Glucokinase regulatory protein
Encyclopedia
The glucokinase regulatory protein (GKRP) also known as glucokinase (hexokinase 4) regulator (GCKR) is a protein
produced in hepatocyte
s (liver
cells). GKRP binds and moves glucokinase
(GK), thereby controlling both activity and intracellular location of this key enzyme
of glucose
metabolism
.
GKRP is a 68 kD protein of 626 amino acid
s. It is coded for by a 19 exon
gene
, GCKR, on the short arm of chromosome
2 (2p23). GKRP was discovered by Emile van Schaftingen and reported in 1989
glucose, preparing it for incorporation into glycogen
. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring. As the glucose supply declines during periods of fasting
, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form. As glucose and insulin levels rise, as during digestion
of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the bifunctional enzyme.
In hepatocytes of various mammal
s, GKRP has always been found in molar
excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin
sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton
.
GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm.
GKRP itself is subject to modulation. Fructose
and sorbitol
can both be converted to fructose-1-phosphate
, which inhibits GKRP and frees GK. Fructose 6-phosphate
binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. In contrast, phosphorylation of GKRP by AMP-activated protein kinase
, induced by elevated levels of AMP
, reduces its capacity to inactivate GK.
coding for it, in small amounts in certain rat lung
cells, in pancreatic
islet
cells, and in periventricular neuron
s of the hypothalamus
in rat
s, but physiological function and significance in these organs are unknown.
liver. GKRP was found to serve a similar function in livers of mice
and humans as well as other animals. Cat
s are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome.
(MODY2) or hyperinsulinemic hypoglycemia
, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia.
The glucokinase of "knockout mice
" who lack GKRP is entirely found in the cytoplasm. They do not respond rapidly to glucose, exhibiting impaired glucose tolerance
.
Mutation
s of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY
), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglyceride
s, C-reactive protein
, and higher or lower risks for type 2 diabetes mellitus.
Activators of GK are being investigated as possible medicine
s for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
produced in hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s (liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
cells). GKRP binds and moves glucokinase
Glucokinase
Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates...
(GK), thereby controlling both activity and intracellular location of this key enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
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...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
GKRP is a 68 kD protein of 626 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. It is coded for by a 19 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, GCKR, on the short arm of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
2 (2p23). GKRP was discovered by Emile van Schaftingen and reported in 1989
Physiological function
Glucokinase (GK) in liver cells phosphorylatesPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
glucose, preparing it for incorporation into glycogen
Glycogen
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...
. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring. As the glucose supply declines during periods of fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form. As glucose and insulin levels rise, as during digestion
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the bifunctional enzyme.
In hepatocytes of various mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, GKRP has always been found in molar
Mole (unit)
The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...
excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
.
GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm.
GKRP itself is subject to modulation. 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 sorbitol
Sorbitol
Sorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
can both be converted to fructose-1-phosphate
Fructose-1-phosphate
Fructose-1-phosphate is a derivative of fructose. It is generated by hepatic fructokinase.It is converted by aldolase B into glyceraldehyde and dihydroxyacetone phosphate ....
, which inhibits GKRP and frees GK. Fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. In contrast, phosphorylation of GKRP by AMP-activated protein kinase
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
, induced by elevated levels of AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
, reduces its capacity to inactivate GK.
Presence of GKRP in other organs
A presence and role of GKRP in other organs and tissues beyond the liver remains uncertain. Some researchers have finding small amounts of GKRP, or at least RNARNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
coding for it, in small amounts in certain rat lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
cells, in pancreatic
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
islet
Islet
An islet is a very small island.- Types :As suggested by its origin as islette, an Old French diminutive of "isle", use of the term implies small size, but little attention is given to drawing an upper limit on its applicability....
cells, and in periventricular neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s, but physiological function and significance in these organs are unknown.
Species differences
GKRP was originally discovered in ratRat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
liver. GKRP was found to serve a similar function in livers of mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
and humans as well as other animals. Cat
Cat
The cat , also known as the domestic cat or housecat to distinguish it from other felids and felines, is a small, usually furry, domesticated, carnivorous mammal that is valued by humans for its companionship and for its ability to hunt vermin and household pests...
s are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome.
Clinical significance
Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetesDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
(MODY2) or hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia
Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.-Causes:...
, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia.
The glucokinase of "knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
" who lack GKRP is entirely found in the cytoplasm. They do not respond rapidly to glucose, exhibiting impaired glucose tolerance
Impaired glucose tolerance
Impaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
.
Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY
Mody
Mody may refer to:* Maturity onset diabetes of the young * Hormusjee Naorojee Mody...
), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s, C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
, and higher or lower risks for type 2 diabetes mellitus.
Activators of GK are being investigated as possible medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
s for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP.