Arg Trp Phe Val Glu  Thr Glu Gly Ala Val  Lys Ala Tyr 
    2360                 2365                 2370             


Leu Trp  Asp Asn Asn Gln Val  Val Val Gln Trp Leu  Glu Gln His 
    2375                 2380                 2385             


Trp Gln  Ala Gly Asp Gly Pro  Arg Ser Thr Ile Arg  Glu Asn Ile 
    2390                 2395                 2400             


Thr Tyr  Leu Lys His Asp Ser  Val Leu Lys Thr Ile  Arg Gly Leu 
    2405                 2410                 2415             


Val Glu  Glu Asn Pro Glu Val  Ala Val Asp Cys Val  Ile Tyr Leu 
    2420                 2425                 2430             


Ser Gln  His Ile Ser Pro Ala  Glu Arg Ala Gln Val  Val His Leu 
    2435                 2440                 2445             


Leu Ser  Thr Met Asp Ser Pro  Ala Ser Thr 
    2450                 2455             


