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61  structures 5432  species 1  interaction 6209  sequences 17  architectures

Family: ADK_lid (PF05191)

Summary: Adenylate kinase, active site lid

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This is the Wikipedia entry entitled "Adenylate kinase". More...

Adenylate kinase Edit Wikipedia article

Adenylate kinase
Adenylate kinase 2C95.png
3D ribbon/surface model of adenylate kinase in complex with bis(adenosine)tetraphosphate (ADP-ADP)
Identifiers
Symbol ADK
Pfam PF00406
InterPro IPR000850
PROSITE PDOC00104
SCOP 1ake
SUPERFAMILY 1ake
ADK_lid
PDB 1zip EBI.jpg
Bacillus stearothermophilus adenylate kinase
Identifiers
Symbol ADK_lid
Pfam PF05191
InterPro IPR007862
PROSITE PDOC00104
SCOP 1ake
SUPERFAMILY 1ake

Adenylate kinase (EC 2.7.4.3) (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis.

Substrate and products[edit]

The reaction catalyzed is:

2 ADPATP + AMP

The equilibrium constant varies with condition, but is close to 1.[1] Thus, the ΔGo for this reaction is close to zero. In muscle of a variety of species of vertebrates and invertebrates, the concentration of ATP is typically 7-10 times that of ADP, and usually greater than 100 times that of AMP.[2] The rate of oxidative phosphorylation is controlled by the availability of ADP. Thus, the mitochondrion attempts to keep ATP levels high due to the combined action of adenylate kinase and the controls on oxidative phosphorylation.

ADK isozymes[edit]

This is an essential reaction for many processes in living cells. Two ADK isozymes have been identified in mammalian cells. These specifically bind AMP and favor binding to ATP over other nucleotide triphosphates (AK1 is cytosolic and AK2 is located in the mitochondria). A third ADK has been identified in bovine heart and human cells,[3] this is a mitochondrial GTP:AMP phosphotransferase, also specific for the phosphorylation of AMP, but can only use GTP or ITP as a substrate.[4] ADK has also been identified in different bacterial species and in yeast.[5] Two further enzymes are known to be related to the ADK family, i.e. yeast uridine monophosphokinase and slime mold UMP-CMP kinase. Within the ADK family there are several conserved regions, including the ATP-binding domains. One of the most conserved areas includes an Arg residue, whose modification inactivates the enzyme, together with an Asp that resides in the catalytic cleft of the enzyme and participates in a salt bridge.

Subfamilies[edit]

Isozymes[edit]

Human genes encoding proteins with adenylate kinase include:

Mechanism[edit]

In Escherichia coli, the crystal structure of ADK was analyzed in a 2005 study.[6] The crystal structure revealed that ADK was complexed with diadenosine pentaphosphate (AP5A), Mg2+, and 4 coordinated water molecules. ATP adenine and ribose moieties are loosely bound to ADK. The phosphates in ATP are strongly bound to surrounding residues. Mg2+, coordination waters, and surrounding charged residues maintain the geometry and distances of the AMP α-phosphate and ATP β- and γ-phosphates. And, this is sufficient to support an associative reaction mechanism for phosphoryl transfer. ADK catalyzes the transfer of a phosphoryl group from ATP to AMP by nucleophilic attack on the γ-phosphate of ATP.[6]

Structure[edit]

Flexibility and plasticity allow proteins to bind to ligands, form oligomers, aggregate, and perform mechanical work.[7] Large conformational changes in proteins play an important role in cellular signaling. Adenylate Kinase is a signal transducing protein; thus, the balance between conformations regulates protein activity. ADK has a locally unfolded state that becomes depopulated upon binding.[8]

A 2007 study by Whitford et al. shows the conformations of ADK when binding with ATP or AMP.[7] The study shows that there are three relevant conformations or structures of ADK—CORE, Open, and Closed. In ADK, there are two small domains called the LID and NMP.[9] ATP binds in the pocket formed by the LID and CORE domains.[7] AMP binds in the pocket formed by the NMP and CORE domains.

