Kinase

Source: Wikipedia, the free encyclopedia.
For kinases that phosphorylate proteins, see Protein kinase.
Dihydroxyacetone kinase in complex with a non-hydrolyzable ATP analog (AMP-PNP). Coordinates from PDB ID:1UN9.[1]

In

substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group (producing a dephosphorylated substrate and the high energy molecule of ATP). These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.[3][4][5]

Kinases are part of the larger family of

secretory processes
and many other cellular pathways, which makes them very important to physiology.

Biochemistry and functional relevance

phosphoanhydride bond contains a high level of energy. Kinases properly orient their substrate and the phosphoryl group within their active sites, which increases the rate of the reaction. Additionally, they commonly use positively charged amino acid residues, which electrostatically stabilize the transition state by interacting with the negatively charged phosphate groups. Alternatively, some kinases utilize bound metal cofactors in their active sites to coordinate the phosphate groups. Protein kinases can be classed as catalytically active (canonical) or as pseudokinases, reflecting the evolutionary loss of one or more of the catalytic amino acids that position or hydrolyse ATP.[6] However, in terms of signalling outputs and disease relevance, both kinases and pseudokinases are important signalling modulators in human cells, making kinases important drug targets.[7]

Kinases are used extensively to

agammaglobulinaemia, and many others.[10]

History and classification

The first protein to be recognized as catalyzing the phosphorylation of another protein using ATP was observed in 1954 by

calmodulin-dependent protein kinases and the finding that proteins can be phosphorylated on more than one amino acid residue. The 1990s may be described as the "decade of protein kinase cascades". During this time, the MAPK/ERK pathway, the JAK kinases (a family of protein tyrosine kinases), and the PIP3-dependent kinase cascade were discovered.[12]

Kinases are classified into broad groups by the substrate they act upon: protein kinases, lipid kinases, carbohydrate kinases. Kinases can be found in a variety of species, from bacteria to mold to worms to mammals.[13] More than five hundred different kinases have been identified in humans.[3] Their diversity and their role in signaling makes them an interesting object of study. Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways. Specific kinases are often named after their substrates. Protein kinases often have multiple substrates, and proteins can serve as substrates for more than one specific kinase. For this reason protein kinases are named based on what regulates their activity (i.e. Calmodulin-dependent protein kinases). Sometimes they are further subdivided into categories because there are several isoenzymatic forms. For example, type I and type II cyclic-AMP dependent protein kinases have identical catalytic subunits but different regulatory subunits that bind cyclic AMP.[14]

Protein kinases

PI3K
).
Main article: Protein kinase

Protein kinases act on proteins, by phosphorylating them on their serine, threonine, tyrosine, or histidine residues. Phosphorylation can modify the function of a protein in many ways. It can increase or decrease a protein's activity, stabilize it or mark it for destruction, localize it within a specific cellular compartment, and it can initiate or disrupt its interaction with other proteins. The protein kinases make up the majority of all kinases and are widely studied.[15] These kinases, in conjunction with phosphatases, play a major role in protein and enzyme regulation as well as signalling in the cell.

A common point of confusion arises when thinking about the different ways a cell achieves biological regulation. There are countless examples of covalent modifications that cellular proteins can undergo; however, phosphorylation is one of the few reversible covalent modifications. This provided the rationale that phosphorylation of proteins is regulatory. The potential to regulate protein function is enormous given that there are many ways to covalently modify a protein in addition to regulation provided by allosteric control. In his Hopkins Memorial Lecture,

Edwin Krebs asserted that allosteric control evolved to respond to signals arising from inside the cell, whereas phosphorylation evolved to respond to signals outside of the cell. This idea is consistent with the fact that phosphorylation of proteins occurs much more frequently in eukaryotic cells in comparison to prokaryotic cells because the more complex cell type evolved to respond to a wider array of signals.[14]

Cyclin dependent kinases

phosphatases (such as Cdc25).[17] Once the CDKs are active, they phosphorylate other proteins to change their activity, which leads to events necessary for the next stage of the cell cycle. While they are most known for their function in cell cycle control, CDKs also have roles in transcription, metabolism, and other cellular events.[18]

Because of their key role in the controlling cell division, mutations in CDKs are often found in cancerous cells. These mutations lead to uncontrolled growth of the cells, where they are rapidly going through the whole cell cycle repeatedly.

tumors, and lung cancer. Therefore, inhibitors of CDK have been developed as treatments for some types of cancer.[19]

Mitogen-activated protein kinases

Main article: Mitogen-activated protein kinase

transcription and translation
. Whereas RAF and MAPK are both serine/threonine kinases, MAPKK is a tyrosine/threonine kinase.

A variety of mitogenic signals engage the MAPK pathway and promote cell growth and differentiation through a kinase cascade.

MAPK can regulate transcription factors directly or indirectly. Its major transcriptional targets include ATF-2, Chop, c-Jun, c-Myc, DPC4, Elk-1, Ets1, Max, MEF2C, NFAT4, Sap1a, STATs, Tal, p53, CREB, and Myc. MAPK can also regulate translation by phosphorylating the S6 kinase in the large ribosomal subunit. It can also phosphorylate components in the upstream portion of the MAPK signalling cascade including Ras, Sos, and the

EGF receptor itself.[20]

The carcinogenic potential of the MAPK pathway makes it clinically significant. It is implicated in cell processes that can lead to uncontrolled growth and subsequent tumor formation. Mutations within this pathway alter its regulatory effects on

cell differentiation, proliferation, survival, and apoptosis, all of which are implicated in various forms of cancer.[20]

Lipid kinases

Lipid kinases phosphorylate lipids in the cell, both on the plasma membrane as well as on the membranes of the organelles. The addition of phosphate groups can change the reactivity and localization of the lipid and can be used in signal transmission.

