Adenylate kinase
Encyclopedia
Adenylate kinase is a phosphotransferase
enzyme
that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis.
2 ADP
⇔ ATP
+ AMP
The equilibrium constant varies with condition, but is close to 1. Thus, the ΔGo for this reaction is close to zero. In muscle of a variety of species of vertebrates and invertebrates, the concentration of ATP
is typically 7-10 times that of ADP
, and usually greater than 100 times that of AMP
. The rate of oxidative phosphorylation
is controlled by the availability of ADP. Thus, the mitochondrion attempts to keep ATP
levels high due to the combined action of adenylate kinase and the controls on oxidative phosphorylation
.
. These specifically bind AMP
and favor binding to ATP
over other nucleotide triphosphates (AK1 is cytosolic and AK2
is located in the mitochondria). A third ADK has been identified in bovine heart and human cells, this is a mitochondrial GTP:AMP phosphotransferase, also specific for the phosphorylation of AMP, but can only use GTP or ITP as a substrate. ADK has also been identified in different bacterial species and in yeast. Two further enzymes are known to be related to the ADK family, i.e. yeast uridine monophosphokinase and slime mold UMP-CMP kinase. Within the ADK family there are several conserved regions, including the ATP-binding domains. One of the most conserved areas includes an Arg residue, whose modification inactivates the enzyme, together with an Asp that resides in the catalytic cleft of the enzyme and participates in a salt bridge.
A 2007 study by Whitford et al. shows the conformations of ADK when binding with ATP or AMP. The study shows that there are three relevant conformations or structures of ADK—CORE, Open, and Closed. In ADK, there are two small domains called the LID and NMP. ATP binds in the pocket formed by the LID and CORE domains. AMP binds in the pocket formed by the NMP and CORE domains.
The study also reported findings that show that localized regions of a protein unfold during conformational transitions. This mechanism reduces the strain
and enhances catalytic efficiency. Local unfolding is the result of competing strain energies in the protein. The interconversion between inactive (open) and active (closed) conformations is rate limiting for catalysis.
Through a chain of sequential reactions, ADK facilitates transfer and utilization of γ- and β-phosphoryls in the ATP molecule.
concentrations.
ADK reads the cellular energy state, generates, tunes, and communicates AMP signals to metabolic sensors. In this way, ADK is able to convey information about the overall energy balance. AMP-sensors inhibit ATP consumption and promote ATP production.
triphosphates. In mutated Escherichia coli
that had a disrupted nucleoside diphosphate kinase, adenylate kinase performed dual enzymatic functions. ADK complements nucleoside diphosphate kinase deficiency.
. This is a rare hereditary erythroenzymopathy that, in some cases, is associated with mental retardation and psychomotor impairment. At least two patients have exhibited neonatal icterus and splenomegaly and required blood transfusions due to this deficiency. In another patient, an abnormal fragment with homozygous and heterozygous A-->G substitutions at codon 164 caused severe erythrocyte ADK deficiency. Two siblings had erythrocyte ADK deficiency, but one did not have evidence of hemolysis
.
) deficiency in humans causes hematopoietic defects associated with sensorineural deafness. Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency
. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear
which indicates why individuals with an AK2 deficiency will have sensorineural deafness.
and mitochondrial metabolism. This supports muscle energy metabolism.
.
Phosphotransferase
Phosphotransferases are a category of enzymes that catalyze phosphorylation reactions. The general form of the reactions they catalyze is: A—P + B ⇔ B—P + A...
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...
that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis.
Substrate and products
The reaction catalyzed is:2 ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
⇔ 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...
+ 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...
The equilibrium constant varies with condition, but is close to 1. Thus, the ΔGo for this reaction is close to zero. In muscle of a variety of species of vertebrates and invertebrates, the concentration of 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...
is typically 7-10 times that of ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, and usually greater than 100 times that 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...
. The rate of oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
is controlled by the availability of ADP. Thus, the mitochondrion attempts to keep 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...
levels high due to the combined action of adenylate kinase and the controls on oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
.
ADK isozymes
This is an essential reaction for many processes in living cells. Two ADK isozymes have been identified in mammalian cellsCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. These specifically bind 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...
and favor binding to 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...
over other nucleotide triphosphates (AK1 is cytosolic and AK2
AK2
Adenylate kinase 2 is an enzyme is encoded in humans by the AK2 gene. The AK2 protein is found in the intermembrane space of the mitochondrian.- Function :...
is located in the mitochondria). A third ADK has been identified in bovine heart and human cells, this is a mitochondrial GTP:AMP phosphotransferase, also specific for the phosphorylation of AMP, but can only use GTP or ITP as a substrate. ADK has also been identified in different bacterial species and in yeast. Two further enzymes are known to be related to the ADK family, i.e. yeast uridine monophosphokinase and slime mold UMP-CMP kinase. Within the ADK family there are several conserved regions, including the ATP-binding domains. One of the most conserved areas includes an Arg residue, whose modification inactivates the enzyme, together with an Asp that resides in the catalytic cleft of the enzyme and participates in a salt bridge.
Subfamilies
- Adenylate kinase, subfamily
- UMP-CMP kinase
- Adenylate kinase, isozyme 1
Isozymes
Human genes encoding proteins with adenylate kinase include:- AK1, AK2AK2Adenylate kinase 2 is an enzyme is encoded in humans by the AK2 gene. The AK2 protein is found in the intermembrane space of the mitochondrian.- Function :...
