Protoporphyrin ferrochelatase is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX in the heme biosynthesis pathway to form heme B. The enzyme is localized to the matrix-facing side of the inner mitochondrial membrane.
Human ferrochelatase is a homodimer composed of two 359 amino acid polypeptide chains. It has a total molecular weight of 85.07 kDa.
The active pocket of ferrochelatase consists of two hydrophobic “lips” and a hydrophilic interior. The interior of the active site pocket contains a highly conserved acidic surface that facilitates proton extraction from protoporphyrin. Histidine and aspartate residues roughly 20 angstroms from the center of the active site on the mitochondrial matrix side of the enzyme coordinate metal binding.
Back in 2016 Bernhard Kuster using chemical proteomics identified ferrochelatase as a common off-target of kinase inhibitors - 29 out of 226 clinical kinase inhibitors were found to be binding FECH at low or submicromolar concentrations, and inhibiting its enzymatic activity in cells.
Later, using thermal proteome profiling, we’ve observed that other classes of small molecule drugs bind to FECH, including:
alpha/beta blockers, such as prazosin and doxazosin,
estrogen receptor modulators, such as raloxifene and bazedoxifene,
xanthine oxidase inhibitors, sush as febuxostat.
Such wide list of potential binders makes ferrochelatase one of the most promiscuous protein targets in human cells. Few questions remain open:
is there any biological consequence of these clinical drugs binding to ferrochelatase?
what drives specificity of drug-FECH binding? Can we predict it based on structure of the small molecule?
should we try to avoid such binding when designing new drugs?