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Information on EC 1.14.99.48 - heme oxygenase (staphylobilin-producing) and Organism(s) Staphylococcus aureus and UniProt Accession Q8NX62
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1.14.99.48 heme oxygenase (staphylobilin-producing)IUBMB Comments
This enzyme, which is found in some pathogenic bacteria, is involved in an iron acquisition system that catabolizes the host's hemoglobin. The two enzymes from the bacterium Staphylococcus aureus, encoded by the isdG and isdI genes, produce 67.5 % and 56.2 % delta-staphylobilin, respectively.
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The taxonomic range for the selected organisms is: Staphylococcus aureus
The expected taxonomic range for this enzyme is: Bacteria, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Archaea
Reaction Schemes
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Synonyms
heme oxidase, haem oxidase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
isdG
isdI
isdG
-
-
-
-
isdI
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
protoheme,hydrogen-donor:oxygen oxidoreductase (delta/beta-methene-oxidizing, hydroxylating)
This enzyme, which is found in some pathogenic bacteria, is involved in an iron acquisition system that catabolizes the host's hemoglobin. The two enzymes from the bacterium Staphylococcus aureus, encoded by the isdG and isdI genes, produce 67.5 % and 56.2 % delta-staphylobilin, respectively.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
protoheme + 5 reduced acceptor + 4 O2
15-oxo-beta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
protoheme + 5 reduced acceptor + 4 O2
5-oxo-delta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
enzyme cleaves the tetrapyrrol ring structure of heme in the presence of NADPH cytochrome P450 reductase, thereby releasing iron
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name NWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name thatNWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
product is a red-orange solid that becomes yellow when dissolved in dimethyl sulfoxide or water/acetonitrile. It is more polar than biliverdin and bilirubin
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
in the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
enzyme cleaves the tetrapyrrol ring structure of heme in the presence of NADPH cytochrome P450 reductase, thereby releasing iron
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name NWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name thatNWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
product is a red-orange solid that becomes yellow when dissolved in dimethyl sulfoxide or water/acetonitrile. It is more polar than biliverdin and bilirubin
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
in the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 5 reduced acceptor + 4 O2
15-oxo-beta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
-
-
-
-
?
protoheme + 5 reduced acceptor + 4 O2
15-oxo-beta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
-
-
-
?
protoheme + 5 reduced acceptor + 4 O2
5-oxo-delta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
-
-
-
-
?
protoheme + 5 reduced acceptor + 4 O2
5-oxo-delta-bilirubin + Fe2+ + formaldehyde + 5 acceptor + 4 H2O
-
-
-
?
additional information
?
-
an apparent meso-hydroxyheme is a likely common intermediate with the canonical heme oxygenases. Unlike heme oxygenases, this intermediate does not form with added H2O2 nor does it convert to verdoheme and CO. Rather, the next intermediates are a set of formyloxobilin isomers. These convert in separate fast and slow phases to beta-/delta-staphylobilin isomers and formaldehyde
-
-
?
additional information
?
-
-
dissociation equilibrium constants of heme are 1.4 nM and 12.9 nM for isoforms IsdG and IsdI, respectively. Heme dissociation rate constants are 0.022 per s for IsdG and 0.092 per s for IsdI. It is proposed that only IsdG is a member of the heme iron acquisition pathway and IsdI regulates heme homeostasis
-
-
?
additional information
?
-
-
the primary C1 product of the both isoform IsdG and IsdH is formaldehyde. In the mechanism, one meso carbon atom of the porphyrin ring is liberated primarily as formaldehyde
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
enzyme cleaves the tetrapyrrol ring structure of heme in the presence of NADPH cytochrome P450 reductase, thereby releasing iron
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name NWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name thatNWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
15-oxo-beta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
product is a red-orange solid that becomes yellow when dissolved in dimethyl sulfoxide or water/acetonitrile. It is more polar than biliverdin and bilirubin
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
enzyme cleaves the tetrapyrrol ring structure of heme in the presence of NADPH cytochrome P450 reductase, thereby releasing iron
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name NWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
oxidoreductase IruO, gene name thatNWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid. The major heme degradation products are 5-oxo-delta-bilirubin and 15-oxo-beta-bilirubin, i.e. staphylobilins
-
?
