Heme Degradation by <i>Staphylococcus aureus</i> IsdG and IsdI Liberates Formaldehyde Rather Than Carbon Monoxide

Matsui, Toshitaka; Nambu, Shusuke; Ono, Yukari; Goulding, Celia W.; Tsumoto, Kouhei; Ikeda‐Saito, Masao

doi:10.1021/bi400382p

Cited by 86 publications

(131 citation statements)

References 18 publications

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“…S7 A and B). Moreover, MS analyses of these 18 O-labeling experiments initiated from heme-MhuD are consistent with the sequential mono/dioxygenation mechanism. In the reductive O 2 activation, the mycobilin isomers appear to accommodate three oxygen atoms from O 2 , one of which is exchangeable with water ( Fig.…”

Section: Firstsupporting

confidence: 72%

“…The ruffling is expected to drastically modulate the hemedependent O 2 activation to initiate this unique mechanism (14). Similar heme ruffling is observed for IsdG and IsdI (hemedegrading components of the iron regulated surface determinant system), MhuD homologs in Staphylococcus aureus, which liberate formaldehyde upon heme degradation instead of CO (17,18).…”

mentioning

confidence: 57%

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Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Matsui

Nambu

Goulding

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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101

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Bacterial pathogens must acquire host iron for survival and colonization. Because free iron is restricted in the host, numerous pathogens have evolved to overcome this limitation by using a family of monooxygenases that mediate the oxidative cleavage of heme into biliverdin, carbon monoxide, and iron. However, the etiological agent of tuberculosis, Mycobacterium tuberculosis, accomplishes this task without generating carbon monoxide, which potentially induces its latent state. Here we show that this unusual heme degradation reaction proceeds through sequential mono- and dioxygenation events within the single active center of MhuD, a mechanism unparalleled in enzyme catalysis. A key intermediate of the MhuD reaction is found to be meso-hydroxyheme, which reacts with O2 at an unusual position to completely suppress its monooxygenation but to allow ring cleavage through dioxygenation. This mechanistic change, possibly due to heavy steric deformation of hydroxyheme, rationally explains the unique heme catabolites of MhuD. Coexistence of mechanistically distinct functions is a previously unidentified strategy to expand the physiological outcome of enzymes, and may be applied to engineer unique biocatalysts.

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Section: Firstsupporting

confidence: 72%

mentioning

confidence: 57%

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Matsui

Nambu

Goulding

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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101

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“…A second class is exemplified by the IsdG family. Through a mechanism that hasn't been fully defined, this family of enzymes generates iron, the novel oxo-bilirubin chromophore staphylobilin, and formaldehyde, rather than carbon monoxide, upon the cleavage of heme (76)(77)(78). ChuS of E. coli O157:H7 may represent a third, structurally distinct class of HOs (79).…”

Section: Bacterial Iron and Heme Acquisition Systemsmentioning

confidence: 99%

Sequestration and Scavenging of Iron in Infection

2013

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The proliferative capability of many invasive pathogens is limited by the bioavailability of iron. Pathogens have thus developed strategies to obtain iron from their host organisms. In turn, host defense strategies have evolved to sequester iron from invasive pathogens. This review explores the mechanisms employed by bacterial pathogens to gain access to host iron sources, the role of iron in bacterial virulence, and iron-related genes required for the establishment or maintenance of infection. Host defenses to limit iron availability for bacterial growth during the acute-phase response and the consequences of iron overload conditions on susceptibility to bacterial infection are also examined. The evidence summarized herein demonstrates the importance of iron bioavailability in influencing the risk of infection and the ability of the host to clear the pathogen.

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“…1) (17). It was recently shown that a C1 product is indeed released by the S. aureus IsdG; however, quite unexpectedly, the major C1 product was determined to be formaldehyde (CH 2 O) instead of CO (18). Unlike CO, formaldehyde may be undetectable by animal immune systems, offering a potential selective advantage for heme-feeding pathogens that use IsdG-type enzymes (5,19,20).…”

mentioning

confidence: 99%

Time-resolved Studies of IsdG Protein Identify Molecular Signposts along the Non-canonical Heme Oxygenase Pathway

Streit

Kant

Tokmina‐Lukaszewska

et al. 2016

Journal of Biological Chemistry

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Heme oxygenases (HOs) 3 are enzymes that oxidatively liberate iron from the heme tetrapyrrole (1-3). In the well characterized HOs from animals and many bacteria, the same heme molecule acts as both the O 2 -activating cofactor and substrate. Three successive monooxygenation steps yield Fe(II), CO, and biliverdin IX␣ as the end products of the reaction (Fig. 1) (2, 3). Animals use HOs to maintain cellular heme homeostasis as part of a constant cycle of heme synthesis and breakdown. The products report on the status of this cycle and serve as antioxidants and signaling agents (4, 5). Many bacteria also use HO homologs, both to control heme homeostasis and to liberate iron from host-derived heme (6, 7). Heme, found primarily in hemoglobin, can therefore be used as a rich nutritional source of iron. Because of the intriguing nature of the reaction, which uses heme as both cofactor and substrate (8 -10), as well as the acute biological importance of HO-mediated processes, HOs from several species have been exceptionally well characterized (2, 3).By the early 2000s, however, it was apparent that many important Gram-positive pathogens that degrade host heme did not possess an HO-encoding gene in their genomes. A new family of heme-degrading proteins known as IsdGs was subsequently discovered, with representatives found in bacteria from both Gram-positive and Gram-negative phyla (11). IsdG family proteins are evolutionarily and structurally distinct from the well studied HOs (12, 13), and they yield different end products. Instead of biliverdin IX␣ and CO, the IsdG protein from Mycobacterium tuberculosis (known as MhuD) generates triply-oxygenated linear tetrapyrroles called mycobilins (Fig. 1) (14, 15). A formyl group remains appended to pyrrole ring A or B at the site of macrocycle cleavage, and an oxo group is generated on the pyrrole ring on the opposite side. Notably, no C1 product is released (16).Although homologous to MhuD, the IsdG from Staphylococcus aureus degrades heme to yet a third set of products. The macrocycle is not cleaved at the ␣-meso-but rather at either the ␤-or ␦-meso-carbon. Oxo groups are generated on both the carbon backbone and the pyrrole rings at the cleavage site, generating tetrapyrrole products known as staphylobilins (Fig. 1) (17). It was recently shown that a C1 product is indeed released by the S. aureus IsdG; however, quite unexpectedly, the major C1 product was determined to be formaldehyde (CH 2 O) instead of CO (18). Unlike CO, formaldehyde may be undetectable by animal immune systems, offering a potential selective advantage for heme-feeding pathogens that use IsdG-type enzymes (5,19,20). Mechanistically, the observation that CH 2 O instead of CO implies that verdoheme, the green inter-* This work was supported in part by National Institutes of Health Grants GM090260 and 5P20RR02437 of the CoBRE Program (to J. L. D.) and Grant RO1 AI069233 (to E. P. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the resp...

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Heme Degradation by Staphylococcus aureus IsdG and IsdI Liberates Formaldehyde Rather Than Carbon Monoxide

Cited by 86 publications

References 18 publications

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Sequestration and Scavenging of Iron in Infection

Time-resolved Studies of IsdG Protein Identify Molecular Signposts along the Non-canonical Heme Oxygenase Pathway

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