Glucose-6-phosphate exchanger SLC37A4, also known as glucose-6-phosphate translocase, is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''SLC37A4''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
It consists of three
subunits, each of which are vital components of the multi-enzyme
Glucose-6-Phosphatase
The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:
: D-glucose 6-pho ...
Complex (G6Pase). This important enzyme complex is located within the
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
of the
endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
, and catalyzes the terminal reactions in both
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanis ...
and
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
.
The G6Pase complex is most abundant in liver tissue, but also present in
kidney cells,
small intestine
The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
,
pancreatic islets
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...
and at a lower concentration in the
gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...
.
The G6Pase complex is highly involved in the regulation of
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
and
blood glucose
The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly blood sugar regulation, regulates blood glucose levels as a part of metabolic homeostasis ...
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
Glucose-6-phosphate translocase is a transmembrane protein providing a selective channel between the
endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
lumen and the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. The enzyme is made up of three separate transporting 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 translocases are spatially located on either side of the active site of the hydrolyzing component within the membrane, which allows the greatest speed and facility of the reaction.
Mechanism
Each of the translocase subunits performs a specific function in the transport of
substrate
Substrate may refer to:
Physical layers
*Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
** Substrate (aquatic environment), the earthy material that exi ...
s 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
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
from the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
into the
lumen of the endoplasmic reticulum, where it is
hydrolyzed
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
by the catalytic subunit of G6Pase. After hydrolysis,
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
and
inorganic phosphate
Phosphates are the naturally occurring form of the element phosphorus.
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphor ...
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
hydrolase
In biochemistry, hydrolases constitute a class of enzymes that commonly function as biochemical catalysts that use water to break a chemical bond:
:\ce \quad \xrightarrowtext\quad \ce
This typically results in dividing a larger molecule into s ...
, suggesting that G6PT1 alone provides the high specificity for the overall reaction by selective transport into the lumen, where hydrolysis occurs. Supporting evidence for this proposed reaction includes the marked decrease in
substrate specificity
Chemical specificity is the ability of binding site of a macromolecule (such as a protein) to bind specific ligands. The fewer ligands a protein can bind, the greater its specificity.
Specificity describes the strength of binding between a given ...
of
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
upon membrane
degradation.

Figure 1 illustrates the role of G6P-Translocase within the G6Pase complex.
Inhibitors
Many inhibitors of glucose-6-phosphate translocase of novel,
semi-synthetic or natural origin are known and of medical importance.
Genetic algorithm
In computer science and operations research, a genetic algorithm (GA) is a metaheuristic inspired by the process of natural selection that belongs to the larger class of evolutionary algorithms (EA). Genetic algorithms are commonly used to g ...
s for synthesizing novel
inhibitor
Inhibitor or inhibition may refer to:
Biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...
s of G6PT1 have been developed and utilized in
drug discovery
In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...
. Inhibitors of G6PT1 are the most studied as this subunit catalyzes the
rate limiting step
In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of the ...
in glucose production through gluconeogenesis or glycogenolysis, and without its function these two processes could not occur. This inhibition holds great potential in drug development (discussed in "Medical and Disease Relevance").
Small-molecule
In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; t ...
inhibitors, such as mercaptopicolinic acid and diazobenzene sulfonate have some degree of inhibiting potential for G6PT1 but systematically lack
specificity in inhibition, rendering them poor drug candidates.
Since the late 1990s, 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 ''Aspergillus terreus'')
and chlorogenic acid.
Other natural product inhibitors of G6PT1 are found in the
fungi
A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
''Chaetomium carinthiacum'', ''Bauhinia magalandra'' leaves, and
streptomyces
''Streptomyces'', from στρεπτός (''streptós''), meaning "twisted", and μύκης (''múkés''), meaning "fungus", is the largest genus of Actinomycetota, and the type genus of the family Streptomycetaceae. Over 700 species of ''St ...
bacteria.
Medical and disease relevance
1) Excessive activity of G6PT1 may contribute to the development of diabetes.
Diabetes mellitus type 2
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
is a disease characterized by chronically elevated blood glucose levels, even when
fasting
Fasting is the act of refraining from eating, and sometimes drinking. However, from a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (before "breakfast"), or to the metabolic sta ...
.
The rapidly rising prevalence of type 2 diabetes, along with its strong correlation to heart disease and other health complications 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. It is possible that this mechanism of inhibition could be developed into a treatment for diabetes.
2) The absence of a functional G6PT1 enzyme causes
glycogen storage disease type I
Glycogen storage disease type I (GSD I) is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD ...
b, commonly referred to as
von Gierke disease, in humans. A common symptom of this disease is a build-up of
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
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 and
proliferation.
See also
*
Solute carrier family
The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO ...
References
Further reading
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{{Membrane transport proteins
Membrane proteins
Solute carrier family