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1 MBE Advance Access published November 12, 2008! # % & ( &) &) % + % # % ( &) &) % +!, (./ # % ##0 & ( &) % +, /77 2, : ; <,! ( ; = ; ; The Author Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 ! # >? ; = = 8 6 6? ? 9 2(!!! ( (! ( =! = # =? = = (! % = % ( ( = Α! (! = =! ( = = > = 9 ( 8 % ( 9? =!!! #?!!!! = ( >!!! (! ( = ( = < ;

3 # %& ( = 8; 9 Β + < 6! = (! = ; 8!( < 33 9!!! ;? 8? 9 6 = (! = 8 ( 33Χ9 >= =? 8%! ! 3 9 #? < = 6 = ( (! + ; % 8 6 < 2 / Χ < +! 6!! α 6 9 ; 8?? α 6 < 9 8 Ε 33/9 # ;! 6 = 8 6 6? = 9 = + α 6 6β 6 < ε 6 > + 6 +? + 6 < & < # = ( 6 6 <! 8> Φ 2 9 ;6 (! 8! 9 6 <! 8# Φ 2 9 (! ;6 8

4 = < 6 6 <! 8 Φ 2 / <! <! 6 < (! 6 < 6Γ6 + 8 Η; 2. 9! 6 < = ( 6 < 6 /6 <! 8Ε 2 Χ 9 α 6 6β 6 < ε 6 = +? 8 ( 33 9! (! (! + = +? 8 ( 7 Ι Ε 7Χ Ι > 7Χ.9 + ( 8&! 753Ι % = 75Χ9 # 6= % =! ( = = = + = Ε = ( ( = =!!? + 8 ( 33 9! =! ( (? = < (!?! = (? = = = = ( ( ( = =! =! % /

5 ( )%! &? = 8! % % ;! 9! Χ33! 8 = ; %# < & ( 8Α! >#Α = = +! 2ΑΑ = ( % 2; + 8&! 33/9 Α ( 8&! 33.9 &22 & 8Φ( Α! + ( (? = 8!?! =! ϑ &3 ΚΙ ( = 6( Λ 3 63! /3Μ9 = = (! < 8 ( = Φ Φ( 33 9 Α % (! &3!! + (?? Φ 3 ( &!? =!! &> 3! =!! =! (!! = <? 8Α2;2 Φ! ; =! =! Φ> #&>! ΕΗ # Χ.! Α / 3 8> 33.9 = Ν>> 8Ν Ο

6 > Ο> 9! 6 8/! 9 6 6! =!!! 6Β! 8;Ν9! 8;2#ΑΕ%Φ 6ΝΦ#;#;Α! 9 %! 8 9 = = &2Π%ΦΦ>! < 8 9 = = <. 3 / 8& 33Χ9 = Ν>> (! 6! 8/! 9 Φ 6 = < ( = 6! 6 > = ( +! 2Α / 3 > 22 #2 8! 77Χ9! = 8! ( = 9 (!&! +!#&!!+% # ( = ( = 8!! # % & 9 (! ( = 2! Ε = ( =! (?? 6 6? ( ( = ; (!!! = Χ33! (! 3 Χ

7 !!! Β!! = 8 9 Ε = ( =!!! (! # <! %! =! =!, % 9 % 8 ( % 6 8% 9 Α 6 8 9!! 8! 3 9 (! (! 6 ( > = = = 8! = 33.9 #!! < 6 > # ;! =! < Ε = ( % < (! 6! =! > Φ Η; + 8! ( 9 = ( 6 > Φ = ( + Η; 8! Θ! 33 Ι ( 33 Ι = 33.9 #! 6 6? =.

8 = 6! (! =?! ; ( (! = 8 9 = 8!! 9 >! 8 9!! = =! > %, = ( ( %! 6 6? = 8> 3 9 #! ( ) Α =!! #!!?! 8! &3 9,!! ( Ο Ο =!!! >!! >!! (! =! ( ( 8 =9 ( = (!!!! 8 33Ι

9 =!!!! ( > =!! 8 (! (,!!!! 8! &3 =? (! 9 >!!!! (! 8 = 9 #! = 6! =! 6 + 8! % 9 8 ( 33 9! ( Ι 339 > =!! + = > 3! = % 8 %!! 6!! 9 Φ (! = 8 ( 33 9 Ε = ( 8> 3 9! ( ( 6! 8! &3 9 > + =! =!! 7

10 > ( = ( ( < # (!!! =! = 8! 3 &3 9 >! ( =!! ( #!! = 2! (?!!!!!! 6 6 8! 3 9 8! 3 9 8! &3 9! = %!!! 8! +! Ι ( = ( 6& 33 9 = ( = 8 9! =!!! Φ Ε = (!! ( 2 >! =! 8! 3 %9 Ε = (! ( = 2 = 8!! & & 9 >!! %! ( ;Ν 3

11 !! 8 = 9 ( = 2 8! = = 9 = Α ( 8 9Ι! #!! = 2 (!!? ( 8> 9! > = 6!! =!? = 8! 9 %! = = <! Φ? = = ( >? =! ( Ρ > < = = =!!!! = Α = = ( (! 6! Ε = ( ( < = ( >! 8 9 %! =!? =!! >! ( 2!! ( =!

12 % 8! 9!! ( > Α>!! = = (?! >! 2 =! = ; (! <! = (! (!!! # <!! = % ( #!! = 8!)!#!+9 = (!! % ( <!! =! < Ε = ( = (!! > = %!!!!! >! ( = < <! = #? = (! (!! ( <!! # 8! 9!! ( 6 < = = = =

13 #! (!!! (! < ( ( = (! 8Ε 757Ι 6 33Ι 339 & %! 8 33 Ι 33.9 > 0! ( ( = = Ε = (!! < =! =? <! 8 + > Φ Φ Ε 9 = <!? = %!! =!! 6! (!! 8% 33 9 #! > = ( #! ( ; ; % = ( ( <? ( = > =! ( (! ( + Φ = 6 = 6! 8 9 > =! (! <! (

14 #% # &!+%! =!!!! 0 =! 8! 9 >! ( (? 8; 33/Ι 33Ι 33ΧΙ Ε 33.9! ( ( 8% 33 Ι Φ 33 9 > = ( ( ( = ( (? ;! =?! ( ( = # = (!! ( = = =! (!! (! /

15 !&,, ( ( ( + &? 8 &3 9! Γ Α % 8 &3 9! =! 8! &3 9! =! (! 8! &3 9!! 8! &3 9 >? 8 9 Φ > 3 # %. ( ( (! > = = 2& 8&) & % + 9 ;? 8% Σ % + 9 = ( = (!

16 ( ( ( #(! %! > Φ 33 > Ε Χ, % & =! & + Α ?! (! ( (!! Α, Χ6 Χ % Η Ν > % 2 ; Ν 33!!! ( Α., % = >! 7.3! + ( ( ( Ν % 3,/Χ6/Χ % = Ε Ν Χ + ( & ( Ν,/Χ6/. ( 6& > 33 >!!! + # Ν & 2(, 7.6 / ( ΕΝ & 33 > = 6 ; = Ν 2(,. 6.. Θ! % 2 33!!!!! Ν % 5/,Χ/5 6Χ/57 ( Ε = 7 > 6 Ν % 57,/ 6/7 = Ν >= =?! Ν % 57, / 6 / Ν 33 ΕΗ # 8! #! 9 ( Χ Α & (! & & #! Η! > 2! Η & Ε & 33 # < ;! < 6 6 < 8 & = Τ? Τ Ν %.., Χ 6 Χ. Α! 2 Α Ε! #( # % 33 2< &, > ( 6 =! ;,.5/6.55 Ε & ; Η Α Β > ; = 33. Α +! =! (! 5! 6 % 2( /,5365 Ε %! ( =!., Α & ΑΑ!! ( ; Χ, /536/5/ Ε > 33/! % 7,..6 5Χ ( Φ Α Α & & Φ %! > 33 ;,? = % 3, 76 3/ Χ

