fer et soufre: un mélange bio-inorganique très réactif · or relics of mineral ancestors capable...
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Marc Fontecave
Laboratoire de Chimie des Processus Biologiques, UMR 8229 CDF/CNRS/UPMCCollège de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05
mfontecave@college-de-france.fr; Phone: (0033)144271360
Fer et Soufre: Un mélange bio-inorganique très réactif
Exotic Iron-sulfur assemblies
Fe SS
Fe
S
FeS
FeS
S S
SCys
Cys
Cys
Cys
NiS
S Ni NN
Cys
Cys
SCys
FeSS
Fe
S
NiS
FeS
S S
SCysCys
Cys
Cys
S
Fe
His
NN
CO dehydrogenase
Acetyl-CoA Synthase
J.W. Peters, J.B. Broderick et al. Biochemistry 2014 53 4090
Hydrogenase
Exotic Iron-sulfur assemblies
greigite
Fe(Ni)S centers of proteins: inventions of the biological world or relics of mineral ancestors capable of catalytic activity ?
pyritemackinawite
Fe SS
Fe
S
FeS
FeS
S S
SCys
Cys
Cys
Cys
NiS
S Ni NN
Cys
Cys
Correlation motif CX 2CX2CX3C (120 genomes):-Methanogenesis-Archaea-Anaerobiosis-hyperthermophily
From archaea to human beings
0 -200 -400 -600+200+400+600+800
Cu2+/1+O2/H20
H+/H2
Cytochromes Fe3+/2+
rubredoxin
ClustersFe-S
[3Fe-4S]
[2Fe-2S]
[4Fe-4S]
Redox potentials of biological metal centers
Iron-Sulfuromics
�How many FeS proteins in an E. coli cell ?�Relative abundance of the various clusters ?�How many different binding motifs ?
~ 110 [Fe-S] proteins (~ 70 systems)(potentially 200)
-Electron transfer: 55%-Non Redox: 17%-Redox (Radical-SAM): 10%-Sensor/Regulator: 6%-Structural: < 4%-Cluster biosynthesis 8%
[2Fe-2S]: < 10% [4Fe-4S]: > 90%
More than 40 signatures !CX2CX2CX3C (72), CX2CX4CX3C (20), CX2CX2CX7C (16),…….
M. Fontecave, Nature Chem. Biol. 2006
Respiration
TCA cycle
Gene regulationRNA modification
DNA repair
FnrYeiL IscRNsrR SoxRRsxBRsxC AcnA
AcnBFumAFumBSdhB
[2Fe-2S] [4Fe-4S]
MutYNth
DmsADmsBFdnGFdnHFdhEFdhFFdoGFdoHFrdB GlpBGlpC
HyaA HybAHybOHycBHycFHycGHydNHyfAHyfHHyfI
NapANapFNapGNapHNarGNarHNarYNarZNirBNuoBNuoENuoFNuoGNuoINrfC
MiaBRumARumBRlmN
SR
RS
SR
RSRS SR
SRRS
FadH (FA)IscA (FeS)IscU (FeS)Fdx (FeS)SufA (FeS)SufB (FeS)ErpA (FeS)NfuA (FeS)
Biosynthetic pathwaysBioB (Biotin) ThiH (Thiamin)NadA (NAD) LipA (Lipoate)GltB (Aa)GltD (Aa)IlvD (Aa)LeuC (Aa)HemN (Heme)IspG (IPP DPP)IspH (IPP DPP)MoaA (Mo-co)
Fe, S, N metabolism
FhuFBfDCysIHcpHcr
Post-translational modification
AslBNrdGPflAYijMYbiYRimO
Other cellular processes
GlcFHcaCHcaESdaASdaBTdcG
FixXPaaE TtdATtdBXdhCXdhD
Unknown
AegAYagTybhJYcbXYccMYdeMYdePYdhVYdhXYdhYYdiJYdiTYdbKYeaWYeaXYeiAYeiTYfaEYfhLYgcF
YgcOYgfKYgfSYgfTYggWYgiQYhcCYjeKYjeSYjjWYkgFYnfEYnfFYnfGYsaA
The computational model was then applied to over550 prokaryotic genomesto screen foriron–sulfur proteomes; the results are publicly available at:http://biodev.extra.cea.fr/isph.This study represents a proof-of-concept for the application of a penalized linear model toidentify metalloprotein superfamilies on a large-scale. The application employed here, screeningfor iron–sulfur proteomes, provides new candidates for further biochemical and structuralanalysis as well as new resources for an extensiveexploration of iron-sulfuromes in themicrobial world
Metallomics 2014, 6, 1913–1930
�Transport et transfert d’électrons (photosynthèse, respiration,…) (1960….)
