A New Way to Degrade Heme

Nambu, Shusuke; Matsui, Toshitaka; Goulding, Celia W.; Takahashi, Satoshi; Ikeda‐Saito, Masao

doi:10.1074/jbc.m112.448399

Cited by 100 publications

(100 citation statements)

References 42 publications

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“…6 The first steps of this proposed mechanism (binding of molecular oxygen, reduction to hydroperoxy, and hydroxylation of the α-meso carbon) are identical to the generally accepted mechanism of canonical HO-catalyzed heme degradation. 16 There has been considerable debate as to whether the canonical HO reaction proceeds through a 2 E g state with a (d xy ) 2 (d xz ,d yz ) 3 electron configuration or a 2 B 2 g state with a (d xz ,d yz ) 4 (d xy ) 1 electron configuration (Figure 1).…”

Section: Introductionmentioning

confidence: 78%

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Graves

Morse²,

Chao³

et al. 2014

Inorg. Chem.

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187

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Mycobacterium heme utilization degrader (MhuD) is a heme-degrading protein from Mycobacterium tuberculosis responsible for extracting the essential nutrient iron from host-derived heme. MhuD has been previously shown to produce unique organic products compared to those of canonical heme oxygenases (HOs) as well as those of the IsdG/I heme-degrading enzymes from Staphylococcus aureus. Here, we report the X-ray crystal structure of cyanide-inhibited MhuD (MhuD–heme–CN) as well as detailed 1H nuclear magnetic resonance (NMR), UV/vis absorption, and magnetic circular dichroism (MCD) spectroscopic characterization of this species. There is no evidence for an ordered network of water molecules on the distal side of the heme substrate in the X-ray crystal structure, as was previously reported for canonical HOs. The degree of heme ruffling in the crystal structure of MhuD is greater than that observed for HO and less than that observed for IsdI. As a consequence, the Fe 3dxz-, 3dyz-, and 3dxy-based MOs are very close in energy, and the room-temperature 1H NMR spectrum of MhuD–heme–CN is consistent with population of both a 2Eg electronic state with a (dxy)2(dxz,dyz)3 electron configuration, similar to the ground state of canonical HOs, and a 2B2g state with a (dxz,dyz)4(dxy)1 electron configuration, similar to the ground state of cyanide-inhibited IsdI. Variable temperature, variable field MCD saturation magnetization data establishes that MhuD–heme–CN has a 2B2g electronic ground state with a low-lying 2Eg excited state. Our crystallographic and spectroscopic data suggest that there are both structural and electronic contributions to the α-meso regioselectivity of MhuD-catalyzed heme cleavage. The structural distortion of the heme substrate observed in the X-ray crystal structure of MhuD–heme–CN is likely to favor cleavage at the α- and γ-meso carbons, whereas the spin density distribution may favor selective oxygenation of the α-meso carbon.

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Section: Introductionmentioning

confidence: 78%

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Graves

Morse²,

Chao³

et al. 2014

Inorg. Chem.

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187

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“…A recent study showed that addition of bilirubin enhanced the survival of Mycobacterium abscessus in HO1-inhibited macrophages, possibly via modulation of intracellular reactive oxygen species (ROS) levels (423). These proteins may also reduce mycobilins (30), the product of the CO bypass pathway of heme oxygenation by mycobacterial MhuD (370). This FDOR group is only the second family of biliverdin reductases to be identified; a previously characterized family of mammalian and cyanobacterial biliverdin reductases employs nicotinamides as an electron source (424,425).…”

Section: Fdors: Flavin/deazaflavin Oxidoreductase Superfamilymentioning

confidence: 99%

“…Preliminary data indicate that a subgroup of the flavin/deazaflavin oxidoreductase superfamily (FDOR-AAs) may also be involved in fatty acid modification (30). Other members of this superfamily (FDOR-Bs) reduce the degradation products formed during heme oxygenation (30): biliverdin (produced by host heme oxygenase-1 and mycobacterial HugZ in the CO-generating pathway) and possibly mycobilin (produced by mycobacterial MhuD in the CO bypass pathway) (369)(370)(371). Our biochemical studies have shown that M. smegmatis carries a gene that encodes a conserved F 420 H 2 -dependent biliverdin reductase that rapidly reduces biliverdin to bilirubin (30), a potent antioxidant (372,373).…”

Section: Mycobacteriamentioning

confidence: 99%

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Greening

Ahmed

Mohamed

et al. 2016

Microbiol Mol Biol Rev

159

208

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SUMMARY5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5-deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate-reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420in methanogenic archaea in processes such as substrate oxidation, C1pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid byMycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Foand F420are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.

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“…MhuD from Mycobacterium tuberculosis is another HO related to IsdG with heme ruffling and which also degrades heme without CO release. However, MhuD produces a novel product named mycobilin, in which the meso-carbon atom at the site of the ring cleavage remains attached as an aldehyde group (Chim et al 2010;Nambu et al 2013).…”

Section: Introductionmentioning

confidence: 99%

In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus

et al. 2016

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In Group A streptococcus (GAS), the metallorepressor MtsR regulates iron homeostasis. Here we describe a new MtsR-repressed gene, which we named hupZ (heme utilization protein). A recombinant HupZ protein was purified bound to heme from Escherichia coli grown in the presence of 5-aminolevulinic acid and iron. HupZ specifically binds heme with stoichiometry of 1:1. The addition of NADPH to heme-bound HupZ (in the presence of cytochrome P450 reductase, NADPH-regeneration system and catalase) triggered progressive decrease of the HupZ Soret band and the appearance of an absorption peak at 660 nm that was resistance to hydrolytic conditions. No spectral changes were observed when ferredoxin and ferredoxin reductase were used as redox partners. Differential spectroscopy with myoglobin or with the ferrous chelator, ferrozine, confirmed that carbon monoxide and free iron are produced during the reaction. ApoHupZ was crystallized as a homodimer with a split β-barrel conformation in each monomer comprising six β strands and three α helices. This structure resembles the split β-barrel domain shared by the members of a recently described family of heme degrading enzymes. However, HupZ is smaller and lacks key residues found in the proteins of the latter group. Phylogenetic analysis places HupZ on a clade separated from those for previously described heme oxygenases. In summary, we have identified a new GAS enzyme-containing split β-barrel and capable of heme biotransformation in vitro; to the best of our knowledge, this is the first enzyme among Streptococcus species with such activity.

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A New Way to Degrade Heme

Cited by 100 publications

References 42 publications

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus

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A New Way to Degrade Heme

Cited by 100 publications

References 42 publications

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Crystallographic and Spectroscopic Insights into Heme Degradation by Mycobacterium tuberculosis MhuD

Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions

In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus

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Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions