Editing Kinase

{{short description|Enzyme catalyzing transfer of phosphate groups onto specific substrates}}
{{For|kinases that phosphorylate proteins|Protein kinase}}
[[File:Active site of Dihydroxyacetone Kinase.png|thumb|upright=1.25|[[Dihydroxyacetone]] kinase in complex with a non-hydrolyzable [[Adenosine triphosphate|ATP]] analog (AMP-PNP). Coordinates from PDB ID:1UN9.<ref>{{cite journal | vauthors = Siebold C, Arnold I, Garcia-Alles LF, Baumann U, HErnia B | title = Crystal structure of the Citrobacter freundii dihydroxyacetone kinase reveals an eight-stranded alpha-helical barrel AKTP-binding domain | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 48236–48244 | date = November 2003 | pmid = 12966101 | doi = 10.1074/jbc.M305942200 | doi-access = free }}</ref>]]

In [[biochemistry]], a '''kinase''' ({{IPAc-en|ˈ|k|aɪ|n|eɪ|s|,_|ˈ|k|ɪ|n|eɪ|s|,_|-|eɪ|z}})<ref>{{cite Dictionary.com|kinase|access-date=2022-06-18}}</ref> is an [[enzyme]] that [[catalysis|catalyzes]] the transfer of [[phosphate]] groups from [[High-energy phosphate|high-energy]], phosphate-donating molecules to specific [[Substrate (biochemistry)|substrate]]s. This process is known as [[phosphorylation]], where the high-energy [[adenosine triphosphate|ATP]] molecule donates a phosphate group to the [[substrate (biology)|substrate]] molecule. As a result, kinase produces a phosphorylated substrate and [[Adenosine diphosphate|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]].<ref name="pmid12471243">{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–1934 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | s2cid = 26554314 | bibcode = 2002Sci...298.1912M }}</ref><ref>{{cite web|title=Kinase|url=http://www.thefreedictionary.com/Kinases}} TheFreeDictionary.com</ref><ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/illpres/history.html |title=History of ATP research milestones from an ATP-related chemistry|publisher= Nobelprize.org}}</ref>

Kinases are part of the larger family of [[phosphotransferase]]s. Kinases should not be confused with [[phosphorylase]]s, which catalyze the addition of inorganic phosphate groups to an acceptor, nor with [[phosphatase]]s, which remove phosphate groups (dephosphorylation). The phosphorylation state of a molecule, whether it be a [[protein]], [[lipid]] or [[carbohydrate]], can affect its activity, reactivity and its ability to bind other molecules. Therefore, kinases are critical in [[metabolism]], [[cell signalling]], [[covalent modulation|protein regulation]], [[cellular transport]], [[secretory pathway|secretory processes]] and many other cellular pathways, which makes them very important to physiology.

==Biochemistry and functional relevance==
[[File:Basic phosphorylation reaction.png|thumb|upright=3|General reaction that is catalyzed by kinases]]Kinases mediate the transfer of a phosphate moiety from a high energy molecule (such as [[adenosine triphosphate|ATP]]) to their substrate molecule, as seen in the figure below. Kinases are needed to stabilize this reaction because the [[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 [[Pseudokinase|pseudokinases]], reflecting the evolutionary loss of one or more of the catalytic amino acids that position or hydrolyse ATP.<ref name="pmid24818526">{{cite journal | vauthors = Reiterer V, Eyers PA, Farhan H | title = Day of the dead: pseudokinases and pseudophosphatases in physiology and disease | journal = Trends in Cell Biology | volume = 24 | issue = 9 | pages = 489–505 | date = September 2014 | pmid = 24818526 | doi = 10.1016/j.tcb.2014.03.008 }}</ref> 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.<ref>Foulkes DM, Byrne DP and Eyers PA (2017) Pseudokinases: update on their functions and evaluation as new drug targets. Future Med Chem. 9(2):245-265</ref>

