Fructose bisphosphatase deficiency
Encyclopedia
In Fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase
for gluconeogenesis
to occur correctly. Glycolysis
(the break-down of glucose
) will still work, as it does not use this enzyme.
stores have been exhausted, and the body has to rely on GNG. When given a dose of glucagon
(which would normally increase blood glucose) nothing will happen, as stores are depleted and GNG doesn't work. (In fact, the patient would already have high glucagon levels.)
There is no problem with the metabolism of glucose or galactose, but fructose
and glycerol
cannot be used as fuels. If fructose or glycerol are given, there will be a build up of phosphorylated three-carbon sugars. This leads to phosphate
depletion within the cells, and also in the blood. Without phosphate, ATP
cannot be made, and many cell processes cannot occur.
High levels of glucagon will tend to release fatty acid
s from adipose tissue
, and this will combine with glycerol
that cannot be used in the liver, to make triacylglycerides causing a fatty liver
.
As three carbon molecules cannot be used to make glucose, they will instead be made into pyruvate and lactate
. These acids cause a drop in the pH
of the blood (a metabolic acidosis
). Acetyl CoA (acetyl co-enzyme A) will also build up, leading to the creation of ketone bodies
.
which breaks down to fructose).
As with all single-gene metabolic disorders, there is always hope for genetic therapy, inserting a healthy copy of the gene into existing liver cells.
Fructose bisphosphatase
Fructose bisphosphatase is an enzyme in the liver that converts fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis . Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase, which is involved in the process of glycolysis...
for gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
to occur correctly. Glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
(the break-down of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
) will still work, as it does not use this enzyme.
Presentation
Without effective gluconeogenesis (GNG), hypoglycaemia will set in after about 12 hours. This is the time when liver glycogenGlycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
stores have been exhausted, and the body has to rely on GNG. When given a dose of glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
(which would normally increase blood glucose) nothing will happen, as stores are depleted and GNG doesn't work. (In fact, the patient would already have high glucagon levels.)
There is no problem with the metabolism of glucose or galactose, but fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
and glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
cannot be used as fuels. If fructose or glycerol are given, there will be a build up of phosphorylated three-carbon sugars. This leads to phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
depletion within the cells, and also in the blood. Without phosphate, ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
cannot be made, and many cell processes cannot occur.
High levels of glucagon will tend to release fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s from adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, and this will combine with glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
that cannot be used in the liver, to make triacylglycerides causing a fatty liver
Fatty liver
Fatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
.
As three carbon molecules cannot be used to make glucose, they will instead be made into pyruvate and lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
. These acids cause a drop in the pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of the blood (a metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
). Acetyl CoA (acetyl co-enzyme A) will also build up, leading to the creation of ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...
.
Treatment
To treat people with a deficiency of this enzyme, they must avoid needing gluconeogenesis to make glucose. This can be accomplished by not fasting for long periods, and eating high-carbohydrate food. They should avoid fructose containing foods (as well as sucroseSucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
which breaks down to fructose).
As with all single-gene metabolic disorders, there is always hope for genetic therapy, inserting a healthy copy of the gene into existing liver cells.