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IUBMB CommentsThis enzyme catalyses the third of three steps leading to the formation of siroheme from uroporphyrinogen III. The first step involves the donation of two S-adenosyl-L-methionine-derived methyl groups to carbons 2 and 7 of uroporphyrinogen III to form precorrin-2 (EC 2.1.1.107, uroporphyrin-III C-methyltransferase) and the second step involves an NAD+-dependent dehydrogenation to form sirohydrochlorin from precorrin-2 (EC 1.3.1.76, precorrin-2 dehydrogenase). In Saccharomyces cerevisiae, the last two steps are carried out by a single bifunctional enzyme, Met8p. In some bacteria, steps 1-3 are catalysed by a single multifunctional protein called CysG, whereas in Bacillus megaterium, three separate enzymes carry out each of the steps, with SirB being responsible for the above reaction.
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precorrin-2 + Co2+
cobalt-precorrin-2 + 2 H+
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + 2 H+
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + H+
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pH 8.0
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-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
sirohydrochlorin + Fe2+
siroheme + H+
precorrin-2 + Co2+
cobalt-precorrin-2 + 2 H+
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SirB, much lower specific activity than with sirohydrochlorin
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?
precorrin-2 + Co2+
cobalt-precorrin-2 + 2 H+
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SirB, much lower specific activity than with sirohydrochlorin
-
?
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + 2 H+
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SirB, lower specificity for cobalt than for iron
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?
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + 2 H+
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SirB, lower specificity for cobalt than for iron
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?
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + 2 H+
-
-
?
sirohydrochlorin + Co2+
cobalt-sirohydrochlorin + 2 H+
-
-
-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
SirB, monofunctional ferrochelatase, higher specificity for iron over cobalt
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?
sirohydrochlorin + Fe2+
siroheme + 2 H+
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SirB is responsible for the final step in siroheme synthesis
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?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
SirB, monofunctional ferrochelatase, higher specificity for iron over cobalt
-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
SirB is responsible for the final step in siroheme synthesis
-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
Met8p catalyzes ferrochelation during the synthesis of siroheme, both ferrochelation and NAD+-dependent dehydrogenation of preccorin-2 to produce sirohydrochlorin take place in a single bifunctional active site, Asp-141 participates in both catalytic reactions, which are not linked mechanistically, mechanism
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?
sirohydrochlorin + Fe2+
siroheme + 2 H+
Met8p structure, bifunctional Met8p catalyzes the final two steps in the biosynthesis of siroheme involving a beta-NAD+-dependent dehydrogenation of precorrin-2 to generate sirohydrochlorin followed by ferrochelation to yield siroheme, both catalytic activities share a single active site, Asp-141 functions as a general base and plays an essential role in both dehydrogenase and chelatase processes
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?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
Met8p catalyzes ferrochelation during the biosynthesis of siroheme
-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
Met8p catalyzes the final two steps in the biosynthesis of siroheme involving a beta-NAD+-dependent dehydrogenation of precorrin-2 to generate sirohydrochlorin followed by ferrochelation to yield siroheme
-
?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
CysG structure, the multifunctional siroheme synthase CysG synthesizes siroheme from uroporphyrinogen III, CysG contains two structurally independent modules: a bismethyltransferase and a dual-function dehydrogenase-chelatase
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?
sirohydrochlorin + Fe2+
siroheme + 2 H+
-
CysG, siroheme biosynthesis
sulfur metabolism depends on siroheme
?
sirohydrochlorin + Fe2+
siroheme + H+
-
-
-
-
?
sirohydrochlorin + Fe2+
siroheme + H+
-
pH 8.0
-
-
?
sirohydrochlorin + Fe2+
siroheme + H+
-
-
-
-
?
sirohydrochlorin + Fe2+
siroheme + H+
-
-
-
-
?
sirohydrochlorin + Fe2+
siroheme + H+
-
-
-
?