Kinases are used extensively to [[signal transduction|transmit signals]] and regulate complex processes in cells. Phosphorylation of molecules can enhance or inhibit their activity and modulate their ability to interact with other molecules. The addition and removal of phosphoryl groups provides the cell with a means of control because various kinases can respond to different conditions or signals. Mutations in kinases that lead to a loss-of-function or gain-of-function can cause cancer<ref>{{cite news| vauthors = Samarasinghe B |title=Hallmarks of Cancer 1|url=http://blogs.scientificamerican.com/guest-blog/2013/09/18/hallmarks-of-cancer-1-self-sufficiency-in-growth-signals|newspaper=Scientific American}}</ref> and disease in humans, including certain types of [[leukemia]] and [[neuroblastoma]]s, [[glioblastoma]],<ref>{{cite journal | vauthors = Bleeker FE, Lamba S, Zanon C, Molenaar RJ, Hulsebos TJ, Troost D, van Tilborg AA, Vandertop WP, Leenstra S, van Noorden CJ, Bardelli A | display-authors = 6 | title = Mutational profiling of kinases in glioblastoma | journal = BMC Cancer | volume = 14 | pages = 718 | date = September 2014 | pmid = 25256166 | pmc = 4192443 | doi = 10.1186/1471-2407-14-718 | doi-access = free }}</ref> [[spinocerebellar ataxia]] (type 14), forms of [[agammaglobulinaemia]], and many others.<ref>{{cite journal | vauthors = Lahiry P, Torkamani A, Schork NJ, Hegele RA | title = Kinase mutations in human disease: interpreting genotype-phenotype relationships | journal = Nature Reviews. Genetics | volume = 11 | issue = 1 | pages = 60–74 | date = January 2010 | pmid = 20019687 | doi = 10.1038/nrg2707 | s2cid = 37398118 }}</ref>

==History and classification==
<!-- Commented out: [[File:Edwin G. Krebs.jpg|thumb|Edwin Krebs won the Nobel prize in physiology or medicine in 1992 for his contributions to enzymology. He described how phosphorylation is reversible and acts a switch to regulate metabolic processes as well as other cellular pathways.]] -->
The first protein to be recognized as catalyzing the phosphorylation of another protein using ATP was observed in 1954 by [[Eugene P. Kennedy]] at which time he described a liver enzyme that catalyzed the phosphorylation of casein.{{cn|date=March 2023}} In 1956, [[Edmond H. Fischer]] and [[Edwin G. Krebs]] discovered that the interconversion between phosphorylase a and phosphorylase b was mediated by phosphorylation and dephosphorylation.<ref>{{cite journal | vauthors = Krebs EG | title = Historical perspectives on protein phosphorylation and a classification system for protein kinases | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 302 | issue = 1108 | pages = 3–11 | date = July 1983 | pmid = 6137005 | doi = 10.1098/rstb.1983.0033 | doi-access = free | bibcode = 1983RSPTB.302....3K }}</ref> The kinase that transferred a phosphoryl group to Phosphorylase b, converting it to Phosphorylase a, was named Phosphorylase Kinase. Years later, the first example of a kinase cascade was identified, whereby Protein Kinase A (PKA) phosphorylates Phosphorylase Kinase. At the same time, it was found that PKA inhibits [[glycogen synthase]], which was the first example of a phosphorylation event that resulted in inhibition. In 1969, Lester Reed discovered that [[pyruvate dehydrogenase]] was inactivated by phosphorylation, and this discovery was the first clue that phosphorylation might serve as a means of regulation in other metabolic pathways besides [[glycogen]] metabolism. In the same year, Tom Langan discovered that PKA phosphorylates histone H1, which suggested phosphorylation might regulate nonenzymatic proteins. The 1970s included the discovery of [[Ca2+/calmodulin-dependent protein kinase|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 [[janus kinase|JAK kinases]] (a family of protein tyrosine kinases), and the PIP3-dependent kinase cascade were discovered.<ref name=origins>{{cite journal | vauthors = Corbellino M, Poirel L, Aubin JT, Paulli M, Magrini U, Bestetti G, Galli M, Parravicini C | display-authors = 6 | title = The role of human herpesvirus 8 and Epstein-Barr virus in the pathogenesis of giant lymph node hyperplasia (Castleman's disease) | journal = Clinical Infectious Diseases | volume = 22 | issue = 6 | pages = 1120–1121 | date = June 1996 | pmid = 8783733 | doi = 10.1093/clinids/22.6.1120 | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Scheeff ED, Bourne PE | title = Structural evolution of the protein kinase-like superfamily | journal = PLOS Computational Biology | volume = 1 | issue = 5 | pages = e49 | date = October 2005 | pmid = 16244704 | pmc = 1261164 | doi = 10.1371/journal.pcbi.0010049 | bibcode = 2005PLSCB...1...49S | doi-access = free }}</ref> More than five hundred different protein kinases have been identified in humans.<ref name="pmid12471243" /> Their diversity and their role in signaling makes them an interesting object of study. Various other kinases act on small molecules such as [[lipid]]s, [[carbohydrate]]s, [[amino acid]]s, and [[nucleotide]]s, 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.<ref name="krebs lec">{{cite journal | vauthors = Krebs EG | title = The phosphorylation of proteins: a major mechanism for biological regulation. Fourteenth Sir Frederick Gowland Hopkins memorial lecture | journal = Biochemical Society Transactions | volume = 13 | issue = 5 | pages = 813–820 | date = October 1985 | pmid = 2998902 | doi = 10.1042/bst0130813 }}</ref>

