Understanding the Logistics for the Distribution of Heme in Cells

Abstract

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.

NO rapidly mobilizes cellular heme to trigger assembly of its own receptor

“…Because the ferrous heme–NO complex of sGCβ is highly stable ( 14 , 59 ), such NO–heme binding would create a positive thermodynamic driving force that supports a heme–NO species transfer from GAPDH to apo-sGCβ. Indeed, NO can promote a heme transfer from purified myoglobin to apo-sGC ( 51 , 60 ), and how thermodynamic gradients might govern heme transfers within cells has been discussed ( 61 ). Our current study shows that heme transfer between proteins can quickly take place in living cells in response to low concentrations of NO, indicating that the process is biologically relevant.…”

Regulation of heme utilization and homeostasis in Candida albicans

“…This sensor is comprised of a green fluorescent protein (GFP) domain into which is embedded a heme-binding cytochrome domain, as well as a red fluorescent domain (mKATE2). Binding of heme to the cytochrome domain causes quenching of the GFP fluorescent signal but not of the mKATE2 signal; hence, the GFP/mKATE2 ratio gives an estimate of cytoplasmic “free” heme levels (or more accurately, “labile” or “exchangeable” heme levels [36, 37]), with lower ratios corresponding to higher heme levels [14, 38]. To extend the dynamic range of detection, a second sensor, with lower affinity due to a mutation (M7A) in the cytochrome domain, is also used.…”

“…External heme uptake must be complemented by a system for transporting the acquired heme from the endocytic system to the different cellular locations where it is required. Our knowledge of intracellular transport mechanisms of externally acquired heme – or, for that matter, of endogenously synthesized heme – is very limited [1,36,48]. Existence of a dedicated uptake system of external heme in C. albicans makes it a pertinent organism to probe these questions.…”

The Novel Role of Heme in Health and Diseases – Heme-Containing Sensor Proteins

“…Volné molekuly hemu (někdy taký nazývané labilní hem nebo ještě lépe směnitelný hem) 18 jsou ve vodném roztoku prakticky nerozpustné a navíc jsou toxické 19 . Tato toxicita se projevuje tvorbou reaktivních forem kyslíku, analogicky jako je tomu v případě volného iontu železa (viz předchozí kapitola).…”

“…Tato toxicita se projevuje tvorbou reaktivních forem kyslíku, analogicky jako je tomu v případě volného iontu železa (viz předchozí kapitola). Z obou těchto důvodů je koncentrace volného hemu v cytosolu buněk objektivně velmi nízká (v rozsahu cca 100 nmol l -1 ) 18,20,21 . Navíc se zdá, že v buňkách existují chaperony resp.…”