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0.0034
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pH 8, cobaltochelation of precorrin-2
0.0054
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isolated recombinant enzyme, with ferrous iron as substrate
0.0138
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S128D mutant CysG, cobalt chelation of sirohydrochlorin
0.0485
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isolated recombinant enzyme, with cobalt as substrate
0.0656
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wild-type CysG, cobalt chelation of sirohydrochlorin
0.243
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S128A mutant CysG, cobalt chelation of sirohydrochlorin
0.337
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pH 8, cobaltochelation of sirohydrochlorin
33.25
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mutant enzyme C199A, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
36.08
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mutant enzyme C213A, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
38.5
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wild type enzyme, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
43
-
mutant enzyme C219A, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
44.67
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mutant enzyme C135A, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
55.17
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mutant enzyme C210A, in 20 mM Tris/HCl (pH 8.0) and 10 mM NaCl, at 23°C
additional information
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C135A
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the mutant shows increased specific activity compared to the wild type enzyme
C199A
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the mutant shows reduced specific activity compared to the wild type enzyme
C210A
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the mutant shows increased specific activity compared to the wild type enzyme
C213A
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the mutant shows reduced specific activity compared to the wild type enzyme
C219A
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the mutant shows increased specific activity compared to the wild type enzyme
H237A
mutant of bifunctional Met8p is active as both dehydrogenase and ferrochelatase
S128A
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mutant has higher cobalt chelatase activity than wild-type CysG with sirohydrochlorin as substrate
S128D
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mutant has lower cobalt chelatase activity than wild-type CysG with sirohydrochlorin as substrate
D141A
mutant of bifunctional Met8p is completely inactive as both dehydrogenase and ferrochelatase
D141A
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mutant of bifunctional Met8p is devoid of both dehydrogenase and ferrochelatase activities
G22D
mutant of bifunctional Met8p is completely inactive as dehydrogenase, but functions as ferrochelatase
G22D
-
mutant of bifunctional Met8p is completely inactive as NAD+-dependent dehydrogenase, but functions as ferrochelatase
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Schubert, H.L.; Raux, E.; Brindley, A.A.; Leech, H.K.; Wilson, K.S.; Hill, C.P.; Warren, M.J.
The structure of Saccharomyces cerevisiae Met8p, a bifunctional dehydrogenase and ferrochelatase
EMBO J.
21
2068-2075
2002
Saccharomyces cerevisiae, Saccharomyces cerevisiae (P15807)
brenda
Raux, E.; Leech, H.K.; Beck, R.; Schubert, H.L.; Santander, P.J.; Roessner, C.A.; Scott, A.I.; Martens, J.H.; Jahn, D.; Thermes, C.; Rambach, A.; Warren, M.J.
Identification and functional analysis of enzymes required for precorrin-2 dehydrogenation and metal ion insertion in the biosynthesis of sirohaem and cobalamin in Bacillus megaterium
Biochem. J.
370
505-516
2003
Priestia megaterium, Priestia megaterium DSM 509
brenda
Schubert, H.L.; Raux, E.; Matthews, M.A.; Phillips, J.D.; Wilson, K.S.; Hill, C.P.; Warren, M.J.
Structural diversity in metal ion chelation and the structure of uroporphyrinogen III synthase
Biochem. Soc. Trans.
30
595-600
2002
Saccharomyces cerevisiae
brenda
Stroupe, M.E.; Leech, H.K.; Daniels, D.S.; Warren, M.J.; Getzoff, E.D.
CysG structure reveals tetrapyrrole-binding features and novel regulation of siroheme biosynthesis
Nat. Struct. Biol.
10
1064-1073
2003
Salmonella enterica
brenda
Raux-Deery, E.; Leech, H.K.; Nakrieko, K.A.; McLean, K.J.; Munro, A.W.; Heathcote, P.; Rigby, S.E.; Smith, A.G.; Warren, M.J.
Identification and characterization of the terminal enzyme of siroheme biosynthesis from Arabidopsis thaliana: a plastid-located sirohydrochlorin ferrochelatase containing a 2FE-2S center
J. Biol. Chem.
280
4713-4721
2005
Arabidopsis thaliana
brenda
Lobo, S.A.; Brindley, A.; Warren, M.J.; Saraiva, L.M.
Functional characterization of the early steps of tetrapyrrole biosynthesis and modification in Desulfovibrio vulgaris Hildenborough
Biochem. J.
420
317-325
2009
no activity in Desulfovibrio vulgaris
brenda
Romao, C.V.; Ladakis, D.; Lobo, S.A.; Carrondo, M.A.; Brindley, A.A.; Deery, E.; Matias, P.M.; Pickersgill, R.W.; Saraiva, L.M.; Warren, M.J.
Evolution in a family of chelatases facilitated by the introduction of active site asymmetry and protein oligomerization
Proc. Natl. Acad. Sci. USA
108
97-102
2011
Priestia megaterium
brenda
Saha, K.; Webb, M.E.; Rigby, S.E.; Leech, H.K.; Warren, M.J.; Smith, A.G.
Characterization of the evolutionarily conserved iron-sulfur cluster of sirohydrochlorin ferrochelatase from Arabidopsis thaliana
Biochem. J.
444
227-237
2012
Arabidopsis thaliana
brenda
Bali, S.; Rollauer, S.; Roversi, P.; Raux-Deery, E.; Lea, S.M.; Warren, M.J.; Ferguson, S.J.
Identification and characterization of the missing terminal enzyme for siroheme biosynthesis in alpha-proteobacteria
Mol. Microbiol.
92
153-163
2014
Paracoccus pantotrophus
brenda
Garai, S.; Joshi, N.C.; Tripathy, B.C.
Phylogenetic analysis and photoregulation of siroheme biosynthesis genes uroporphyrinogen III methyltransferase and sirohydrochlorin ferrochelatase of Arabidopsis thaliana
Physiol. Mol. Biol. Plants
22
351-359
2016
Arabidopsis thaliana (Q84JH7)
brenda