PGI

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Phosphoglucose isomerase, as its name suggests, is the enzyme crucial for the interconversion of D-glucose 6-phosphate and D-fructose 6-phosphate.  PGI is the enzyme responsible for the second step of glycolysis and is involved in glucogenesis.  Thus, it is highly conserved in bacteria and eukaryotes.  Besides functioning as an isomerase, PGI serves as a neuroleukin, autocrine motility factor, and a differentiation and maturation mediator.  Neuroleukins, potent cytokins, are secreted by T-cells and promote the survival of specific embryonic and sensory nerves. In addition, neuroleukins allow B cells to mature into antibody secreting cells.  Autocrine motility factor causes cancer cells to migrate and appears to be involved in tumor metasis and invasion.  Further, it has been shown that differentiation and maturation mediator cause differentiation of myeloid leukemia H-60 cells to terminal monocytic cells. Thus, phosphoglucose isomerase is one protein with four unique functions.

Figure 1. Structure of Phosphoglucose isomerase.

Introductions

It is thought that each of these functions is controlled by a unique active site.  This makes PGI a classic example of a moonlighting protein, a protein that has more than one independent function.  Originally it was estimated that there are 80,000 to 100,000 genes in the human genome.  However, with the completion of the sequence of the human genome, it is now estimated that there are closer to 30,000 total genes.  One possible explanation for this discrepancy is moonlighting proteins which perform multiple functions.  Other examples of moonlighting proteins found in the literature include Thrombin, an enzyme that causes blood to clot and functions as a cytokin. Further, Methionine aminopeptidase removes the amino-terminal methoinine residue from synthesized proteins and acts as a specific co-factor in translational machinery of the ribosome.

Structures

Rabbit PG1 is a dimer composed of two chemically identical polypeptide chains, each of which is composed of 555 amino acids. Each subunit of the dimer contains two separate β sheets and is surrounded by α helices. Alpha helix and beta sheet constitute two asymmetric domains in each subunit. The small domain contains a central five-strand parallel β sheet surrounded by loops and α helices, while the large domain has four parallel β-strands and two anti-parallel strands near the N-terminus. The carboxy terminus of each subunit consists of two helices and a loop extending into the adjacent subunit. The amino terminus consists of 36 amino acid residues, forming an alpha helix, followed by a loop and a beta sheet. Hooks may participate in extracellular functions or the attachment of subunits, extending from the side of each subunit in a helix-turn-helix motif. Therefore, a subunit clearly shows the relative position of the carboxy terminal amino terminal and the hook. Each subunit is co-crystallized with 6-phosphogluconate (an inhibitor). It is believed that PGI has a unique secondary structure.

Mechanism of Isomerization

In the proposed mechanism of isomerization, the cyclic form of glucose 6-phosphate binds to the active site and its ring oxygen is protonated by the enzyme.  This would cause the ring to open and the C-2 proton of glucose 6-phosphate to become relatively acidic. His-388 in a His-388/Glu-216 catalytic diad deprotonates C-2 causing an electron shift that results in the formation of a double bond between between C-1 and C-2. This is accompanied by the addition of a proton from Lys-518and the formation of the cis-enediol intermediate. 

Clinical significance

• Acute myocardial infarction can cause the patient's serum GPI activity to increase, reaching a peak value within 24 hours after chest pain, and quickly returning to normal within 48 hours to 3 days. 63% of patients with decompensated heart failure may be due to tissue hypoxia, leading to increased GPI activity.
• Serum GPI activity is significantly increased in acute hepatitis.
• The most prominent change in GPI activity is seen in patients with various types of lung cancer, and the increase is about 6 times the control value.
• Other malignant tumors can also cause increased serum GPI activity.
• In primary muscle and dermatomyositis, the patient's serum GPI activity increases.
• Children with GPI congenital defects often have chronic hemolysis.
• About 60% of patients with central nervous system malignant tumors have elevated enzyme activity in cerebrospinal fluid, while those with benign tumors have normal enzyme activities.
• Patients with bacterial or tuberculous meningitis have elevated GPI activity in the cerebrospinal fluid.
• GPI activity in vaginal fluid of patients with uterine cancer is significantly increased.