==Protein kinases==
[[File:signal transduction pathways.png|thumb|upright=2|right|Overview of signal transduction pathways. Many of the proteins involved are kinases, including protein kinases (such as [[MAPK]] and [[Janus kinase|JAK]]) and lipid kinases (such as [[PI3K]]).]]
{{main|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.<ref>{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–1934 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | s2cid = 26554314 | bibcode = 2002Sci...298.1912M }}</ref> These kinases, in conjunction with [[phosphatase]]s, 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 [[eukaryote|eukaryotic cells]] in comparison to [[prokaryote|prokaryotic cells]] because the more complex cell type evolved to respond to a wider array of signals.<ref name="krebs lec"/>

===Cyclin dependent kinases===

[[Cyclin dependent kinase]]s (CDKs) are a group of several different kinases involved in regulation of the [[cell cycle]]. They phosphorylate other proteins on their serine or threonine residues, but CDKs must first bind to a [[cyclin]] protein in order to be active.<ref name="cdk review">{{cite journal | vauthors = Harper JW, Adams PD | title = Cyclin-dependent kinases | journal = Chemical Reviews | volume = 101 | issue = 8 | pages = 2511–2526 | date = August 2001 | pmid = 11749386 | doi = 10.1021/cr0001030 }}</ref> Different combinations of specific CDKs and cyclins mark different parts of the cell cycle. Additionally, the phosphorylation state of CDKs is also critical to their activity, as they are subject to regulation by other kinases (such as [[CDK-activating kinase]]) and [[phosphatases]] (such as [[Cdc25]]).<ref>{{cite book| vauthors = Karp G |title=Cell and molecular biology : concepts and experiments|year=2010|publisher=John Wiley|location=Hoboken, NJ|isbn=9780470483374|edition=6th}}</ref> 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.<ref>{{cite journal | vauthors = Lim S, Kaldis P | title = Cdks, cyclins and CKIs: roles beyond cell cycle regulation | journal = Development | volume = 140 | issue = 15 | pages = 3079–3093 | date = August 2013 | pmid = 23861057 | doi = 10.1242/dev.091744 | doi-access = free }}</ref>