Phosphatidylinositol kinases

See also: Phosphatidylinositol phosphate kinases
Insulin binding to its receptor leads allows PI3 kinase to dock at the membrane where it can phosphorylate PI lipids

Phosphatidylinositol kinases phosphorylate

cellular signalling, such as in the insulin signalling pathway, and also has roles in endocytosis, exocytosis and other trafficking events.[21][22] Mutations in these kinases, such as PI3K, can lead to cancer or insulin resistance.[23]

The kinase enzymes increase the rate of the reactions by making the inositol hydroxyl group more nucleophilic, often using the side chain of an amino acid residue to act as a general base and

deprotonate the hydroxyl, as seen in the mechanism below.[24] Here, a reaction between adenosine triphosphate (ATP) and phosphatidylinositol is coordinated. The end result is a phosphatidylinositol-3-phosphate as well as adenosine diphosphate (ADP). The enzymes can also help to properly orient the ATP molecule, as well as the inositol group, to make the reaction proceed faster. Metal ions are often coordinated for this purpose.[24]

Mechanism of phosphatidylinositol-3 kinase. ATP and phosphatidylinositol react to form phosphatidylinositol-3-phosphate and ADP, with the help of general base B.[24]

Sphingosine kinases

Sphingosine kinase (SK) is a lipid kinase that catalyzes the conversion of

HDACs. In contrast, the dephosphorylated sphingosine promotes cell apoptosis
, and it is therefore critical to understand the regulation of SKs because of its role in determining cell fate. Past research shows that SKs may sustain cancer cell growth because they promote cellular-proliferation, and SK1 (a specific type of SK) is present at higher concentrations in certain types of cancers.

There are two kinases present in mammalian cells, SK1 and SK2. SK1 is more specific compared to SK2, and their expression patterns differ as well. SK1 is expressed in lung, spleen, and leukocyte cells, whereas SK2 is expressed in kidney and liver cells. The involvement of these two kinases in cell survival, proliferation, differentiation, and inflammation makes them viable candidates for chemotherapeutic therapies.[25]

Carbohydrate kinases

Glycolysis includes four phosphorylations, two that create ATP from ADP and two that use ATP and converting it into ADP. Glycolysis is the first step of metabolism and includes ten reaction ultimately resulting in one glucose molecule producing two pyruvate molecules

For many mammals, carbohydrates provide a large portion of the daily

phosphoenolpyruvate
to ADP, generating ATP and pyruvate.

Hexokinase is the most common enzyme that makes use of glucose when it first enters the cell. It converts D-glucose to glucose-6-phosphate by transferring the gamma phosphate of an ATP to the C6 position. This is an important step in glycolysis because it traps glucose inside the cell due to the negative charge. In its dephosphorylated form, glucose can move back and forth across the membrane very easily.[26] Mutations in the hexokinase gene can lead to a hexokinase deficiency which can cause nonspherocytic hemolytic anemia.[27]

Tarui's disease, a glycogen storage disease that leads to exercise intolerance, is due to a mutation in the PFK gene that reduces its activity.[28]

Other kinases

The active site of riboflavin kinase bound to its products--FMN (on left) and ADP (on right). Coordinates from PDB ID: 1N07.[29]

Kinases act upon many other molecules besides proteins, lipids, and carbohydrates. There are many that act on nucleotides (DNA and RNA) including those involved in nucleotide interconverstion, such as

shikimate
, and many others.

Riboflavin kinase

Main article:
cations help coordinate the nucleotide.[31] The general mechanism is shown in the figure below.

Mechanism of riboflavin kinase.

Riboflavin kinase plays an important role in cells, as

redox cofactor used by many enzymes, including many in metabolism. In fact, there are some enzymes that are capable of carrying out both the phosphorylation of riboflavin to FMN, as well as the FMN to FAD reaction.[32] Riboflavin kinase may help prevent stroke, and could possibly be used as a treatment in the future.[33] It is also implicated in infection, when studied in mice.[34]

Thymidine kinase

Main article: Thymidine kinase

Thymidine kinase is one of the many nucleoside kinases that are responsible for nucleoside phosphorylation. It phosphorylates thymidine to create thymidine monophosphate (dTMP). This kinase uses an ATP molecule to supply the phosphate to thymidine, as shown below. This transfer of a phosphate from one nucleotide to another by thymidine kinase, as well as other nucleoside and nucleotide kinases, functions to help control the level of each of the different nucleotides.

Overall reaction catalysed by thymidine kinase.

After creation of the dTMP molecule, another kinase, thymidylate kinase, can act upon dTMP to create the diphosphate form, dTDP. Nucleoside diphosphate kinase catalyzes production of thymidine triphosphate, dTTP, which is used in DNA synthesis. Because of this, thymidine kinase activity is closely correlated with the cell cycle and used as a tumor marker in clinical chemistry.[35] Therefore, it can sometime be used to predict patient prognosis.[36] Patients with mutations in the thymidine kinase gene may have a certain type of mitochondrial DNA depletion syndrome, a disease that leads to death in early childhood.[37]

See also

Wikimedia Commons has media related to Kinases.

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