Nucleoside-phosphate kinase

A number of crystal structures have been solved for this class of enzymes, revealing that they share a common ATP binding domain. This section of the enzyme is commonly referred to as the P-loop,{{cite journal | vauthors = Dreusicke D, Schulz GE | title = The glycine-rich loop of adenylate kinase forms a giant anion hole | journal = FEBS Letters | volume = 208 | issue = 2 | pages = 301–4 | date = November 1986 | pmid = 3023140 | doi = 10.1016/0014-5793(86)81037-7 | bibcode = 1986FEBSL.208..301D | s2cid = 11786335 }} in reference to its interaction with the phosphoryl groups on ATP. This binding domain also consists of a β sheet flanked by α helices.

The [P-loop] typically has the amino acid sequence of Gly-X-X-X-X-Gly-Lys.{{cite journal | vauthors = Byeon L, Shi Z, Tsai MD | title = Mechanism of adenylate kinase. The "essential lysine" helps to orient the phosphates and the active site residues to proper conformations | journal = Biochemistry | volume = 34 | issue = 10 | pages = 3172–82 | date = March 1995 | pmid = 7880812 | doi = 10.1021/bi00010a006 }} Similar sequences are found in many other nucleotide-binding proteins.

File:Adenylate kinase 2.png, an example nucleoside-phosphate kinase, is shown here in both an open, unbound conformation{{cite journal | vauthors = Müller CW, Schlauderer GJ, Reinstein J, Schulz GE | title = Adenylate kinase motions during catalysis: an energetic counterweight balancing substrate binding | journal = Structure | volume = 4 | issue = 2 | pages = 147–56 | date = February 1996 | pmid = 8805521 | doi = 10.2210/pdb4ake/pdb }} (left) and with the lid domain closed around Ap5A (right). The P-loop is shown here in green while Ap5A is orange.]]

To allow for interaction with this class of enzymes, ATP must first bind to a metal ion such as magnesium or manganese.{{cite book | vauthors = Berg JM, Tymoczko JL, Stryer L |title= Biochemistry |url= https://archive.org/details/biochemistrychap00jere |access-date= 2016-01-08 |year= 2002 |publisher= W H Freeman |location= New York |isbn= 0-7167-3051-0 |url-access= registration }} The metal ion forms a complex with the phosphoryl-group, as well as several water molecules.{{cite journal | vauthors = Krishnamurthy H, Lou H, Kimple A, Vieille C, Cukier RI | title = Associative mechanism for phosphoryl transfer: a molecular dynamics simulation of Escherichia coli adenylate kinase complexed with its substrates | journal = Proteins | volume = 58 | issue = 1 | pages = 88–100 | date = January 2005 | pmid = 15521058 | doi = 10.1002/prot.20301 | s2cid = 20874015 }} These water molecules then form hydrogen bonds to a conserved aspartate residue on the enzyme.{{cite journal | vauthors = Pai EF, Sachsenheimer W, Schirmer RH, Schulz GE | title = Substrate positions and induced-fit in crystalline adenylate kinase | journal = Journal of Molecular Biology | volume = 114 | issue = 1 | pages = 37–45 | date = July 1977 | pmid = 198550 | doi = 10.1016/0022-2836(77)90281-9 }}

The metal ion interaction facilitates binding by holding the ATP molecule in a position allowing for specific binding to the active site and by providing additional points for binding between the substrate and the enzyme. This increases the binding energy.

Binding of ATP causes the P-loop to move, in turn making the lid domain lower and secure the ATP in place.{{cite journal | vauthors = Müller CW, Schulz GE | title = Structure of the complex between adenylate kinase from Escherichia coli and the inhibitor Ap5A refined at 1.9 A resolution. A model for a catalytic transition state | journal = Journal of Molecular Biology | volume = 224 | issue = 1 | pages = 159–77 | date = March 1992 | pmid = 1548697 | doi = 10.2210/pdb1ake/pdb }}{{cite journal | vauthors = Schlauderer GJ, Proba K, Schulz GE | title = Structure of a mutant adenylate kinase ligated with an ATP-analogue showing domain closure over ATP | journal = Journal of Molecular Biology | volume = 256 | issue = 2 | pages = 223–7 | date = February 1996 | pmid = 8594191 | doi = 10.1006/jmbi.1996.0080 }} Nucleoside monophosphate binding induces further changes that render the enzyme catalytically capable of facilitating a transfer of the phosphoryl group from ATP to nucleoside monophosphate.{{cite journal | vauthors = Vonrhein C, Schlauderer GJ, Schulz GE | title = Movie of the structural changes during a catalytic cycle of nucleoside monophosphate kinases | journal = Structure | volume = 3 | issue = 5 | pages = 483–90 | date = May 1995 | pmid = 7663945 | doi = 10.1016/s0969-2126(01)00181-2 | doi-access = free }}

The necessity of these conformational changes prevents the wasteful hydrolysis of ATP.

This enzyme mechanism is an example of catalysis by approximation: the nucleoside-phosphate kinase binds the substrates to bring them together in the correct position for the phosphoryl group to be transferred.

Similar catalytic domains are present in a variety of proteins, including:

• ATP synthase
• Myosin, and other molecular motor proteins
• G protein and other proteins involved in signal transduction
• Helicases for unwinding DNA and RNA
• Pyrimidine metabolism

When a phylogenetic tree composed of members of the nucleoside-phosphate kinase family was made,{{cite journal | vauthors = Fukami-Kobayashi K, Nosaka M, Nakazawa A, Go M | title = Ancient divergence of long and short isoforms of adenylate kinase: molecular evolution of the nucleoside monophosphate kinase family | journal = FEBS Letters | volume = 385 | issue = 3 | pages = 214–20 | date = May 1996 | pmid = 8647254 | doi = 10.1016/0014-5793(96)00367-5 | s2cid = 24934783 | doi-access = free | bibcode = 1996FEBSL.385..214F }} it showed that these enzymes had originally diverged from a common ancestor into long and short varieties. This first change was drastic – the three-dimensional structure of the lid domain changed significantly.

Following the evolution of long and short varieties of NMP-kinases, smaller changes in the amino acid sequences resulted in the differentiation of subcellular localization.

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{{Kinases}}

{{Enzymes}}

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Category:EC 2.7.4

Category:Enzymes of known structure