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.<ref name=can>{{cite journal | vauthors = Canavese M, Santo L, Raje N | title = Cyclin dependent kinases in cancer: potential for therapeutic intervention | journal = Cancer Biology & Therapy | volume = 13 | issue = 7 | pages = 451–457 | date = May 2012 | pmid = 22361734 | doi = 10.4161/cbt.19589 | doi-access = free }}</ref> CDK mutations can be found in [[lymphoma]]s, [[breast cancer]], [[pancreas|pancreatic]] [[tumor]]s, and [[lung cancer]]. Therefore, [[CDK inhibitor|inhibitors of CDK]] have been developed as treatments for some types of cancer.<ref name=can />

===Mitogen-activated protein kinases===
{{main|Mitogen-activated protein kinase}}

[[Mitogen-activated protein kinase|MAP kinases]] (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all considered mitogenic stimuli that can engage the MAPK pathway. Activation of this pathway at the level of the receptor initiates a signaling cascade whereby the [[Ras subfamily|Ras GTPase]] exchanges [[Guanosine diphosphate|GDP]] for [[Guanosine triphosphate|GTP]]. Next, Ras activates [[Raf kinase]] (also known as MAPKKK), which activates [[Mitogen-activated protein kinase kinase|MEK]] (MAPKK). MEK activates [[Mitogen-activated protein kinase|MAPK]] (also known as ERK), which can go on to regulate [[transcription (genetics)|transcription]] and [[translation (biology)|translation]]. Whereas RAF and MAPK are both serine/threonine kinases, MAPKK is a tyrosine/threonine kinase.

[[File:Components of the MAPK Pathway.png|thumb|upright=2|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.<ref name=MAPK>{{cite journal | vauthors = Garrington TP, Johnson GL | title = Organization and regulation of mitogen-activated protein kinase signaling pathways | journal = Current Opinion in Cell Biology | volume = 11 | issue = 2 | pages = 211–218 | date = April 1999 | pmid = 10209154 | doi = 10.1016/s0955-0674(99)80028-3 }}</ref>

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]].<ref name=MAPK />

==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}}
[[File:PI3 Kinase.tif|thumb|upright=1|Insulin binding to its receptor leads allows PI3 kinase to dock at the membrane where it can phosphorylate PI lipids]]
Phosphatidylinositol kinases phosphorylate [[phosphatidylinositol]] species, to create species such as [[phosphatidylinositol 3,4-bisphosphate]] (PI(3,4)P<sub>2</sub>), [[phosphatidylinositol 3,4,5-trisphosphate]] (PIP<sub>3</sub>), and [[phosphatidylinositol 3-phosphate]] (PI3P). The kinases include [[phosphoinositide 3-kinase]] (PI3K), [[phosphatidylinositol-4-phosphate 3-kinase]], and [[phosphatidylinositol-4,5-bisphosphate 3-kinase]]. The phosphorylation state of phosphatidylinositol plays a major role in [[cellular signalling]], such as in the insulin signalling pathway, and also has roles in [[endocytosis]], [[exocytosis]] and other trafficking events.<ref>{{cite journal | vauthors = Sun Y, Thapa N, Hedman AC, Anderson RA | title = Phosphatidylinositol 4,5-bisphosphate: targeted production and signaling | journal = BioEssays | volume = 35 | issue = 6 | pages = 513–522 | date = June 2013 | pmid = 23575577 | pmc = 3882169 | doi = 10.1002/bies.201200171 }}</ref><ref>{{cite journal | vauthors = Heath CM, Stahl PD, Barbieri MA | title = Lipid kinases play crucial and multiple roles in membrane trafficking and signaling | journal = Histology and Histopathology | volume = 18 | issue = 3 | pages = 989–998 | date = July 2003 | pmid = 12792909 | doi = 10.14670/HH-18.989 }}</ref> Mutations in these kinases, such as PI3K, can lead to [[cancer]] or [[insulin resistance]].<ref>{{cite journal| vauthors = Cantley LC |title=PI 3-kinase and disease|journal=BMC Proceedings|year=2012|volume=6|issue=Suppl 3|pages=O2|doi=10.1186/1753-6561-6-S3-O2 |pmc=3395034 |doi-access=free}}</ref>

