Deficiency in
ferrochelatase (FECH), the last
enzyme in the
heme biosynthetic pathway, leads to an accumulation of
protoporphyrin IX (
PPIX) that causes a severely painful phototoxic reaction of the skin in patients with
erythropoietic protoporphyria (EPP). Besides
phototoxicity of the skin, EPP patients often present with symptoms of
iron deficiency in form of a microcytic and
hypochromic anemia with low serum
iron and
ferritin. In addition, elevated
aminolevulinic acid synthase 2 (ALAS2) both at the
mRNA and
protein levels have been observed among EPP patients. ALAS is the first
enzyme in the pathway and exists in two
isoforms, whereby the
isoform 2 (ALAS2) is expressed exclusively in erythropoiesis. The
mRNA of ALAS2 contains an
iron response element (IRE) at its
5'UTR. When
iron is limited,
iron response element
binding protein 2 (IRP2) binds to the IRE of ALAS2
mRNA and suppresses its translation. In this study, we demonstrated that
iron deprivation increased the amount of ALAS2
mRNA as well as the ratio of ALAS2 to FECH mRNAs in cultured erythroleukemic K562 cells. At the
protein level, however,
iron deprivation in the cell line caused reductions in both
enzymes as shown by the Western blot analysis. A comparable increase in the ratio of ALAS2 to FECH mRNAs was also found in EPP patients indicating an imbalance in
heme biosynthesis. As
iron cannot be completely missing from an organism, we assume that in EPP patients, a certain amount of ALAS2
mRNA is translated despite a partial deficiency of FECH. The increase in ALAS2
enzyme contributes to the accumulation in
PPIX in the patients. Targeted inhibition of ALAS2 could therefore be a treatment option for EPP.