, AK3, AK3L1AK3L1Adenylate kinase isoenzyme 4, mitochondrial is an enzyme that in humans is encoded by the AK3L1 gene.-Further reading:...
, AK5, CMPK1, CMPK2
Mechanism
In Escherichia coli, the crystal structure of ADK was analyzed in a 2005 study. The crystal structure revealed that ADK was complexed with diadenosine pentaphosphate (AP5A), Mg2+, and 4 coordinated water molecules. ATP adenine and ribose moieties are loosely bound to ADK. The phosphates in ATP are strongly bound to surrounding residues. Mg2+, coordination waters, and surrounding charged residues maintain the geometry and distances of the AMP α-phosphate and ATP β- and γ-phosphates. And, this is sufficient to support an associative reaction mechanism for phosphoryl transfer. ADK catalyzes a phosphoryl group from ATP to AMP by nucleophilic attack on the γ-phosphate of ATP.Structure
Flexibility and plasticity allow proteins to bind to ligands, form oligomers, aggregate, and perform mechanical work. Large conformational changes in proteins play an important role in cellular signaling. Adenylate Kinase is a signal transducing protein; thus, the balance between conformations regulates protein activity. ADK has a locally unfolded state that becomes depopulated upon binding.A 2007 study by Whitford et al. shows the conformations of ADK when binding with ATP or AMP. The study shows that there are three relevant conformations or structures of ADK—CORE, Open, and Closed. In ADK, there are two small domains called the LID and NMP. ATP binds in the pocket formed by the LID and CORE domains. AMP binds in the pocket formed by the NMP and CORE domains.
The study also reported findings that show that localized regions of a protein unfold during conformational transitions. This mechanism reduces the strain
Strain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a micro-organism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...
and enhances catalytic efficiency. Local unfolding is the result of competing strain energies in the protein. The interconversion between inactive (open) and active (closed) conformations is rate limiting for catalysis.
Metabolic monitoring
ADK uses AMP metabolic signals produced or downregulated during exercise, stress response, food consumption, hormone changes. ADK relays deliver AMP signals to metabolic sensors. It facilitates decoding of cellular information by catalyzing nucleotide exchange in the intimate “sensing zone” of metabolic sensors.Through a chain of sequential reactions, ADK facilitates transfer and utilization of γ- and β-phosphoryls in the ATP molecule.
ADK shuttle
The energy of two high-energy phosphoryls, γ- and β-phosphoryls in the ATP molecule, is made available by the ADK present in mitochondrial and myofibrillar compartments. ATP and AMP are transferred between ATP-production and ATP-consumption sights that involve multiple, sequential phosphotransfer relays. This results in a flux wave propagation along groups of ADK molecules. This ligand conduction mechanism facilitates metabolic flux without apparent changes in metaboliteMetabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
concentrations.
ADK reads the cellular energy state, generates, tunes, and communicates AMP signals to metabolic sensors. In this way, ADK is able to convey information about the overall energy balance. AMP-sensors inhibit ATP consumption and promote ATP production.
Nucleoside diphosphate kinase deficiency
Nucleoside diphosphate (NDP) kinase catalyzes in vivo ATP-dependent synthesis of riobo- and deoxyribonucleosideDeoxyribonucleoside
A deoxyribonucleoside is a type of nucleoside including deoxyribose as a component.An example is deoxycytidine....
triphosphates. In mutated Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
that had a disrupted nucleoside diphosphate kinase, adenylate kinase performed dual enzymatic functions. ADK complements nucleoside diphosphate kinase deficiency.
Hemolytic anemia
Adenylate kinase deficiency in the erythrocyte is associated with hemolytic anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. This is a rare hereditary erythroenzymopathy that, in some cases, is associated with mental retardation and psychomotor impairment. At least two patients have exhibited neonatal icterus and splenomegaly and required blood transfusions due to this deficiency. In another patient, an abnormal fragment with homozygous and heterozygous A-->G substitutions at codon 164 caused severe erythrocyte ADK deficiency. Two siblings had erythrocyte ADK deficiency, but one did not have evidence of hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
.
AK1 and post-ischemic coronary reflow
Knock out of AK1 disrupts the synchrony between inorganic phosphate and turnover at ATP-consuming sites and ATP synthesis sites. This reduces the energetic signal communication in the post-ischemic heart and precipitates inadequate coronary reflow flowing ischemia-reperfusion.ADK2 deficiency
Adenylate Kinase 2 (AK2AK2
Adenylate kinase 2 is an enzyme is encoded in humans by the AK2 gene. The AK2 protein is found in the intermembrane space of the mitochondrian.- Function :...
) deficiency in humans causes hematopoietic defects associated with sensorineural deafness. Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear
Inner ear
The inner ear is the innermost part of the vertebrate ear. In mammals, it consists of the bony labyrinth, a hollow cavity in the temporal bone of the skull with a system of passages comprising two main functional parts:...
which indicates why individuals with an AK2 deficiency will have sensorineural deafness.
Structural adaptations
AK1 genetic ablation decreases tolerance to metabolic stress. AK1 deficiency induces fiber-type specific variation in groups of transcripts in glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and mitochondrial metabolism. This supports muscle energy metabolism.
Plastidial ADK deficiency in Arabidopsis thaliana
Enhanced growth and elevated photosynthetic amino acid is associated with plastidial adenylate kinase deficiency in Arabidopsis thalianaArabidopsis thaliana
Arabidopsis thaliana is a small flowering plant native to Europe, Asia, and northwestern Africa. A spring annual with a relatively short life cycle, arabidopsis is popular as a model organism in plant biology and genetics...
.