Sulfate-Iron Link to Anemia
Sulfation (the addition of a sulfate group to a molecule) is an important biochemical process that aids in the detoxification of xenobiotic compounds and plays a role in the biosynthesis of a variety of molecules. In mammalian cells, sulfation requires PAPS (3´-phosphoadenosine 5´-phosphosulfate), which donates its activated sulfate group to the target molecule, producing PAP (3´-phosphoadenosine 5´-phosphate) as a product. Degradation of cytosolic PAP then occurs through the action of the enzyme Bpnt1 (bisphosphate 3’-nucleotidase). In recent studies, Vanderbilt Basic Sciences investigator John York and his laboratory discovered that mice bearing a genetic deletion of the gene encoding Bpnt1 exhibit iron-deficiency anemia in addition to other abnormalities. To explain the unexpected anemia, the researchers hypothesized that the accumulation of PAP that occurred in the absence of Bpnt1 is toxic to cells. Support for this hypothesis came from Bpnt1-deficient mice that were also deficient for the enzyme that synthesizes PAPS. PAP did not accumulate in the cells of these mice, and they did not suffer from anemia. Further study suggested that the site of PAP toxicity was the intestine, so the York group created a mouse model in which Bpnt1 was deficient only in the intestinal epithelium. These mice developed anemia, but none of the other abnormalities previously associated with Bpnt1 deficiency. The finding that feeding an iron-deficient diet markedly exacerbated the anemia of Bpnt1-deficient mice pointed to a failure of intestinal cells to respond to a lack of available iron. This response relies on signaling controlled by the transcription factor HIF-2α (hypoxia inducible factor 2α), and gene expression analysis demonstrated marked similarities between the intestinal cells of mice deficient in Bpnt1 and mice deficient in HIF-2α. Together, the results suggest that an accumulation of PAP resulting from Bpnt1 deficiency leads to a failure of HIF-2α-dependent signaling in response to iron deficiency. The mechanism linking PAP toxicity to HIF-2α function will be the subject of ongoing research. However, the findings demonstrate a previously unknown link between sulfate and iron metabolism and a possible genetic cause for iron deficiency anemia. It will be interesting to determine if Bpnt1 deficiency is a cause of anemia in humans. If so, then therapy targeting PAPS biosynthesis could be of value. The work is published in the journal Proceedings of the National Academy of Sciences [Hudson, et al., (2018) Proc. Natl. Acad. Sci. U.S.A., 115, 3000].