fructose ring. Isomerization of glucose Glucose 6-phosphate binds to GPI in its pyranose form. The ring is opened in a "push-pull" mechanism by His388, which protonates the C5 oxygen, and Lys518, which deprotonates the C1 hydroxyl group. This creates an open chain aldose. Then, the substrate is rotated about the C3-C4 bond to position it for isomerization. At this point, Glu357 deprotonates C2 to create a cis-enediolate intermediate stabilized by Arg272. To complete the isomerization, Glu357 donates its proton to C1, the C2 hydroxyl group loses its proton and the open-chain ketose fructose 6-phosphate is formed. Finally, the ring is closed by rotating the substrate about the C3-C4 bond again and deprotonating the C5 hydroxyl with Lys518. Function This gene belongs to the GPI family. The protein encoded by this gene is a dimeric enzyme that catalyzes the reversible isomerization of G6P and F6P. Since the reaction is reversible, its direction is determined by G6P and F6P concentrations. glucose 6-phosphate ↔ fructose 6-phosphate The protein has different functions inside and outside the cell. In the cytoplasm, the protein is involved in glycolysis and gluconeogenesis, as well as the pentose phosphate pathway. Outside the cell, it functions as a neurotrophic factor for spinal and sensory neurons, called neuroleukin. The same protein is also secreted by cancer cells, where it is called autocrine motility factor and stimulates metastasis. Extracellular GPI is also known to function as a maturation factor. Neuroleukin Though originally treated as separate proteins, cloning technology demonstrated that GPI is almost identical to the protein neuroleukin. Neuroleukin is a neurotrophic factor for spinal and sensory neurons. It is found in large amounts in muscle, brain, heart, and kidneys. Neuroleukin also acts as a lymphokine secreted by T cells stimulated by lectin. It induces immunoglobulin secretion in B cells as part of a response that activates antibody-secreting cells. Autocrine motility factor Cloning experiments also revealed that GPI is identical to the protein known as autocrine motility factor (AMF). AMF produced and secreted by cancer cells and stimulates cell growth and motility as a growth factor. AMF is thought to play a key role in cancer metastasis by activating the MAPK/ERK or PI3K/AKT pathways. In the PI3K/AKT pathway, AMF interacts with gp78/AMFR to regulate ER calcium release, and therefore protect against apoptosis in response to ER stress. Prokaryotic bifunctional glucose-6-phosphate isomerase In some archaea and bacteria glucose-6-phosphate isomerase activity occurs via a