bifunctional enzyme that also exhibits phosphomannose isomerase (PMI) activity. Though not closely related to eukaryotic GPIs, the bifunctional enzyme is similar enough that the sequence includes the cluster of threonines and serines that forms the sugar phosphate-binding site in conventional GPI. The enzyme is thought to use the same catalytic mechanisms for both glucose ring-opening and isomerization for the interconversion of G6P to F6P. Clinical significance A deficiency of GPI is responsible for 4% of the hemolytic anemias due to glycolytic enzyme deficiencies. Several cases of GPI deficiency have recently been identified. Elevated serum GPI levels have been used as a prognostic biomarker for colorectal, breast, lung, kidney, gastrointestinal, and other cancers. As AMF, GPI is attributed with regulating cell migration during invasion and metastasis. One study showed that the external layers of breast tumor spheroids (BTS) secrete GPI, which induces epithelial–mesenchymal transition (EMT), invasion, and metastasis in BTS. The GPI inhibitors ERI4P and 6PG were found to block metastasis of BTS but not BTS glycolysis or fibroblast viability. In addition, GPI is secreted exclusively by tumor cells and not normal cells. For these reasons, GPI inhibitors may be a safer, more targeted approach for anti-cancer therapy. GPI also participates in a positive feedback loop with HER2, a major breast cancer therapeutic target, as GPI enhances HER2 expression and HER2 overexpression enhances GPI expression, and so on. As a result, GPI activity likely confers resistance in breast cancer cells against HER2-based therapies using Herceptin/Trastuzumab, and should be considered as an additional target when treating patients. Applications Human GPI is capable of inducing arthritis in mice with varied genetic backgrounds via intradermal injection. See also Fructose-1-phosphate-aldolase enzyme, which converts fructose to glucose Interactions GPI is known to interact with: AMFR, and HER2. Interactive pathway map References Further reading External links Glucose-6-phosphate isomerase in PROSITE Phosphoglucose Isomerase Glucose phosphate isomerase deficiency Protein domains EC 5.3.1 Tumor markers Glycolysis enzymes Glycolysis