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Above is a ball-and-stick model of the inorganic phosphate molecule (HPO42−). Colour coding: P (orange); O (red); H (white).
Above is a ball-and-stick model of the inorganic phosphate molecule (HPO42−). Ball-and-stick models and Space-filling models (also known as Calotte models) are 3D or spatial Molecular models which serve to display the structure Traditionally inorganic compounds are considered to be of mineral not biological origin In Chemistry, a molecule is defined as a sufficiently stable electrically neutral group of at least two Atoms in a definite arrangement held together by Colour coding: P (orange); O (red); H (white). Phosphorus, (ˈfɒsfərəs is the Chemical element that has the symbol P and Atomic number 15 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1

A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). In Chemistry and Biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of Enzyme that transfers Phosphate Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule This class of protein is further separated into subsets such as PKC alpha, PKC beta, and PKC gamma, each with specific functions. Protein kinase C alpha, also known as PRKCA, is a human Gene. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. Catalysis is the process in which the rate of a Chemical reaction is increased by means of a Chemical substance known as a catalyst Up to 30% of all proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction, the transmission of signals within the cell. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes. Animals Plants fungi, and Protists are eukaryotes (juːˈkærɪɒt or -oʊt Organisms whose cells are organized into complex

The chemical activity of a kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group. Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Hydroxyl in Chemistry stands for a molecule consisting of an Oxygen atom and a Hydrogen atom connected by a Covalent bond. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual specificity kinases) act on all three. Serine (abbreviated as Ser or S) is an Organic compound with the formula H[[oxygen O]]2 CCH NH sub>2CH2OH Threonine (abbreviated as Thr or T) is an α- Amino acid with the Chemical formula HO2CCH(NH2CH(OHCH3 Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize

Because protein kinases have profound effects on a cell, their activity is highly regulated. Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation/autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates. An activator is a DNA-binding protein that regulates one or more Genes by increasing the rate of transcription. Enzyme inhibitors are Molecules that bind to Enzymes and decrease their activity.

Deregulated kinase activity is a frequent cause of disease, particularly cancer, where kinases regulate many aspects that control cell growth, movement and death. Drugs which inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (imatinib) and Iressa (gefitinib). Imatinib is a drug used to treat certain types of Cancer. It is currently marketed by Novartis as Gleevec ( USA) or Glivec Gefitinib ( INN) (gɛˈfɪtɨnɪb (originally coded ZD1839 is a drug used in the treatment of certain types of Cancer.

Contents

Serine/threonine-specific protein kinases

Calcium/calmodulin-dependent protein kinase II (CaMKII) is an example of a serine/threonine-specific protein kinase.
Calcium/calmodulin-dependent protein kinase II (CaMKII) is an example of a serine/threonine-specific protein kinase.
Main article: Serine/threonine-specific protein kinases

Serine/threonine protein kinases (EC 2.7.11.1) phosphorylate the OH group of serine or threonine (which have similar sidechains). Serine/threonine Protein kinases ( phosphorylate the OH group of Serine or Threonine (which have similar sidechains This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. Serine (abbreviated as Ser or S) is an Organic compound with the formula H[[oxygen O]]2 CCH NH sub>2CH2OH Threonine (abbreviated as Thr or T) is an α- Amino acid with the Chemical formula HO2CCH(NH2CH(OHCH3 Activity of these protein kinases can be regulated by specific events (e. g. DNA damage), as well as numerous chemical signals, including cAMP/cGMP, Diacylglycerol, and Ca2+/calmodulin. Cyclic adenosine monophosphate ( cAMP, cyclic AMP or 3'-5'-cyclic Adenosine monophosphate) is a Second messenger that is important in many biological A diglyceride, or a diacylglycerol (DAG is a Glyceride consisting of two Fatty acid chains covalently bonded to a Glycerol Calcium (Ca2+ plays a vital role in the Anatomy, Physiology and Biochemistry of Organisms and of the cell, particularly Calmodulin ( CaM) (an abbreviation for CAL cium MODUL ated prote' IN') is a calcium-binding protein expressed in all Eukaryotic cells

Tyrosine-specific protein kinases

Main article: Tyrosine kinase

Tyrosine-specific protein kinases (EC 2.7.10.1) phosphorylate tyrosine amino acid residues, and are, like serine/threonine-specific kinases, used in signal transduction. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another They act primarily as growth factor receptors and in downstream signaling from growth factors; some examples:

Receptor tyrosine kinases

These kinases consist of a transmembrane receptor with a tyrosine kinase domain protruding into the cytoplasm. Transmembrane receptors are Integral membrane proteins which reside and operate typically within a cell's Plasma membrane, but also in the membranes of A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. They play an important role in regulating cell division, cellular differentiation, and morphogenesis. Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. In Developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized Cell type. MOrphogenesis is an EP by Industrial Black metal band.And Oceans. More than 50 receptor tyrosine kinases are known in mammals.