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.<ref name="PI" /> Here, a reaction between [[adenosine triphosphate|adenosine triphosphate (ATP)]] and phosphatidylinositol is coordinated. The end result is a phosphatidylinositol-3-phosphate as well as [[adenosine diphosphate|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.<ref name="PI" />

[[File:PI3kinase mechanism.png|thumb|upright=2.7|center|Mechanism of phosphatidylinositol-3 kinase. ATP and phosphatidylinositol react to form phosphatidylinositol-3-phosphate and ADP, with the help of general base ''B''.<ref name="PI">{{cite journal | vauthors = Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM, Williams RL | title = Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34 | journal = Science | volume = 327 | issue = 5973 | pages = 1638–1642 | date = March 2010 | pmid = 20339072 | pmc = 2860105 | doi = 10.1126/science.1184429 | bibcode = 2010Sci...327.1638M }}</ref>]]

===Sphingosine kinases===
Sphingosine kinase (SK) is a lipid kinase that catalyzes the conversion of [[sphingosine]] to [[sphingosine-1-phosphate]] (S1P). Sphingolipids are ubiquitous membrane lipids. Upon activation, sphingosine kinase migrates from the cytosol to the plasma membrane where it transfers a γ phosphate (which is the last or terminal phosphate) from [[Adenosine triphosphate|ATP]] or [[Guanosine triphosphate|GTP]] to sphingosine. The S1P receptor is a [[GPCR]] receptor, so S1P has the ability to regulate G protein signaling. The resulting signal can activate intracellular effectors like ERKs, [[Rho family of GTPases|Rho GTPase]], [[Rac (GTPase)|Rac GTPase]], [[phospholipase C|PLC]], and AKT/PI3K. It can also exert its effect on target molecules inside the cell. S1P has been shown to directly inhibit the histone deacetylase activity of [[HDAC]]s. 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 [[chemotherapy|chemotherapeutic therapies]].<ref>{{cite journal | vauthors = Neubauer HA, Pitson SM | title = Roles, regulation and inhibitors of sphingosine kinase 2 | journal = The FEBS Journal | volume = 280 | issue = 21 | pages = 5317–5336 | date = November 2013 | pmid = 23638983 | doi = 10.1111/febs.12314 | doi-access = free }}</ref>

==Carbohydrate kinases==
[[File:Glycolysis including irreversible steps.png|frameless|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 [[calorie|caloric]] requirement. To harvest energy from [[oligosaccharide]]s, they must first be broken down into [[monosaccharide]]s so they can enter [[cellular metabolism|metabolism]]. Kinases play an important role in almost all metabolic pathways. The figure on the left shows the second phase of [[glycolysis]], which contains two important reactions catalyzed by kinases. The [[anhydride]] linkage in 1,3 bisphosphoglycerate is unstable and has a high energy. 1,3-bisphosphogylcerate kinase requires ADP to carry out its reaction yielding 3-phosphoglycerate and ATP. In the final step of glycolysis, pyruvate kinase transfers a phosphoryl group from [[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.<ref name=Carb>{{cite journal | vauthors = Holzer H, Duntze W | title = Metabolic regulation by chemical modification of enzymes | journal = Annual Review of Biochemistry | volume = 40 | pages = 345–374 | year = 1971 | pmid = 4399446 | doi = 10.1146/annurev.bi.40.070171.002021 }}</ref> Mutations in the hexokinase gene can lead to a [[hexokinase deficiency]] which can cause nonspherocytic hemolytic [[anemia]].<ref>{{cite web|title=Nonspherocytic hemolytic anemia due to hexokinase deficiency|url=http://rarediseases.info.nih.gov/gard/3672/nonspherocytic-hemolytic-anemia-due-to-hexokinase-deficiency/resources/1|access-date=2014-02-24|archive-date=2015-09-05|archive-url=https://web.archive.org/web/20150905121422/https://rarediseases.info.nih.gov/gard/3672/nonspherocytic-hemolytic-anemia-due-to-hexokinase-deficiency/resources/1|url-status=dead}}</ref>

