Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres.

@article{Shimizu2019HemeER,
  title={Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres.},
  author={Toru Shimizu and Alzbeta Lengalova and V{\'a}clav Mart{\'i}nek and Mark{\'e}ta Mart{\'i}nkov{\'a}},
  journal={Chemical Society reviews},
  year={2019}
}
Protoporphyrin IX iron complex (heme) is an important cofactor for oxygen transfer, oxygen storage, oxygen activation, and electron transfer when bound to the heme proteins hemoglobin, myoglobin, cytochrome P450 and cytochrome c, respectively. In addition to these prototypical heme proteins, there are emergent, critical roles of exchangeable/labile heme in signal transduction. Specifically, it has been shown that association/dissociation of heme to/from heme-responsive sensors regulates… 
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Regulation of protein function and degradation by heme, heme responsive motifs, and CO
TLDR
The importance of understanding the various roles of heme and the distribution of the different heme pools as they relate to the heme redox state, CO, and heme binding affinities is stressed.
Heme binding to NosP inhibits the activity of a c-di-GMP phosphodiesterase in Vibrio cholerae
TLDR
It is demonstrated that the N-terminal domain of CdpA is a NosP domain capable of heme binding, which consequently inhibits the c-di-GMP hydrolysis activity of the C-terminals of the phosphodiesterase domain.
Heme inhibits the activity of a c-di-GMP phosphodiesterase in Vibrio cholerae.
Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins
TLDR
This review has attempted to describe how the heme synthesis machinery is regulated by mitochondrial homeostasis as a means of coupling heME synthesis to its utilization and to the metabolic requirements of the cell.
Heme as a differentiation-regulatory transcriptional cofactor
TLDR
The hematopoietic transcription factor GATA1 induces heme accumulation during erythropoiesis by directly activating genes mediating heme biosynthesis, which leads to a paradigm in which cell type-specific transcriptional mechanisms determine the expression of enzymes mediating the synthesis of small molecules, which generate feedback loops, converging upon the transcription factor itself and the genome.
Understanding the Logistics for the Distribution of Heme in Cells
TLDR
Recent information on the quantification of heme in cells is summarized, and a discussion of a mechanistic framework that could meet the logistical challenge ofHeme distribution is presented.
Crosstalk between Heme Oxygenase-1 and Iron Metabolism in Macrophages: Implications for the Modulation of Inflammation and Immunity
TLDR
Changes in intracellular iron levels play important roles in the regulation of cellular oxidation reactions as well as in the transcriptional and translational regulation of the expression of proteins related to inflammation and immune responses, and therefore, iron metabolism represents a potential target for the development of novel therapeutic strategies focused on the modulation of immunity and inflammation.
Unravelling the mechanisms controlling heme supply and demand
TLDR
It is shown that the cell exhibits exquisite control over release of heme by limiting its availability to one molecule or less within cellular compartments, and an exchange mechanism between protein partners to control supply and demand is suggested.
One ring to bring them all and in the darkness bind them: The Trafficking of Heme without Deliverers.
Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance
TLDR
The underlying mechanisms by which heme contributes to the development of cardiovascular diseases through oxidative stress, relative pathway gene expression regulation and phenotypic changes in cells are summarized.
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References

SHOWING 1-10 OF 228 REFERENCES
Redox Regulation of Heme Oxygenase-2 and the Transcription Factor, Rev-Erb, Through Heme Regulatory Motifs.
TLDR
The subject of this review is a subset of hemoproteins that contain at least one heme regulatory motif (HRM), which is a short sequence containing a Cys-Pro core that binds heme with the Cys acting as an axial ligand.
Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects.
Redox-dependent axial ligand replacement and its functional significance in heme-bound iron regulatory proteins.
Structural Basis for the Transcriptional Regulation of Heme Homeostasis in Lactococcus lactis*
TLDR
HrtR senses and binds a heme molecule as its physiological effector to regulate the expression of the heme-efflux system responsible for heme homeostasis in L. lactis and adopts a unique mechanism for its functional regulation upon heme sensing.
A heme-binding domain controls regulation of ATP-dependent potassium channels
TLDR
Heme-dependent regulation of KATP channels is demonstrated and the heme-binding location is identified as being on a sulphonylurea receptor subunit of the channel, which is used to present a hypothesis for how heme regulation across numerous ion channels may occur.
Binding of cysteine thiolate to the Fe(III) heme complex is critical for the function of heme sensor proteins.
  • Toru Shimizu
  • Biology, Chemistry
    Journal of inorganic biochemistry
  • 2012
Elucidation of the Heme Binding Site of Heme-regulated Eukaryotic Initiation Factor 2α Kinase and the Role of the Regulatory Motif in Heme Sensing by Spectroscopic and Catalytic Studies of Mutant Proteins*
TLDR
It is proposed that heme regulation is induced by interactions between heme and the catalytic domain in conjunction with global tertiary structural changes at the N-terminal domain that accompany heme coordination and not merely by coordination of the heme iron with amino acids on the protein surface.
Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells
TLDR
GAPDH binds and chaperones labile heme to create a heme pool that is bioavailable to downstream proteins, solving a fundamental question in cell biology and providing a new foundation for exploring heme homeostasis in health and disease.
Heme dynamics and trafficking factors revealed by genetically encoded fluorescent heme sensors
TLDR
The nature and dynamics of LH are elucidated using genetically encoded ratiometric fluorescent heme sensors in the unicellular eukaryote Saccharomyces cerevisiae and it is found that the subcellular distribution of LH is heterogeneous; the cytosol maintains LH at ∼20–40 nM, whereas the mitochondria and nucleus maintain it at concentrations below 2.5 nM.
Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2.
...
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