e- + [xFe-xS]2+ [xFe-xS]+
Complexe I from Thermus thermophilus7 subunits, 9 FeS clusters (Science 2006)
Hydrogénase H2 2H+ + 2e-
Iron-sulfur clusters in Biology
Aconitase
HOOC-CH2-C-CH2COOH
OH
COOH
HOOC-CH=C
CH2COOH
COOH
- H2O
Citrate
aconitate
B H
�Catalyse non rédox (dehydratases, ACONITASE ,…) (1970….)
Iron-sulfur clusters in Biology
�Modulation of gene expression (FNR, SoxR, IRP,…) (1980….)
IRP « apo »: se fixe sur l’ARNmIRP « Fe-S »: ne se fixe pas sur l’ARNm
IRP: Iron Regulatory protein
Iron-sulfur clusters in Biology
�Transport et transfert d’électrons (photosynthèse, respiration,…) (1960….)
e- + [xFe-xS]2+ [xFe-xS]+
�Catalyse non rédox(déhydratases, ACONITASE ,…) (1970….)
� Modulation de l’expression des gènes(FNR, SoxR, IRP,…) (1990….)
�Catalyse rédox(enzymes Radical-SAM) (2000…)
SAM:S-adenosylmethionine
Iron-sulfur clusters : ever expanding rolesM. Fontecave
Nature Chemical Biology 2006, 2, 171-174
Iron-sulfur clusters in Biology
Radical-SAM Enzyme Superfamily
Biosynthesisof:-Cofactors (lipoate, PQQ, molybdopterin…)-Antibiotics (desosamine, mitomycine, fosfomycine,…)-Vitamins (biotin, thiamin,…)-Alkaloïdes-ChlorophylleMetabolism of:-Sugars-Amino-acids-HydrocarbonsModification of-RNA (tRNA, rRNA,..)-Enzymes (hydrogenase, nitrogenase, RNR,PFL…)Repair of:- DNA
SAMCX3CX2C
HydE
Y. Nicolet, M. Fontecave, J. C. Fontecilla-Camps et alJ. Biol. Chem. 2008, 283, 18861-18872
Adenosylmethionine as a source of 5’-deoxyadenosyl radicalsM. Fontecave, E. Mulliez, S. Ollagnier-de ChoudensCurrent Opinion in Chemical Biology 2001, 5, 506-511
S-Adenosylmethionine-dependent radical-based modification of biological macromoleculesM. Atta, E. Mulliez, S. Arragain, F. Forouhar, J. F. Hunt, M. FontecaveCurr. Op. Struct. Biol. 2010, 20, 684-692
Radical SAM, a novel protein superfamily…H.J. Sofia et alNucleic Acid Res. 2001, 1097-1106
RimO-S12 complex:a model
CH2
C
CH
O-O
CH
C
CH
O-O
SH3C
ribosomal protein S12 [D88]
RimO (yliG)
SAM, "S"
CH3S Fe
+
2+RH
SAM
SFe
2+
2+RH
Ado°
CH3S Fe
S
2+
2+R°
AdoH
CH3S Fe
S
2+
2+RSCH3
e-
AdoH
R-HNCH C
C
R
O
CO2H
H
H
Ado° AdoH
R-HNCH C
C°
R
O
CO2HH
CH3S°
R-HNCH C
C
R
O
CO2H
H3CS
H
RimO
Iron-sulfur centers: biosynthesis and repair
FeOn(OH)p
Fe ?
