New human bisphosphoglycerate mutase structures provide insights into the structural basis of BPGM deficiency and citrate inhibition.

Erythrocyte bisphosphoglycerate mutase (BPGM) plays a major role in regulating hemoglobin (Hb) oxygen affinity by controlling levels of its allosteric effector 2,3-bisphosphoglycerate (2,3-BPG). Besides its well-documented function in glycolysis, BPGM has been proposed as a regulator of serine pathway flux via 3-phosphoglycerate and as an antimalarial target. In humans, BPGM malfunction reduces intracellular concentrations of 2,3-BPG, producing a leftward shift in the hemoglobin‑oxygen dissociation curve. This shift enhances the affinity of hemoglobin for oxygen, thereby impairing oxygen release to peripheral tissues. The resulting tissue hypoxia induces a compensatory erythropoietic response that clinically manifests as polycythemia/ erythrocytosis, characteristic of familial erythrocytosis type 8 (ECYT8). BPGM deficiency is rare, and a comprehensive study has been conducted in only a few patients with this disease, revealing different missense mutations. In the present study, we structurally characterized clinical variants of human BPGM (hBPGM), i.e., Arg62Gln, Arg90Cys, Arg90His, and Gln102Lys, in order to explore the molecular basis of this rare disease. Analysis of the four structural models and of a new citrate-bound hBPGM structure yielded a partial description of further open/closed conformational changes associated with enzyme activity.