UCK2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | UCK2 , TSA903, UK, UMPK, uridine-cytidine kinase 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 609329 MGI: 1931744 HomoloGene: 40850 GeneCards: UCK2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene. [5]
The protein encoded by this gene catalyzes the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. This is the first step in the production of the pyrimidine nucleoside triphosphates required for RNA and DNA synthesis. In addition, an allele of this gene may play a role in mediating nonhumoral immunity to Hemophilus influenzae type B. [5]
Uridine-cytidine kinase 2 is a tetramer with molecular mass of about 112 kDa. [6] In the UCK2 monomer, the active site is composed of a five-stranded β-sheet, surrounded by five α-helices and a β-hairpin loop. [7] The β-hairpin loop in particular forms a significant portion of a deep binding pocket for the uridine/cytidine substrate to moderate binding and release of substrate and products. Binding specificity for nucleosides is determined by the His-117 and Tyr-112 residues, which hydrogen bond with the 4-amino group or the 6-oxo group of cytidine and uridine, respectively. [7] A magnesium ion is coordinated in the active site by Glu-135, Ser-34, and Asp-62.
The Asp-62 residue is responsible for the catalytic activity in the enzyme active site; [8] the acidic side chain of the Asp-62 residue deprotonates the 5’-hydroxyl group on the substrate and activates it to attack the γ-phosphorus of ATP. [9] Structural analyses have shown that the side chain of the catalytic Asp-62 changes conformation before and after the reaction. It has been suggested that this conformational change occurs following phosphorylation, with the negatively charged Asp-62 moving away from the newly attached 5’-phosphate of the UMP/CMP product. [7]
Though uridine and cytidine are the physiologically preferred substrates for the enzyme, UCK2 has been shown to phosphorylate other nucleoside analogues. Examples of successfully phosphorylated substrates include 6-azauridine, 5-azacytidine, 4-thiouridine, 5-fluorocytidine, and 5-hydroxyuridine. [10] Alternatively to ATP, GTP has been shown to act comparably as a phosphate donor. [11] This promiscuity enables the important role for UCK2 as an in vivo activator of clinically active nucleoside prodrugs, such as cylcopentenylcytidine. [12]
Despite flexibility for different nucleoside analogs, UCK is unique among other nucleic acid kinases in its specificity for ribose analogs over 2’-deoxyribose forms; whereas other proteins in the NMP kinase family will indiscriminately phosphorylate both deoxyribonucleosides and ribonucleosides, UCK2 only accepts ribonucleosides. [6] This unique selectivity can be induced fit mechanisms and structural features that are unique to UCK2 among the NMP kinase family. Studies have shown that the binding of the cytidine/uridine sugar moiety results in the conformational change to reduce the distance between the His-117 and Arg-176 residues. Without the 2’-hydroxyl group on the sugar moiety, hydrogen bonding with Asp-84 and Arg-166 will be greatly reduced, resulting in diminished conformational change and weakened substrate binding. [6]
UCK2 is one of two human uridine-cytidine kinases. The other UCK protein is uridine-cytidine kinase 1, which shares about 70% sequence identity with UCK2. [7] While UCK1 is expressed ubiquitously in a variety of healthy tissues including the liver, skeletal muscle, and heart, UCK2 has only been detected in placental tissue. [10] UCK2, however, is of particular scientific interest due to its overexpression in tumor cell lines, [13] which makes it a target in anti-cancer treatments.
Studies determining the Michaelis-Menten kinetic parameters for these enzymes revealed that UCK2 had a four to sixfold higher binding affinity, faster maximal rates, and greater efficiencies for uridine and cytidine substrates than did UCK1. [10]
Both uridine-cytidine kinases, however, plays a crucial role in the biosynthesis of the pyrimidine nucleotides that compose RNA and DNA. Pyrimidine biosynthesis can occur through two pathways: de novo synthesis, which relies on L-glutamine as the pathway precursor, and salvage, which recycles cellular uridine and cytidine. [14] UCK2 catalyzes the first step of pyrimidine salvage, and is the rate limiting enzyme in the pathway. [15]
UCK1 is expressed ubiquitously in healthy tissue, but found in low levels in tumor tissues. Conversely, UCK2 has been detected mostly in cancerous cells and healthy placental tissue. The selective expression in target tissues has resulted in the identification of UCK2 as a target in anti-cancer therapies. [16]
One strategy for anti-cancer and anti-viral therapies involves using UCK2 to activate anti-tumor prodrugs through phosphorylation. [17] As an example, 1-(3-C-ethynyl-β-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-β-D-ribopentofuranosyl)uridine (EUrd) are RNA polymerase inhibitors that are under investigation for use as anticancer drugs. [18] The nucleoside, however, only gains its clinical activity after three phosphorylations; therefore, UCK2 plays a key role in initiating the activation of the drug. An alternate strategy involves inhibition of UCK2 to block pyrimidine salvage in cancerous cells. [19] In certain cancer cell lines, pyrimidine biosynthesis primarily occurs through the salvage pathway. [20] Blocking pyrimidine salvage can prevent DNA and RNA biosynthesis, resulting in reduced cell proliferation.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.
Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nucleic acids, the others being adenosine, thymidine, cytidine and guanosine. The five nucleosides are commonly abbreviated to their symbols, U, A, dT, C, and G, respectively. However, thymidine is more commonly written as 'dT' ('d' represents 'deoxy') as it contains a 2'-deoxyribofuranose moiety rather than the ribofuranose ring found in uridine. This is because thymidine is found in deoxyribonucleic acid (DNA) and usually not in ribonucleic acid (RNA). Conversely, uridine is found in RNA and not DNA. The remaining three nucleosides may be found in both RNA and DNA. In RNA, they would be represented as A, C and G whereas in DNA they would be represented as dA, dC and dG.
A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.
The enzyme Uridine monophosphate synthase catalyses the formation of uridine monophosphate (UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene that codes for this enzyme is located on the long arm of chromosome 3 (3q13).
A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.
Adenylate kinase is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates. By constantly monitoring phosphate nucleotide levels inside the cell, ADK plays an important role in cellular energy homeostasis.
Cytidine monophosphate, also known as 5'-cytidylic acid or simply cytidylate, and abbreviated CMP, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside cytidine. CMP consists of the phosphate group, the pentose sugar ribose, and the nucleobase cytosine; hence, a ribonucleoside monophosphate. As a substituent it takes the form of the prefix cytidylyl-.
Nucleoside-diphosphate kinases are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleotide triphosphates. Many NDP serve as acceptor while NTP are donors of phosphate group. The general reaction via ping-pong mechanism is as follows: XDP + YTP ←→ XTP + YDP. NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP). Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction
Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.
Pyrimidine biosynthesis occurs both in the body and through organic synthesis.
CTP synthase is an enzyme involved in pyrimidine biosynthesis that interconverts UTP and CTP.
Orotate phosphoribosyltransferase (OPRTase) or orotic acid phosphoribosyltransferase is an enzyme involved in pyrimidine biosynthesis. It catalyzes the formation of orotidine 5'-monophosphate (OMP) from orotate and phosphoribosyl pyrophosphate. In yeast and bacteria, orotate phosphoribosyltransferase is an independent enzyme with a unique gene coding for the protein, whereas in mammals and other multicellular organisms, the catalytic function is carried out by a domain of the bifunctional enzyme UMP synthase (UMPS).
Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.
Deoxyuridine monophosphate (dUMP), also known as deoxyuridylic acid or deoxyuridylate in its conjugate acid and conjugate base forms, respectively, is a deoxynucleotide.
In enzymology, a cytidylate kinase is an enzyme that catalyzes the chemical reaction
Cytosolic 5'-nucleotidase 3 (NTC53), also known as cytosolic 5'-nucleotidase 3A, pyrimidine 5’-nucleotidase, and p56, is an enzyme that in humans is encoded by the NT5C3, or NT5C3A, gene on chromosome 7.
UMP-CMP kinase is an enzyme that in humans is encoded by the CMPK1 gene.
5', 3'-nucleotidase, cytosolic, also known as 5'(3')-deoxyribonucleotidase, cytosolic type (cdN) or deoxy-5'-nucleotidase 1 (dNT-1), is an enzyme that in humans is encoded by the NT5C gene on chromosome 17.
CTP synthase 1 is an enzyme that is encoded by the CTPS1 gene in humans. CTP synthase 1 is an enzyme in the de novo pyrimidine synthesis pathway that catalyses the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP). CTP is a key building block for the production of DNA, RNA and some phospholipids.