The study also reported findings that show that localized regions of a protein unfold during conformational transitions.[7] This mechanism reduces the strain and enhances catalytic efficiency. Local unfolding is the result of competing strain energies in the protein.[7] The interconversion between inactive (open) and active (closed) conformations is rate limiting for catalysis.[10]

Function[edit]

Metabolic monitoring[edit]

ADK uses AMP metabolic signals produced or downregulated during exercise, stress response, food consumption, hormone changes. ADK relays deliver AMP signals to metabolic sensors.[11] It facilitates decoding of cellular information by catalyzing nucleotide exchange in the intimate “sensing zone” of metabolic sensors.[11]

Through a chain of sequential reactions, ADK facilitates transfer and utilization of γ- and β-phosphoryls in the ATP molecule.[11]

ADK shuttle[edit]

The energy of two high-energy phosphoryls, γ- and β-phosphoryls in the ATP molecule, is made available by the ADK present in mitochondrial and myofibrillar compartments.[11] ATP and AMP are transferred between ATP-production and ATP-consumption sites that involve multiple, sequential phosphotransfer relays. This results in a flux wave propagation along groups of ADK molecules. This ligand conduction mechanism facilitates metabolic flux without apparent changes in metabolite concentrations.[11]

ADK reads the cellular energy state, generates, tunes, and communicates AMP signals to metabolic sensors.[11] In this way, ADK is able to convey information about the overall energy balance. AMP-sensors inhibit ATP consumption and promote ATP production.[11]

Disease relevance[edit]

Nucleoside diphosphate kinase deficiency[edit]

Nucleoside diphosphate (NDP) kinase catalyzes in vivo ATP-dependent synthesis of riobo- and deoxyribonucleoside triphosphates. In mutated Escherichia coli that had a disrupted nucleoside diphosphate kinase, adenylate kinase performed dual enzymatic functions. ADK complements nucleoside diphosphate kinase deficiency.[12]

Hemolytic anemia[edit]

Adenylate kinase deficiency in the erythrocyte is associated with hemolytic anemia.[13] This is a rare hereditary erythroenzymopathy that, in some cases, is associated with mental retardation and psychomotor impairment.[14] At least two patients have exhibited neonatal icterus and splenomegaly and required blood transfusions due to this deficiency.[15] In another patient, an abnormal fragment with homozygous and heterozygous A-->G substitutions at codon 164 caused severe erythrocyte ADK deficiency.[16] Two siblings had erythrocyte ADK deficiency, but one did not have evidence of hemolysis.[17]

AK1 and post-ischemic coronary reflow[edit]

Knock out of AK1 disrupts the synchrony between inorganic phosphate and turnover at ATP-consuming sites and ATP synthesis sites. This reduces the energetic signal communication in the post-ischemic heart and precipitates inadequate coronary reflow flowing ischemia-reperfusion.[18]

ADK2 deficiency[edit]

Adenylate Kinase 2 (AK2) deficiency in humans causes hematopoietic defects associated with sensorineural deafness.[19] Recticular dysgenesis is an autosomal recessive form of human combined immunodeficiency. It is also characterized by an impaired lymphoid maturation and early differentiation arrest in the myeloid lineage. AK2 deficiency results in absent or a large decrease in the expression of proteins. AK2 is specifically expressed in the stria vascularis of the inner ear which indicates why individuals with an AK2 deficiency will have sensorineural deafness.[19]

Structural adaptations[edit]

AK1 genetic ablation decreases tolerance to metabolic stress. AK1 deficiency induces fiber-type specific variation in groups of transcripts in glycolysis and mitochondrial metabolism.[20] This supports muscle energy metabolism.

Plastidial ADK deficiency in Arabidopsis thaliana[edit]

Enhanced growth and elevated photosynthetic amino acid is associated with plastidial adenylate kinase deficiency in Arabidopsis thaliana.[21]

References[edit]

