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159  structures 3215  species 3  interactions 6954  sequences 122  architectures

Family: ADK (PF00406)

Summary: Adenylate kinase

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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)
Symbol ADK
Pfam PF00406
InterPro IPR000850
SCOP 1ake
PDB 1zip EBI.jpg
Bacillus stearothermophilus adenylate kinase
Symbol ADK_lid
Pfam PF05191
InterPro IPR007862
SCOP 1ake
Adenylate kinase
EC number
CAS number 2598011
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Adenylate kinase (EC (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

The reaction catalyzed is:


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

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.



Human genes encoding proteins with adenylate kinase include:


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]


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]


Metabolic monitoring

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

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

Nucleoside diphosphate kinase deficiency

Nucleoside diphosphate (NDP) kinase catalyzes in vivo ATP-dependent synthesis of ribo- 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

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

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

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

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

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


  1. ^ The NIST Thermodynamics of Enzyme-Catalyzed Reactions database,, Goldberg, R. N.; Tewari, Y. B.; Bhat, T. N. (2004). "Thermodynamics of enzyme-catalyzed reactions--a database for quantitative biochemistry". Bioinformatics. 20 (16): 2874–7. doi:10.1093/bioinformatics/bth314. PMID 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. doi:10.1042/bj1520023. PMC 1172435Freely accessible. 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 2561047Freely accessible. 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. PMC 2761315Freely accessible. 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. PMC 2902635Freely accessible. 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 2680645Freely accessible. 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. PMC 39127Freely accessible. 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. doi:10.1046/j.1365-2141.1997.4953299.x. 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. PMC 1129224Freely accessible. 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. PMC 3232003Freely accessible. 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 2612090Freely accessible. 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. PMC 548839Freely accessible. PMID 15618410. 

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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

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 199 members:

6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_5 AAA_6 AAA_7 AAA_8 AAA_PrkA ABC_ATPase ABC_tran Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arf ArgK ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 ATPase ATPase_2 Bac_DnaA CbiA CBP_BcsQ CDC73_C CLP1_P CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1611 DUF2075 DUF2326 DUF2478 DUF258 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N ERCC3_RAD25_C Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GTP_EFTU Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK Hydin_ADK IIGP IPPT IPT IstB_IS21 KAP_NTPase KdpD Kinesin KTI12 Lon_2 LpxK MCM MEDS Mg_chelatase Microtub_bd MipZ MMR_HSR1 MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 NTPase_P4 ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase Roc RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulphotransf T2SSE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind TsaE UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE Zeta_toxin Zot


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Curation and family details

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Seed source: Prosite
Previous IDs: adenylatekinase;
Type: Domain
Author: Finn RD
Number in seed: 21
Number in full: 6954
Average length of the domain: 167.00 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 59.60 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.8 26.8
Trusted cut-off 26.8 26.8
Noise cut-off 26.7 26.7
Model length: 151
Family (HMM) version: 20
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 3 interactions for this family. More...

ADK_lid ADK_lid ADK


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 domain has been found. There are 159 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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