The family of heme-containing proteins is vast, and heme proteins are responsible for a multitude of catalytic and non-catalytic functions that are essential for the survival of almost all organisms. Well-known functions of heme proteins include electron-transfer, respiration, and oxygen transport; and oxidative heme enzymes are central to many metabolic pathways in biology. Recently, however, this decades-long picture of the role of heme in biology has needed revision, in the light of a persuasive body of evidence that demonstrates heme is a primary or secondary regulator of other complex processes in cells. These newly discovered roles for heme include transcriptional regulation of the circadian clock, neurodegeneration and aging, and the gating of ion channels (1-3).
For heme to have such wide-ranging control over so many cellular processes, it follows that the supply of heme and its distribution around the cell must be highly coordinated, to respond to levels of demand and to ensure timely availability of the tetrapyrrole (4). The supply of heme is dependent on the processes that control heme biosynthesis (an 8-step enzymatic process) and heme degradation (catalysed by heme oxygenase). The interplay between these two opposing processes, and how they connect to the much wider aspects of cellular function, is not understood.
To address this question, we have built sensors to quantify heme concentrations (5). Using these methods, we examined how alterations in intracellular heme levels affect the balance between heme biosynthesis and degradation. The results demonstrate a timely, wide-ranging and well-coordinated strategy to cope with perturbations in heme concentration that extend far beyond the immediate need for direct regulation of heme synthesis and degradation.
1. Kapetanaki, S. M.; Raven, E. L. et al. 2018 Nat Commun 9, 907.
2. Burton, M. J.; Raven, E. L. et al. 2020 J Biol Chem 295, 13277-13286.
3. Freeman, S. L.; Raven, E. L. et al. 2019 PNAS 116, 19911-19916.
4. Gallio, A. E.; Fung, S. S.; Cammack-Najera, A.; Hudson, A. J.; Raven, E. L. 2021 JACS Au 1, 1541-1555.
5. Leung, G. C.; Gallio, A. E.; Hudson, A. J.; Raven, E. L. et al. 2021 PNAS 118, e2104008118.