User:Baileypatricia/draft article on G6PT

Introduction
Glucose-6-Phosphate Translocase is an enzyme, encoded by the SLC37A4 gene. It consists of three subunits, each of which are vital components of the multienzyme Glucose-6-Phosphatase Complex (G6Pase). This important enzyme complex is located within the membrane of the endoplasmic reticulum, and catalyzes the terminal reactions in both glycogenolysis and gluconeogenesis. The G6Pase complex is most abundant in liver tissue, but also present in kidney cells, small intestine, pancreatic islets and at a lower concentration in the gallbladder. The G6Pase complex is highly involved in regulation of homeostasis and blood glucose levels. Within this framework of glucose regulation, the translocase components are responsible for transporting the substrates and products across the endoplasmic reticulum membrane, resulting in the release of free glucose into the bloodstream.

Structure
The exact structure of the translocase components remain unresolved, however glucose-6-phosphate translocase is made up of 3 subunits referred to as G6PT1 (subunit 1), G6PT2 (subunit 2) and G6PT3 (subunit 3). While the hydrolyzing component of the G6Pase complex is located on the side of the membrane on which it acts, namely facing the lumen, the translocases are all integral membrane proteins in order to perform their function as cross-membrane transporters. The spatial location of the translocases within the membrane are likely to be found on either side of the active site of the hydrolyzing component, in order to best facilitate the reaction.

Mechanism
Each of the translocase subunits performs a specific function in the transport substrates and products, and finally release of glucose (which will eventually reach the bloodstream), as a step in glycogenolysis or gluconeogenesis. G6PT1 transports Glucose-6-Phosphate from the cytosol into the lumen of the endoplasmic reticulum, where it is hydrolyzed by the catalytic subunit of G6Pase. After hydrolysis, glucose and inorganic phosphate are transported back into the cytosol by G6PT2 and G6PT3, respectively. While the exact chemistry of the enzyme remains unknown, studies have shown that the mechanism of the enzyme complex is highly dependent upon the membrane structure. For instance, the Michaelis Constant of the enzyme for glucose-6-phosphate decreases significantly upon membrane disruption. The originally proposed mechanism of the G6Pase system involved a relatively unspecific hydrolysis enzyme, suggesting that G6PT1 had provided the high specificity for the overall reaction.

Inhibitors
Many inhibitors of Glucose-6-Phosphate Translocase of novel, semi-synthetic or natural origin are known and of importance considering the medical relevance of the enzyme (see Medical Relevance below). Genetic algorithms for synthesizing novel inhibitors of G6PT1 have been developed and utilized in drug discovery. Inhibitors of G6PT1 are the most studied as this subunit holds the greatest promise as a drug target for disease treatment, as it catalyzes the rate limiting step in glucose production through gluconeogenesis or glycogenolysis and thus without its function, these two processes cannot occur. Small-molecule inhibitors, such as mercaptopicolinic acid and diazobenzene sulfonate have some degree of inhibiting potential for G6PT1 but systematically lack specificity. Since the late 1990's, natural products have been increasingly studied as potent and specific inhibitors of G6PT1. Prominent examples of natural inhibitors include mumbaistatin and analogs, kodaistatin (harvested from extracts of Asperigillus terreus) and chlorogenic acid. Other natural product inhibitors of G6PT1 are found in the fungi Chaetomium carinthiacum, Bauhinia magalandra leaves, and streptomyces bacteria.

Medical and Disease Relevance
1) Excessive activity of G6PT1 may contribute to the development of diabetes. Diabetes mellitus type 2 is a disease characterized by chronically elevated blood glucose levels, even when fasting. The rapidly rising prevalence of type 2 diabetes, along with its strong correlation to coronary heart disease has rendered it an area of intense research with an urgent need for treatment options. Studies monitoring blood glucose levels in rabbits revealed that the activity of G6Pase, and therefore G6PT1, is increased in specimens with diabetes. This strong correlation with diabetes type 2 makes the G6Pase complex, and G6PT1 in particular, an appealing drug target for control of blood glucose levels as its inhibition would directly prevent the release of free glucose into the bloodstream.

2) The absense of a functional G6PT1 enzyme causes glycogen storage disease type 1b, commonly referred to as von Gierke disease, in humans. A common symptom of this disease is a build-up of glycogen in the liver and kidney causing enlargement of the organs.

3) G6PT1 activity contributes to the survival of cells during hypoxia, which enables tumor cell growth.