Structure

The extracellular domain serves as the ligand-binding part of the molecule. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule It can be a separate unit that is attached to the rest of the receptor by a disulfide bond. In Chemistry, a disulfide bond is a single Covalent bond derived from the coupling of Thiol groups The same mechanism can be used to bind two receptors together to form a homo- or heterodimer. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces The transmembrane element is a single α helix. The intracellular or cytoplasmic domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.

Regulation

Ligand binding causes two reactions:

  1. Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces Many ligands of receptor tyrosine kinases are multivalent. In Chemistry, valence, also known as valency or valency number, is a measure of the number of Chemical bonds formed by the Atoms Some tyrosine receptor kinases (e. g. , the platelet-derived growth factor receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal. In Molecular biology, Platelet-derived growth factor ( PDGF) is one of the numerous Growth factors or Proteins that regulate cell growth
  2. Trans-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase.

The autophosphorylation causes the two subdomains of the intrinsic kinase to shift, opening the kinase domain for ATP binding. In the inactive form, the kinase subdomains are aligned so that ATP cannot reach the catalytic center of the kinase. When several amino acids suitable for phosphorylation are present in the kinase domain (e. g. , the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation is said to be a cis-autophosphorylation, switching the kinase from "off" to "standby".

Signal transduction

The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain. In Molecular biology, Ras is the name of a Protein, the Gene that encodes it and the family and superfamily ( see Ras superfamily

Receptor-associated tyrosine kinases

Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a number of signalling cascades, principally those involved in cytokine signalling (but also others, including growth hormone). Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Growth hormone ( GH) is a Peptide hormone that stimulates growth and cell reproduction in humans and other animals One such receptor-associated tyrosine kinase is Janus kinase (JAK), many of whose effects are mediated by STAT proteins. Janus kinase ( JAK) is a family of intracellular non-receptor Tyrosine kinases that transduce Cytokine -mediated signals via the JAK-STAT pathway The Signal Transducers and Activator of Transcription (STAT also called signal transduction and transcription protein s regulate many aspects of Cell growth, survival and (See JAK-STAT pathway. The JAK-STAT signaling pathway takes part in the regulation of cellular responses to Cytokines and Growth factors Employing Janus kinases (JAKs and )

Histidine-specific protein kinases

Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. Histidine (abbreviated as His or H) is one of the 20 standard Amino acids present in Proteins In the Nutritional sense in The prokaryotes (proʊˈkærioʊts singular prokaryote /proʊˈkæriət/ are a group of Organisms that lack a Cell nucleus (= karyon or any other A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an aspartate residue on a 'receiver domain' on a different protein, or sometimes on the kinase itself. Aspartic acid (abbreviated as Asp or D; Asx or B represent either aspartic acid or Asparagine) is an α- Amino acid The aspartyl phosphate residue is then active in signaling.

Histidine kinases are found widely in prokaryotes, as well as in plants and fungi. The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate. Pyruvate dehydrogenase (E1 is the first component Enzyme of Pyruvate dehydrogenase complex (PDC

Aspartic acid/glutamic acid-specific protein kinases


Mixed kinases

Some kinases have mixed kinase activities. For example, MEK (MAPKK), which is involved in the MAP kinase cascade, is a mixed serine/threonine and tyrosine kinase. Butanone is a manufactured organic chemical. It is a colorless liquid with a sharp sweet butterscotch odor reminiscent of Acetone. Mitogen-activated protein (MAP kinases ( are Serine/threonine-specific protein kinases that respond to extracellular stimuli ( Mitogens and regulate various cellular

Inhibitors

Kinase assays and profilings

Drug developments for kinase inhibitors are started from kinase assays, the lead compounds are usually profiled for specificity before moving into further tests. Anthrapyrazol-6(2H-one is chemical compound anti Cancer agent selective c-Jun N-terminal Protein kinase ( JNK) inhibitor Staurosporine (antibiotic AM-2282 is a Natural product originally isolated in 1977 from bacterium Streptomyces staurosporeus. Many profiling services are available from fluorescent based assays to radioisotope based detections.

See also

External links

Further reading

Orientations of Proteins in Membranes (OPM database provides spatial positions of protein three-dimensional structures with respect to the Lipid bilayer. Orientations of Proteins in Membranes (OPM database provides spatial positions of protein three-dimensional structures with respect to the Lipid bilayer.
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