Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme ( ) that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme (glucose-6-phosphate isomerase) that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein (also referred to as neuroleukin) functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia, and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014] Structure Functional GPI is a 64-kDa dimer composed of two identical monomers. The two monomers interact notably through the two protrusions in a hugging embrace. The active site of each monomer is formed by a cleft between the two domains and the dimer interface. GPI monomers are made of two domains, one made of two separate segments called the large domain and the other made of the segment in between called the small domain. The two domains are each αβα sandwiches, with the small domain containing a five-strand β-sheet surrounded by α-helices while the large domain has a six-stranded β-sheet. The large domain, located at the N-terminal, and the C-terminal of each monomer also contain "arm-like" protrusions. Several residues in the small domain serve to bind phosphate, while other residues, particularly His388, from the large and C-terminal domains are crucial to the sugar ring-opening step catalyzed by this enzyme. Since the isomerization activity occurs at the dimer interface, the dimer structure of this enzyme is critical to its catalytic function. It is hypothesized that serine phosphorylation of this protein induces a conformational change to its secretory form. Mechanism The mechanism that GPI uses to interconvert glucose 6-phosphate and fructose 6-phosphate (aldose to ketose) consists of three major steps: opening the glucose ring, isomerizing glucose into fructose through an enediol intermediate, and closing the