  1. ^ The NIST Thermodynamics of Enzyme-Catalyzed Reactions database, http://xpdb.nist.gov/enzyme_thermodynamics/enzyme1.pl, Goldberg RN, Tewari YB, Bhat TN, "Thermodynamics of Enzyme-Catalyzed Reactions -a Database for Quantitative Biochemistry", Bioinformatics 2004;20(16):2874-2877, http://www.ncbi.nlm.nih.gov/pubmed/15145806, gives equilibrium constants, search for adenylate kinase under enzymes
  2. ^ Beis I, Newsholme EA (October 1975). "The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates". Biochem. J. 152 (1): 23–32. PMC 1172435. PMID 1212224. 
  3. ^ Schulz GE, Frank R, Tomasselli AG, Noda LH, Wieland B (1984). "The amino acid sequence of GTP:AMP phosphotransferase from beef-heart mitochondria. Extensive homology with cytosolic adenylate kinase". Eur. J. Biochem. 143 (2): 331–339. doi:10.1111/j.1432-1033.1984.tb08376.x. PMID 6088234. 
  4. ^ Tomasselli AG, Noda LH (1979). "Mitochondrial GTP-AMP phosphotransferase. 2. Kinetic and equilibrium dialysis studies". Eur. J. Biochem. 93 (2): 263–270. doi:10.1111/j.1432-1033.1979.tb12819.x. PMID 218813. 
  5. ^ Cooper AJ, Friedberg EC (1992). "A putative second adenylate kinase-encoding gene from the yeast Saccharomyces cerevisiae". Gene 114 (1): 145–148. doi:10.1016/0378-1119(92)90721-Z. PMID 1587477. 
  6. ^ a b Krishnamurthy, H.; Lou, H.; Kimple, A.; Vieille, C.; Cukier, RI. (Jan 2005). "Associative mechanism for phosphoryl transfer: a molecular dynamics simulation of Escherichia coli adenylate kinase complexed with its substrates.". Proteins 58 (1): 88–100. doi:10.1002/prot.20301. PMID 15521058. 
  7. ^ a b c d e Whitford PC, Miyashita O, Levy Y, Onuchic JN (March 2007). "Conformational transitions of adenylate kinase: switching by cracking". J. Mol. Biol. 366 (5): 1661–71. doi:10.1016/j.jmb.2006.11.085. PMC 2561047. PMID 17217965. 
  8. ^ Schrank, TP.; Bolen, DW.; Hilser, VJ. (Oct 2009). "Rational modulation of conformational fluctuations in adenylate kinase reveals a local unfolding mechanism for allostery and functional adaptation in proteins.". Proc Natl Acad Sci U S A 106 (40): 16984–9. doi:10.1073/pnas.0906510106. PMID 19805185. 
  9. ^ Daily, MD.; Phillips, GN.; Cui, Q. (Jul 2010). "Many local motions cooperate to produce the adenylate kinase conformational transition.". J Mol Biol 400 (3): 618–31. doi:10.1016/j.jmb.2010.05.015. PMID 20471396. 
  10. ^ Olsson, U.; Wolf-Watz, M. (2010). "Overlap between folding and functional energy landscapes for adenylate kinase conformational change.". Nat Commun 1 (8): 111. doi:10.1038/ncomms1106. PMID 21081909. 
  11. ^ a b c d e f g Dzeja P, Terzic A (April 2009). "Adenylate kinase and AMP signaling networks: Metabolic monitoring, signal communication and body energy sensing". Int J Mol Sci 10 (4): 1729–72. doi:10.3390/ijms10041729. PMC 2680645. PMID 19468337. 
  12. ^ Lu, Q.; Inouye, M. (Jun 1996). "Adenylate kinase complements nucleoside diphosphate kinase deficiency in nucleotide metabolism.". Proc Natl Acad Sci U S A 93 (12): 5720–5. doi:10.1073/pnas.93.12.5720. PMID 8650159. 
  13. ^ Matsuura, S.; Igarashi, M.; Tanizawa, Y.; Yamada, M.; Kishi, F.; Kajii, T.; Fujii, H.; Miwa, S.; Sakurai, M.; Nakazawa, A. (Jun 1989). "Human adenylate kinase deficiency associated with hemolytic anemia. A single base substitution affecting solubility and catalytic activity of the cytosolic adenylate kinase.". J Biol Chem 264 (17): 10148–55. PMID 2542324. 
  14. ^ Abrusci, P.; Chiarelli, LR.; Galizzi, A.; Fermo, E.; Bianchi, P.; Zanella, A.; Valentini, G. (Aug 2007). "Erythrocyte adenylate kinase deficiency: characterization of recombinant mutant forms and relationship with nonspherocytic hemolytic anemia.". Exp Hematol 35 (8): 1182–9. doi:10.1016/j.exphem.2007.05.004. PMID 17662886. 
  15. ^ Corrons, JL.; Garcia, E.; Tusell, JJ.; Varughese, KI.; West, C.; Beutler, E. (Jul 2003). "Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118GA, 190GA, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia.". Blood 102 (1): 353–6. doi:10.1182/blood-2002-07-2288. PMID 12649162. 
  16. ^ Qualtieri, A.; Pedace, V.; Bisconte, MG.; Bria, M.; Gulino, B.; Andreoli, V.; Brancati, C. (Dec 1997). "Severe erythrocyte adenylate kinase deficiency due to homozygous A-->G substitution at codon 164 of human AK1 gene associated with chronic haemolytic anaemia.". Br J Haematol 99 (4): 770–6. PMID 9432020. 
  17. ^ Beutler, E.; Carson, D.; Dannawi, H.; Forman, L.; Kuhl, W.; West, C.; Westwood, B. (Aug 1983). "Metabolic compensation for profound erythrocyte adenylate kinase deficiency. A hereditary enzyme defect without hemolytic anemia.". J Clin Invest 72 (2): 648–55. doi:10.1172/JCI111014. PMID 6308059. 
  18. ^ Dzeja, PP.; Bast, P.; Pucar, D.; Wieringa, B.; Terzic, A. (Oct 2007). "Defective metabolic signaling in adenylate kinase AK1 gene knock-out hearts compromises post-ischemic coronary reflow.". J Biol Chem 282 (43): 31366–72. doi:10.1074/jbc.M705268200. PMID 17704060. 
  19. ^ a b Lagresle-Peyrou C, Six EM, Picard C, et al. (January 2009). "Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness". Nat. Genet. 41 (1): 106–11. doi:10.1038/ng.278. PMC 2612090. PMID 19043416. 
  20. ^ Janssen, E.; de Groof, A.; Wijers, M.; Fransen, J.; Dzeja, PP.; Terzic, A.; Wieringa, B. (Apr 2003). "Adenylate kinase 1 deficiency induces molecular and structural adaptations to support muscle energy metabolism.". J Biol Chem 278 (15): 12937–45. doi:10.1074/jbc.M211465200. PMID 12562761. 
  21. ^ Carrari, F.; Coll-Garcia, D.; Schauer, N.; Lytovchenko, A.; Palacios-Rojas, N.; Balbo, I.; Rosso, M.; Fernie, AR. (Jan 2005). "Deficiency of a plastidial adenylate kinase in Arabidopsis results in elevated photosynthetic amino acid biosynthesis and enhanced growth.". Plant Physiol 137 (1): 70–82. doi:10.1104/pp.104.056143. PMID 15618410. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR000850