« S »
Cys-SH
[Fe-S]Fe-S
Fe-S Fe-S
stress
repair
regulation
E. Coli cell
ISCSUF
maturation
SufE
SufD
SufB
SufS
L-cysteine L-alanine
S-
Cys
S-Cys
S-ATP
ADP + Pi
S
sufA sufB sufC sufD sufS sufE
G. Layer, S. Aparna Gaddam, S. Ollagnier-de-Choudens, D. Lascoux, M. Fontecave, F. Wayne OuttenJ. Biol. Chem. 2007, 282, 13342-13350
L. Loiseau, S. Ollagnier-de-Choudens, L. Nachin, M. Fontecave, F. Barras J. Biol. Chem. 2003, 278, 38352
S. Ollagnier-de-Choudens, M. Fontecave et al Febs Letters 2003, 555, 263
S. Ollagnier-de-Choudens, M. Fontecave, F. Barras et al J. Biol. Chem. (2003) 278, 17993
Cysteinedésulfurase
ATPase
L. Nachin, F. Barras et al. , EMBO J. (2003) 22 427
S. Ollagnier-de-Choudens, M. Fontecave et al J. Am. Chem. Soc. 2009, 131, 6149
SufC
SCAFFOLD
FADH2
N
N
N
N
O
O
H3C
H3C
H
R
H
H Flred
Marc Fontecave
Laboratoire de Chimie des Processus Biologiques, UMR 8229 CDF/CNRS/UPMCCollège de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05
mfontecave@college-de-france.fr; Phone: (0033)144271360
Fer et Soufre: Un mélange bio-inorganique très réactif
+ L-Cysteine+ CyaY-Fe3+
SufESufS SufESufS
SufC
SufB
SufD
SufC
4Fe-4S
Apo-aconitaseHolo-aconitase
SufC
SufB SufD
SufCFADH2
Fe-SSufA
SufA
Holo-proteinApo-protein
Flavin reductase
NAD(P)H
NAD(P)+
FAD
L-alanine, CyaY
FAD
SufC
SufB SufD
SufCFADH2
SufC
SufB SufD
SufC
1 2
3
4
5
Iron-sulfur Cluster Assembly: the SufBCD complex is a new type of Fe-S scaffold with a flavin redox cofactorS. Wollers1, G. Layer, R. Garcia-Serres, L. Signor, J.-M. Latour, M. Fontecave, S. Ollagnier de ChoudensJ. Biol. Chem. 2010, 285, 23331-41
Electron transfer (52)Ferredoxins (fdx, bfd, yfaE)Succinate dehydrogenase (sdhB)Sulfite reductase (cysI)Nitrite reductase (nirB)Formate-dependent nitrite reductase (nrfC)2,4-dienoyl-CoA reductase (fadH)DMSO reductase (dmsA, dmsB)SoxR reductase (rseC, rsxB, rsxC)Formate dehydrogenase N (fdnG, fdnH, fdhD)Formate dehydrogenase H (fdhF)Formate dehydrogenase O (fdoG, fdoH)Ferrichrome reductase (fhuF)Fumarate reductase (frdB)Glutamate synthase (gltB, gltD)Hybrid cluster protein (hcp)HCP reductase (hcr)Periplasmic nitrate reductase (napA, napF, napG, napH)Respiratory nitrate reductase 1 (narG, narH)Respiratory nitrate reductase 2 (narY, narZ)NADH:quinone oxidoreductase (nuoB, nuoE, nuoF, nuoG, nuoI)Anaerobic glycerol phosphate dehydrogenase (glpB)Hydrogenase 1 (hyaA)Hydrogenase 2 (hybO, hybA)Hydrogenase 3 (hycB, hycF, hycG)Hydrogenase 4 (hyfA, hyfH, hyfI, hyfR)Xanthine dehydrogenase (xdhC)
Metallosite assembly (7)Scaffold proteins (iscU, nfuA)A-type transporters (iscA, sufA, erpA)Mo-co biosynthesis protein (moaA)SufB (sufB)
Nucleic acid-binding proteins (7)- gene expression regulators (4)Fumarate and nitrate reduction regulator (fnr)Isc regulator (iscR)Redox sensitive transcriptional activator (soxR)Transcriptional activator (yeiL)- DNA repair (2)Adenine glycosylase (mutY)Endonuclease III (nth)- RNA modification (1)RNA 5-methyluridine methyl transferase (rumA)Redox catalysis (12)- Radical-SAM (10)Biotin synthase (bioB)Coproporphyrinogen synthase (hemN)Lipoate synthase (lipA)Thiazole biosynthesis protein (thiH)RNA thiomethyl transferase (miaB)Anaerobic ribonucleotide reductase activating component (nrdG)Pyruvate-formate lyase activating component (pflA)Sulfatase maturase (aslB or atsB)Methylthiotransferase (rimO)- Others (2)4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase (ispG)4-hydroxy-3-methylbut-2-enyl diphosphate reductase (ispH)
Non redox catalysis (10)Aconitases (acnA, acnB)Fumarases (fumA, fumB)Dihydroxyacid dehydratase (ilvD)Isopropylmalate dehydratase (leuC)Quinolinate synthase (nadA)Serine-threonine deaminase (sdaA, sdaB)Serine dehydratase (tdcG)
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