I chose phosphoglucose isomerase (GPI) because I like its bilateral symmetry, which reminds me of the shape of the human heart. GPI is the second enzyme in the glycolysis pathway. It is an isomerase, which means no atoms are added or removed. Rather, it changes the shape of glucose 6-phosphate to fructose 6-phosphate and vice versa, based on the cellular needs at the time. The small yellow part in David Goodsell’s image represents fructose-6-phosphate, thus in his drawing, it has just changed a glucose-6-phosphate into a fructose-6-phosphate ("PDB101: Molecule of the Month: Glycolytic Enzymes"). As described in this week’s lecture, this is done by shifting a 6-membered ring into a 5-membered ring. In addition to Goodsell's image, I also included an image from Wikipedia of a rabbit GPI as it has a nice depiction of the alpha-helixes.
Image 1: Drawing by David Goodsell from Molecule of the Month: https://pdb101.rcsb.org/motm/50 Links to an external site.
Image 2: Wikipedia.” Glucose-6-phosphate Isomerase - Wikipedia, en.wikipedia.org/wiki/Glucose-6-phosphate_isomerase
What is fascinating about GPI (also called glucose-6-phosphate isomerase, phosphoglucoisomerase and phospohexose isomerase) is that scientists have recently discovered that this enzyme has numerous other functions, in addition to its activity in the cytosol during glycolysis. Outside the cell, GPI functions as a neurotrophic factor, promoting the growth of motor and sensory nerve cells. In this role, GPI is also sometimes referred to as a neuroleukin. Other important functions of this versatile enzyme include its role as a lymphokine that promotes antibody secretion and as AMF (autocrine motility factor), which gathers at tumor sites and functions as a cytokine (Ahmad et al. 2022).
Although I chose this enzyme randomly, or simply because I liked its shape, an eerie coincidence emerged. Just a few days ago, during a routine check-up, I asked my doctor if there was a blood test that could detect cancer in its early stages. My mother has stage 4 cancer, and it’s tragic that this recurrence of cancer, which she has had three times now, wasn’t caught earlier this time, and had already significantly metastasized. It would save countless lives if there existed a simple blood test to detect early-stage cancer, that people could include as part of routine check-ups. My doctor informed me that such a test does not yet exist, but that scientists are working on it.
How does this relate to GPI, the second enzyme in glycolysis? When GPI is found outside the cell as an AMF, it has been secreted by a tumor and is found in higher concentrations at that site. AMF is structurally identical to GPI but named differently due to its distinct location, function, origin, and role. AMF contributes to metastasis by enabling the movement of tumor cells by decreasing the tumor’s adhesion and fostering its motility, migration, survival, and proliferation (Funasaka et al., 2007).
What is very exciting in cancer research, is that scientists have recently created a biosensor that detects excess phosphoglucose isomerase (or AMF) in human plasma using an enzyme inhibitor that selectively interacts with AMF. The technology can identify excess AMF in 10 minutes. Developing cancer biomarker equipment that is fast, manageable in size, and readily available to the public is revolutionary for the early detection of cancer. And the use of inhibitors as identifiers will be applicable in the early detection of other diseases as well (Ahmad, Lama, et al. 2022). While I initially imagined this post to be an in-depth exploration of one enzyme in one step of glycolysis, I never imagined it would unpack what seems to be a revolutionary technology that may serve as a significant factor in the detection of early cancer.
REFERENCES
“PDB101: Molecule of the Month: Glycolytic Enzymes.” RCSB: PDB-101, pdb101.rcsb.org/motm/50. Accessed 18 Nov. 2022.
“Glucose-6-phosphate Isomerase - Wikipedia.” Glucose-6-phosphate Isomerase - Wikipedia, en.wikipedia.org/wiki/Glucose-6-phosphate_isomerase. Accessed 18 Nov. 2022.
Funasaka, Tatsuyoshi, and Avraham Raz. “The role of autocrine motility factor in tumor and tumor microenvironment.” Cancer metastasis reviews vol. 26,3-4 (2007): 725-35. doi:10.1007/s10555-007-9086-7
Ahmad, Lama, et al. “Electrochemical Detection of the Human Cancer Biomarker ‘Autocrine Motility Factor-Phosphoglucose Isomerase’ Based on a Biosensor Formed with a Monosaccharidic Inhibitor.” Sensors and Actuators. B, Chemical, vol. 299, 2019, p. 126933., https://doi.org/10.1016/j.snb.2019.126933. Accessed 19 Nov. 2022.