protoheme + 4 AH2 + 4 O2
5-oxo-delta-bilirubin + Fe2+ + CO + 4 A + 4 H2O
-
product is a red-orange solid that becomes yellow when dissolved in dimethyl sulfoxide or water/acetonitrile. It is more polar than biliverdin and bilirubin
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
in the absence of heme, isoform IsdG is targeted for degradation by internally coded sequences. A flexible loop near the heme-binding pocket is required for IsdG degradation in the absence of heme. IsdG stability is increased by inhibiting ATPases
physiological function
physiological function
isoform IsdI complements the heme utilization deficiency of a Corynebacterium ulcerans heme oxygenase mutant
physiological function
isoforms IsdG and IsdI are both important for Staphylococcus aureus growth on haemin as a sole iron source and are necessary for full Staphylococcus aureus pathogenesis. Strains lacking IsdG, IsdI or both exhibit significantly impaired growth on hemin as a sole iron source when compared with wild-type. Inactivation of IsdG and IsdI in combination does not enhance the hemin utilization defect over that of either individual mutant strain. Overexpression of either IsdG or IsdI complements the loss of both enzymes, and expression of IsdG and IsdI is regulated by iron in a Fur-dependent manner and differentially regulated by iron and hemin
physiological function
isoforms IsdG and IsdI are both important for Staphylococcus aureus growth on haemin as a sole iron source and are necessary for full Staphylococcus aureus pathogenesis. Strains lacking IsdG, IsdI or both exhibit significantly impaired growth on hemin as a sole iron source when compared with wild-type. Inactivation of IsdG and IsdI in combination does not enhance the hemin utilization defect over that of either individual mutant strain. Overexpression of either IsdG or IsdI complements the loss of both enzymes, and expression of IsdG and IsdI is regulated by iron in a Fur-dependent manner and differentially regulated by iron and hemin. Hemin-dependent upregulation of IsdG is occurring post-transcriptionally by enhancing its protein stability
physiological function
oxidoreductase IruO, gene name thatNWMN2274, is the likely in vivo reductant required for heme degradation by Staphylococcus aureus. In the presence of NADPH and IruO, either IsdI or IsdG degrade bound heme 10fold more rapidly than with the chemical reductant ascorbic acid
physiological function
in the vertebrate host, Staphylococcus aureus fulfills its iron requirement by obtaining heme-iron from host hemoproteins via IsdG- and IsdI-mediated heme degradation. Isoforms IsdG and IsdI are structurally and mechanistically analogous but are differentially regulated by iron and heme availability
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
12500
x * 12500, recombinant His-tagged protein, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
an optical spectroscopic and density functional theory characterization of azide- and cyanide-inhibited wild type and N7A IsdG. Residue Asn7 perturbs the electronic structure of azide-inhibited, but not cyanide-inhibited, IsdG. The terminal amide of Asn7 is a hydrogen bond donor to the alpha-atom of a distal ligand to heme in IsdG. The Asn7-N3 hydrogen bond influences the orientation of a distal azide ligand with respect to the heme substrate. Asn7-N3 hydrogen bond donation causes the azide ligand to rotate about an axis perpendicular to the porphyrin plane and weakens the pi-donor strength of the azide ligand
to 1.5 A resolution. Structure of the enzyme resembles the ferredoxin-like fold and forms a beta-barrel at the dimer interface. Two large pockets found on the outside of the barrel contain the putative active sites
inactive N7A variant of IsdG in complex with Fe3+-protoporphyrin IX, to 1.8 A resolution. The metalloporphyrin is buried into a deep clefts such that the propionic acid forms salt bridges to two Arg residues. His77, a critical residue required for activity, is coordinated to the Fe3+ atom. The bound porphyrin ring forms extensive steric interactions in the binding cleft such that the ring is highly distorted from the plane. This distortion is best described as ruffled and places the beta- and delta-meso carbons proximal to the distal oxygen-binding site. In the IsdG-hemin structure, Fe3+ is pentacoordinate, and the distal side is occluded by the side chain of Ile55
isoform IsdI in complex with cobalt protoporphyrin IX, to 1.8 A resolution. The metalloporphyrin is buried into a deep cleft such that the propionic acid forms salt bridges to two Arg residues. His76, a critical residue required for activity, is coordinated to the Co3+ atom. The bound porphyrin ring forms extensive steric interactions in the binding cleft such that the ring is highly distorted from the plane. This distortion is best described as ruffled and places the beta- and delta-meso carbons proximal to the distal oxygen-binding site. in the structure of IsdI-cobalt protoporphyrin IX, the distal side of the cobalt protoporphyrin IX accommodates a chloride ion in a cavity formed through a conformational change in Ile55. The chloride ion participates in a hydrogen bond to the side chain amide of Asn6
isoform IsdI in complex with heme, heme ruffling and constrained binding of oxygen is consistent with cleavage of the porphyrin ring at the beta- or delta-meso carbon atoms
mutant W66Y in complex with heme and its cyanide-bound form. Heme binds to the mutant with less heme ruffling than observed for wild-type IsdI. The reduction potential of the variant (-96 mV versus standard hydrogen electrode) is similar to that of wild-type IsdI (-89 mV)
to 1.5 A resolution. Structure of the enzyme resembles the ferredoxin-like fold and forms a beta-barrel at the dimer interface. Two large pockets found on the outside of the barrel contain the putative active sites
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F23A
mutation does not significantly affect heme binding or degradation
L17A
mutation does not significantly affect heme binding or degradation
M38A
slight reduction of heme degradation, mutation shifts the peak absorbance of the Soret band to 430 nm
S70A
mutation does not significantly affect heme binding or degradation
W66A
Trp66 is a conserved heme pocket residue implicated in heme ruffling. Mutant is inactive
W66F
Trp66 is a conserved heme pocket residue implicated in heme ruffling. Mutant shows about half of wild-type heme degradation activity
W66L
Trp66 is a conserved heme pocket residue implicated in heme ruffling. Mutant is inactive
W66Y
Trp66 is a conserved heme pocket residue implicated in heme ruffling. Mutant shows about half of wild-type heme degradation activity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expresssion in Escherichia coli, cultures overexpressing isoforms IsdG or IsdI exhibit a bright yellow color
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
reconstitution of both isoform IsdG and IsdI with heme at pH 8.0 generates optical absorption spectra containing a Soret band at about 412 nm, and alpha/beta bands at about 567 and 532 nm
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Skaar, E.P.; Gaspar, A.H.; Schneewind, O.
IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus
J. Biol. Chem.
279
436-443
2004
Staphylococcus aureus (Q7A649), Staphylococcus aureus (Q7A827), Staphylococcus aureus N315 (Q7A649), Staphylococcus aureus N315 (Q7A827)
Wu, R.; Skaar, E.P.; Zhang, R.; Joachimiak, G.; Gornicki, P.; Schneewind, O.; Joachimiak, A.
Staphylococcus aureus IsdG and IsdI, heme-degrading enzymes with structural similarity to monooxygenases
J. Biol. Chem.
280
2840-2846
2005
Staphylococcus aureus (Q8NX62), Staphylococcus aureus (Q99X56), Staphylococcus aureus ATCC 700699 (Q99X56), Staphylococcus aureus MW2 (Q8NX62)
Lee, W.C.; Reniere, M.L.; Skaar, E.P.; Murphy, M.E.
Ruffling of metalloporphyrins bound to IsdG and IsdI, two heme-degrading enzymes in Staphylococcus aureus
J. Biol. Chem.
283
30957-30963
2008
Staphylococcus aureus (Q7A649), Staphylococcus aureus (Q7A827)
Loutet, S.A.; Kobylarz, M.J.; Chau, C.H.; Murphy, M.E.
IruO is a reductase for heme degradation by IsdI and IsdG proteins in Staphylococcus aureus
J. Biol. Chem.
288
25749-25759
2013
Staphylococcus aureus (Q7A649), Staphylococcus aureus (Q7A827), Staphylococcus aureus N315 (Q7A649), Staphylococcus aureus N315 (Q7A827)
Reniere, M.L.; Skaar, E.P.
Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem
Mol. Microbiol.
69
1304-1315
2008
Staphylococcus aureus (Q7A649), Staphylococcus aureus (Q7A827), Staphylococcus aureus N315 (Q7A649), Staphylococcus aureus N315 (Q7A827)
Reniere, M.L.; Ukpabi, G.N.; Harry, S.R.; Stec, D.F.; Krull, R.; Wright, D.W.; Bachmann, B.O.; Murphy, M.E.; Skaar, E.P.
The IsdG-family of haem oxygenases degrades haem to a novel chromophore
Mol. Microbiol.
75
1529-1538
2010
Staphylococcus aureus (Q7A649), Staphylococcus aureus (Q7A827), Staphylococcus aureus N315 (Q7A649), Staphylococcus aureus N315 (Q7A827)
Reniere, M.L.; Haley, K.P.; Skaar, E.P.
The flexible loop of Staphylococcus aureus IsdG is required for its degradation in the absence of heme
Biochemistry
50
6730-6737
2011
Staphylococcus aureus (A6QG37), Staphylococcus aureus Newman (A6QG37)
Matsui, T.; Nambu, S.; Ono, Y.; Goulding, C.W.; Tsumoto, K.; Ikeda-Saito, M.
Heme degradation by Staphylococcus aureus IsdG and IsdI liberates formaldehyde rather than carbon monoxide
Biochemistry
52
3025-3027
2013
Staphylococcus aureus
Ukpabi, G.; Takayama, S.J.; Mauk, A.G.; Murphy, M.E.
Inactivation of the heme degrading enzyme IsdI by an active site substitution that diminishes heme ruffling
J. Biol. Chem.
287
34179-34188
2012
Staphylococcus aureus (Q7A827), Staphylococcus aureus N315 (Q7A827)
Streit, B.R.; Kant, R.; Tokmina-Lukaszewska, M.; Celis, A.I.; Machovina, M.M.; Skaar, E.P.; Bothner, B.; DuBois, J.L.
Time-resolved studies of IsdG protein identify molecular signposts along the non-canonical heme oxygenase pathway
J. Biol. Chem.
291
862-871
2016
Staphylococcus aureus (Q7A649), Staphylococcus aureus N315 (Q7A649)
Lockhart, C.L.; Conger, M.A.; Pittman, D.S.; Liptak, M.D.
Hydrogen bond donation to the heme distal ligand of Staphylococcus aureus IsdG tunes the electronic structure
J. Biol. Inorg. Chem.
20
757-770
2015
Staphylococcus aureus (Q8NX62), Staphylococcus aureus MW2 (Q8NX62)
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