Control of cytochromes P450 expression in Gunn rat liver: Implication of the intracellular heme pool

Celier, Chantal; Cresteil, Thierry

doi:10.1016/0003-9861(91)90559-2

Cited by 4 publications

(2 citation statements)

References 13 publications

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“…The foundation for the model is an exchange mechanism for managing heme supply and demand in cells involving a body of reversible heme-binding partners, which might be known heme proteins or other proteins (see legend). In earlier publications, the existence of what was termed a regulatory heme pool ( 48 , 49 ) or intracellular heme pool ( 50 ) was proposed to account for varied observations in blood disorders such as porphyria ( 51 , 52 ), gene expression ( 22 , 53 , 54 ), heme protein levels ( 23 ), and heme biosynthesis ( 55 , 56 ). More recently, the weakly bound fraction of the total heme complement has been referred to as labile heme ( 41 , 42 , 57 ) and regulatory heme ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Unravelling the mechanisms controlling heme supply and demand

Leung

Fung

Gallio

et al. 2021

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

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In addition to heme’s role as the prosthetic group buried inside many different proteins that are ubiquitous in biology, there is new evidence that heme has substantive roles in cellular signaling and regulation. This means that heme must be available in locations distant from its place of synthesis (mitochondria) in response to transient cellular demands. A longstanding question has been to establish the mechanisms that control the supply and demand for cellular heme. By fusing a monomeric heme-binding peroxidase (ascorbate peroxidase, mAPX) to a monomeric form of green-fluorescent protein (mEGFP), we have developed a heme sensor (mAPXmEGFP) that can respond to heme availability. By means of fluorescence lifetime imaging, this heme sensor can be used to quantify heme concentrations; values of the mean fluorescence lifetime (τMean) for mAPX-mEGFP are shown to be responsive to changes in free (unbound) heme concentration in cells. The results demonstrate that concentrations are typically limited to one molecule or less within cellular compartments. These miniscule amounts of free heme are consistent with a system that sequesters the heme and is able to buffer changes in heme availability while retaining the capability to mobilize heme when and where it is needed. We propose that this exchangeable supply of heme can operate using mechanisms for heme transfer that are analogous to classical ligand-exchange mechanisms. This exquisite control, in which heme is made available for transfer one molecule at a time, protects the cell against the toxic effect of excess heme and offers a simple mechanism for heme-dependent regulation in single-molecule steps.

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Section: Discussionmentioning

confidence: 99%

Unravelling the mechanisms controlling heme supply and demand

Leung

Fung

Gallio

et al. 2021

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

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“…The existence of a form of regulatory heme is conceptually useful, and because of this the nature of regulatory heme has been debated as long ago as 1975 when new roles for hemeabove and beyond the traditional roles in oxygen binding, electron transfer, and catalysiswere identified by Granick . In Granick’s work, the regulation of heme biosynthesis was proposed as being controlled by fluctuations in the concentrations of heme in a dedicated heme pool where heme was envisaged as being weakly associated with an ensemble of cytosolic proteins. , These weak binding interactions were considered important for heme to be readily exchangeable. , The terms were then later adopted by scientists in multiple fields. ,,− Hence, since Granick’s initial studies, the phrases “regulatory heme” and “free heme” have been widely used although not precisely defined.…”

Section: Terminologymentioning

confidence: 99%

Understanding the Logistics for the Distribution of Heme in Cells

Gallio

Fung

Cammack-Najera

et al. 2021

JACS Au

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Heme is essential for the survival of virtually all living systems—from bacteria, fungi, and yeast, through plants to animals. No eukaryote has been identified that can survive without heme. There are thousands of different proteins that require heme in order to function properly, and these are responsible for processes such as oxygen transport, electron transfer, oxidative stress response, respiration, and catalysis. Further to this, in the past few years, heme has been shown to have an important regulatory role in cells, in processes such as transcription, regulation of the circadian clock, and the gating of ion channels. To act in a regulatory capacity, heme needs to move from its place of synthesis (in mitochondria) to other locations in cells. But while there is detailed information on how the heme lifecycle begins (heme synthesis), and how it ends (heme degradation), what happens in between is largely a mystery. Here we summarize recent information on the quantification of heme in cells, and we present a discussion of a mechanistic framework that could meet the logistical challenge of heme distribution.

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