17 ( Φ Ν % %! > Φ 33! =, ( 2 &., 76. % Α % = ; ( 3 %, 7/.6 7/5 335!! Ν 2( ΧΧ, ΧΧ6.? & 335!! 2 & 5,5.67. & 33 ; 6! 6!! Φ # & 7, Χ36. ( 33Χ ; ; & %,Χ 6Χ/ 33Χ (! +! Ν 2( Χ, 6 / 6 % Φ ( Υ ( 2 & 33 Θ Φ # & 7, /Χ6 7 & +! & ( & Ν 33 (! Φ # & 7,/ 6.Χ ; Η # > Ε Α Β > 33/ %! +!! ; Α Χ,.Χ36.ΧΧ ; % ; Ε%Ν # 77. Α, + Α 2 %;2 ;2 & /, / Φ ( & Η#! + #% ( +!! Α % /, Φ Φ( 33!! =, (! Φ %., 56 Φ( %! > % >! Β 333! ;,Χ7 6.3 Ν2 33,!6 % % 7Χ, 3 6 Ν2 33! < 2< //, 76//! 77Χ > =,! %,.6 5 % Ν 33 ( ( = +! ; Α.,. 6. Ν > Ε 2 Φ 33 > ( ; 7, 6 > ( >! 33 ; %# &? 8 &?9, 6?! ;, 3 63/!( < Α Φ 33! ; %,Χ5 6Χ73 & Φ! 753 Ν Α,/Χ6/..

18 &! #! 2! Α Ε Ε Α &! 33/ % 2; +, Β = ( ;, / 6/ &! Ν Ε Ε ( > Α Α= 6Α! ; Φ 33. >#Α Α,!!! ;, Χ36 Χ/ & 33Χ < 6 #6Ε, < 6! = < < %, Χ556 Χ73 > Ν ; & 33. 2Α /, 2( Α 8 2Α 9 = ( / 3 % 2( /, 7Χ6 77 > Α Α Ν < 2 7Χ. # 6! ! 6 Ν % 7, Χ56.Χ Ν & 2 > ΕΑ 7.5 & + 2 Ν %, 36 / Α Ε 7Χ > 6 Ν % 5, 6 7 Ν %Β Ε Ν! &! Ε Ε Α Ν# 33! ( = 6% & 77, 3./6 3.Χ Ν = ( & % Ε # & %, Χ 5

19 (! /0, Α? %! % 1 % % ( & ( 3Χ 3//5 7 Χ33 Χ3 Χ3 6 6 ( > 7 ( 533/ ( 56 3 ς 3/ 3 3//Χ Χ5 Χ5 Χ /.5 73 Χ/ Χ/ Χ/ 6 6 ( 3 ΦΦ /3.. 7 / 7 / 5 / / 6 6 ( 3 5 ΦΦ 53 Χ/ 3Χ & >ς. 3 6 / & / Χ 6 Χ Χ / > Χ7 35Χ5 Ε> 7 2,! 2 / 2 ) % 5 ) %%. 2 ) Ε>.3 2 7ς 2 /ς %% 5ς %%.ς %.3ς 3 Χ / /57 3./ Χ.Χ /5 7 Χ 3 // 3 Χ/ 3..Χ 7 Χ 3 /5 3 3 / ΧΧ Χ 3 // 375 Χ 3/77 3 / Χ 3Χ ) 3 Β ς 3../ 3/7 33Χ /3 /3Χ ) Ν# 3 05Χ ) 2. 2 # >353! 6 2 & > ς Α Φς # ς.33.ς %! Ε> 3 2 % 3 ς Χ5 3/5 3 / /5 3 /5/ Χ5 Χ / / /. 3 3 / 3. 3 /. 3 / Χ % ς / ! ; > 7 / % /. 33 #6/5 %> Χ/ 5/!! 5 Α Χ Ω Φ! (!!?! Β 2 Φ! =!?!! 9 # = 8 9 = = = (!, 8 3/ ς3//χ9 = 8 3 ς 3 9! Ι

20 + & ( ( (! /0! 3 & ( 6 Ξ Ψ = 6 Ξ Ψ Φ ( > + 2 = < 6 < /5 6 & (! = 8 9! Β! 2< =! =, 7!, + 8 < 9Ι, 8 6> 9Ι / % Ε 8 9Ι ( (! & 8 6 9Ι! Φ Ι 6 >>Φ 8Α 6 9Ι 7! Φ, %. 8 9Ι & 8 6 9Ι 0 8Α 6 9 /8 9 : 7 : 7 %! ;! 8 ( = ( ;Ν Φ ( Ζ Χ3Μ = 9 3

21 De novo eukaryotic pathway De novo prokaryotic pathway Anthranilate branch kynureninase (KYN) EC encoded by kynu gene Anthranilate L-tryptophan tryptophan 2,3-dioxygenase (TDO) EC encoded by kyna gene N-formyl-L-kynurenine kynurenine formamidase (KFA) EC encoded by kynb gene L-Kynurenine kynurenine 3-monooxygenase (KMO) EC encoded by kmo gene 3-hydroxy-L-kynurenine kynureninase (KYN) EC encoded by kynu gene Dihydroxyacetone phosphate L-aspartate L-aspartate oxidase (NadB) EC encoded by nadb gene Iminoaspartate quinolinate synthetase (NadA) encoded by nada gene 3-hydroxyanthranilate 3-hydroxyanthranilate 3,-dioxygenase (HAD) EC encoded by haao gene 2-amino-3-carboxymuconate semialdehyde (non enzymatic) quinolinic acid (quinolinate) (pyridine-2,3-dicarboxylate) FIGURE 01 NAD (Nicotinamide adenine dinucleotide)

22 FIGURE 02

23 98 Xanthomonas campestris pv. vesicatoria Xanthomonas oryzae pv. oryzae 97 Xanthomonas campestris pv. campestris A) Stenotrophomonas maltophilia 81 Pseudomonas fluorescens 85 Salinispora arenicola Monosiga brevicollis Gemmata sp. Acidobacteria bacterium Myxococcus xanthus Stigmatella aurantiaca Flavobacteriales bacterium Polaribacter filamentus Tenacibaculum sp. Flavobacterium johnsoniae Robiginitalea biformata Flavobacteria bacterium Sus scrofa Homo sapiens Polaribacter irgensii Leeuwenhoekiella blandensis Psychroflexus torquis Cellulophaga sp. Salinispora tropica Croceibacter atlanticus Dictyostelium discoideum Tetraodon nigroviridis Brachydanio rerio Xenopus tropicalis Rattus norvegicus Mus musculus 98 Anopheles stephensi 95 Anopheles gambiae Aedes aegypti Bombyx mori Drosophila melanogaster Tribolium castaneum Caenorhabditis elegans Caenorhabditis briggsae 97 Xanthomonas axonopodis pv. citri Legionella pneumophila Neurospora crassa Aspergillus oryzae Emericella nidulans Cryptococcus neoformans Candida albicans Debaryomyces hansenii Ashbya gossypii Saccharomyces cerevisiae Xanthomonadales Flavobacteriales Flavobacteriales Eukaryota B) Cellulophaga sp. Leeuwenhoekiella blandensis Croceibacter atlanticus Psychroflexus torquis Flavobacteriales bacterium Tenacibaculum sp. Polaribacter filamentus Polaribacter irgensii Myxococcus xanthus Stigmatella aurantiaca Stenotrophomonas maltophilia Xanthomonas campestris pv. campestris 95 Xanthomonas oryzae pv. oryzae Xanthomonas campestris pv. vesicatoria Xanthomonas axonopodis pv. citri Flavobacteria bacterium Robiginitalea biformata Flavobacterium johnsoniae Acidobacteria bacterium Salinispora tropica Salinispora arenicola Schistosoma japonicum Mus musculus Rattus norvegicus Homo sapiens Caenorhabditis briggsae Caenorhabditis elegans Candida albicans 9 Ashbya gossypii 98 Saccharomyces cerevisiae 93 Yarrowia lipolytica Monosiga brevicollis Leishmania major Trypanosoma cruzi Dictyostelium discoideum Neurospora crassa 98 Chaetomium globosum 77 Gibberella zeae 98 Aspergillus oryzae Aspergillus fumigatus Aspergillus nidulans Cytophaga hutchinsonii Bacillus thuringiensis Bacillus anthracis Bacillus cereus Bacillus clausii Oceanobacillus iheyensis Exiguobacterium sibiricum Kineococcus radiotolerans Idiomarina loihiensis Roseobacter denitrificans Silicibacter pomeroyi Jannaschia sp. 95 Rhodobacter sphaeroides 98 Bradyrhizobium japonicum Rhizobium loti Paracoccus denitrificans Thermobifida fusca Streptomyces coelicolor Streptomyces avermitilis Marinomonas sp. Erythrobacter litoralis Maricaulis maris Sphingopyxis laskensis Nitrococcus mobilis Roseiflexus sp. Acidovorax avenae Polaromonas sp. Bordetella pertussis Bordetella bronchiseptica 90 8 Burkholderia cepacia Burkholderia vietnamiensis Burkholderia mallei Ralstonia eutropha Ralstonia metallidurans Ralstonia solanacearum Pseudomonas aeruginosa Pseudomonas fluorescens Flavobacteriales Xanthomonadales Eukaryota Firmicutes Proteobacteria

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