'''[[Phosphofructokinase]]''', or PFK, catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and is an important point in the regulation of glycolysis. High levels of ATP, H<sup>+</sup>, and [[citrate]] inhibit PFK. If citrate levels are high, it means that glycolysis is functioning at an optimal rate. High levels of [[adenosine monophosphate|AMP]] stimulate PFK. [[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.<ref>{{cite web|title=Phosphofructokinase Deficiency Glycogen Storage Disease|url=http://www.patient.co.uk/doctor/phosphofructokinase-deficiency-glycogen-storage-disease}}</ref>

==Other kinases==
[[File:Riboflavin kinase.png|thumb|The active site of riboflavin kinase bound to its products--FMN (on left) and ADP (on right). Coordinates from PDB ID: 1N07.<ref>{{cite journal | vauthors = Bauer S, Kemter K, Bacher A, Huber R, Fischer M, Steinbacher S | title = Crystal structure of Schizosaccharomyces pombe riboflavin kinase reveals a novel ATP and riboflavin-binding fold | journal = Journal of Molecular Biology | volume = 326 | issue = 5 | pages = 1463–1473 | date = March 2003 | pmid = 12595258 | doi = 10.1016/s0022-2836(03)00059-7 }}</ref>]]
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 [[nucleoside-phosphate kinase]]s and [[nucleoside-diphosphate kinase]]s.<ref>{{cite book | vauthors = Voet D, Voet JC, Pratt CW |title=Fundamentals of biochemistry : life at the molecular level|year=2008|publisher=Wiley|location=Hoboken, NJ|isbn=9780470129302|edition=3rd}}</ref> Other small molecules that are substrates of kinases include [[creatine]], [[phosphoglycerate]], [[riboflavin]], [[dihydroxyacetone]], [[shikimate]], and many others.

===Riboflavin kinase===
{{main|Riboflavin kinase}}Riboflavin kinase catalyzes the phosphorylation of [[riboflavin]] to create [[flavin mononucleotide]](FMN). It has an ordered binding mechanism where riboflavin must bind to the kinase before it binds to the ATP molecule.<ref name="sdf">{{cite journal | vauthors = Karthikeyan S, Zhou Q, Osterman AL, Zhang H | title = Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism | journal = Biochemistry | volume = 42 | issue = 43 | pages = 12532–12538 | date = November 2003 | pmid = 14580199 | doi = 10.1021/bi035450t }}</ref> [[Divalent]] [[cation]]s help coordinate the [[nucleotide]].<ref name="sdf" /> The general mechanism is shown in the figure below.[[File:Riboflavin mechanism.png|thumb|upright=2.5|center|Mechanism of riboflavin kinase.]]
Riboflavin kinase plays an important role in cells, as [[flavin mononucleotide|FMN]] is an important [[cofactor (biochemistry)|cofactor]]. [[flavin mononucleotide|FMN]] also is a precursor to [[flavin adenine dinucleotide]](FAD), a [[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 [[flavin mononucleotide|FMN]], as well as the [[flavin mononucleotide|FMN]] to [[flavin adenine dinucleotide|FAD]] reaction.<ref>{{cite journal | vauthors = Galluccio M, Brizio C, Torchetti EM, Ferranti P, Gianazza E, Indiveri C, Barile M | title = Over-expression in Escherichia coli, purification and characterization of isoform 2 of human FAD synthetase | journal = Protein Expression and Purification | volume = 52 | issue = 1 | pages = 175–181 | date = March 2007 | pmid = 17049878 | doi = 10.1016/j.pep.2006.09.002 }}</ref> Riboflavin kinase may help prevent stroke, and could possibly be used as a treatment in the future.<ref>{{cite journal | vauthors = Zou YX, Zhang XH, Su FY, Liu X | title = Importance of riboflavin kinase in the pathogenesis of stroke | journal = CNS Neuroscience & Therapeutics | volume = 18 | issue = 10 | pages = 834–840 | date = October 2012 | pmid = 22925047 | pmc = 6493343 | doi = 10.1111/j.1755-5949.2012.00379.x }}</ref> It is also implicated in infection, when studied in mice.<ref>{{cite journal | vauthors = Brijlal S, Lakshmi AV, Bamji MS, Suresh P | title = Flavin metabolism during respiratory infection in mice | journal = The British Journal of Nutrition | volume = 76 | issue = 3 | pages = 453–462 | date = September 1996 | pmid = 8881717 | doi = 10.1079/BJN19960050 | doi-access = free }}</ref>