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Adenylate kinase, active site lid Provide feedback

Comparisons of adenylate kinases have revealed a particular divergence in the active site lid. In some organisms, particularly the Gram-positive bacteria, residues in the lid domain have been mutated to cysteines and these cysteine residues are responsible for the binding of a zinc ion. The bound zinc ion in the lid domain, is clearly structurally homologous to Zinc-finger domains. However, it is unclear whether the adenylate kinase lid is a novel zinc-finger DNA/RNA binding domain, or that the lid bound zinc serves a purely structural function [1].

Literature references

  1. Berry MB, Phillips GN Jr; , Proteins 1998;32:276-288.: Crystal structures of Bacillus stearothermophilus adenylate kinase with bound Ap5A, Mg2+ Ap5A, and Mn2+ Ap5A reveal an intermediate lid position and six coordinate octahedral geometry for bound Mg2+ and Mn2+. PUBMED:9715904 EPMC:9715904


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR007862

Adenylate kinases (ADK; EC) are phosphotransferases that catalyse the Mg-dependent reversible conversion of ATP and AMP to two molecules of ADP, an essential reaction for many processes in living cells. In large variants of adenylate kinase, the AMP and ATP substrates are buried in a domain that undergoes conformational changes from an open to a closed state when bound to substrate; the ligand is then contained within a highly specific environment required for catalysis. Adenylate kinase is a 3-domain protein consisting of a large central CORE domain flanked by a LID domain on one side and the AMP-binding NMPbind domain on the other [PUBMED:17299745]. The LID domain binds ATP and covers the phosphates at the active site. The substrates first bind the CORE domain, followed by closure of the active site by the LID and NMPbind domains.

Comparisons of adenylate kinases have revealed a particular divergence in the active site lid. In some organisms, particularly the Gram-positive bacteria, residues in the lid domain have been mutated to cysteines and these cysteine residues (two CX(n)C motifs) are responsible for the binding of a zinc ion. The bound zinc ion in the lid domain is clearly structurally homologous to Zinc-finger domains. However, it is unclear whether the adenylate kinase lid is a novel zinc-finger DNA/RNA binding domain, or that the lid bound zinc serves a purely structural function [PUBMED:9715904].

Gene Ontology

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Domain organisation

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(141)
Full
(6209)
Representative proteomes NCBI
(2972)
Meta
(552)
RP15
(385)
RP35
(706)
RP55
(964)
RP75
(1176)
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  Seed
(141)
Full
(6209)
Representative proteomes NCBI
(2972)
Meta
(552)
RP15
(385)
RP35
(706)
RP55
(964)
RP75
(1176)
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Seed source: Manual
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 141
Number in full: 6209
Average length of the domain: 36.00 aa
Average identity of full alignment: 57 %
Average coverage of the sequence by the domain: 18.92 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.2 22.2
Trusted cut-off 22.2 22.2
Noise cut-off 22.1 22.1
Model length: 36
Family (HMM) version: 9
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ADK

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the ADK_lid domain has been found. There are 61 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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