===Thymidine kinase===
{{main|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.

[[File:Thymidine kinase.png|thumb|center|upright=2.5|Overall reaction catalysed by thymidine kinase.]]

After creation of the dTMP molecule, another kinase, [[thymidylate kinase]], can act upon dTMP to create the [[thymidine diphosphate|diphosphate]] form, dTDP. [[Nucleoside-diphosphate kinase|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 [[Thymidine kinase in clinical chemistry|clinical chemistry]].<ref>{{cite journal | vauthors = Aufderklamm S, Todenhöfer T, Gakis G, Kruck S, Hennenlotter J, Stenzl A, Schwentner C | title = Thymidine kinase and cancer monitoring | journal = Cancer Letters | volume = 316 | issue = 1 | pages = 6–10 | date = March 2012 | pmid = 22068047 | doi = 10.1016/j.canlet.2011.10.025 }}</ref> Therefore, it can sometime be used to predict patient prognosis.<ref>{{cite journal | vauthors = Topolcan O, Holubec L | title = The role of thymidine kinase in cancer diseases | journal = Expert Opinion on Medical Diagnostics | volume = 2 | issue = 2 | pages = 129–141 | date = February 2008 | pmid = 23485133 | doi = 10.1517/17530059.2.2.129 }}</ref> 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.<ref>{{cite journal | vauthors = Götz A, Isohanni P, Pihko H, Paetau A, Herva R, Saarenpää-Heikkilä O, Valanne L, Marjavaara S, Suomalainen A | display-authors = 6 | title = Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome | journal = Brain | volume = 131 | issue = Pt 11 | pages = 2841–2850 | date = November 2008 | pmid = 18819985 | doi = 10.1093/brain/awn236 | doi-access = free }}</ref>

== See also ==
{{commons category|Kinases}}
* [[Activation loop]]
* [[Autophosphorylation]]
* [[Ca2+/calmodulin-dependent protein kinase|Ca<sup>2+</sup>/calmodulin-dependent protein kinase]]
* [[Cell signaling]]
* [[Cyclin-dependent kinase]]
* [[G protein-coupled receptor]]
* [[NDR kinase]]
* [[Nucleoside-diphosphate kinase]]
* [[Phosphatase]]
* [[Phosphatidylinositol phosphate kinases]]
* [[Phospholipid]]
* [[Phosphoprotein]]
* [[Phosphorylation]]
* [[Phosphotransferase]]
* [[Signal transduction]]
* [[Thymidine kinase]]
* [[Thymidine kinase in clinical chemistry]]
* [[Thymidylate kinase]]
* [[Wall-associated kinase]]

== References ==
{{Reflist|30em}}

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{{Kinases}}
{{Enzymes}}
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[[Category:EC 2.7.1]]