Adenylate Kinase - an overview (2023)

Adenylate kinase-2 (AK2) deficiency, also known as reticular dysgenesis (OMIM #267500), is a profound inherited immune deficiency characterized by severe lymphopenia and marrow failure.

From: Clinical Immunology (Fifth Edition), 2019

Related terms:

  • Mitochondrion
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  • Adenosine Phosphate
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Adenylate Kinase

H.-Y. Chang, C.-Y. Fu, in Encyclopedia of Food Microbiology (Second Edition), 2014

Abstract

Adenylate kinase (AK) is a ubiquitous and abundant enzyme catalyzing the phosphoryl transfer between two adenosine diphosphate (ADP) molecules to yield adenosine triphosphate (ATP) and adenosine monophosphate (AMP). The enzyme has gained much attention recently because it can be used as a cell marker to replace ATP in the luciferase-based bioluminescence assay. The use of AK has the potential to offer much greater sensitivity than ATP measurement and is more reliable in determining cell numbers. AK can be used to regenerate ATP from the AMP produced in the luciferase reaction. This creates a cyclic loop of ATP amplification and can significantly enhance the bioluminescence assay sensitivity.

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ADENYLATE KINASE

M.J. Murphy, D.J. Squirrell, in Encyclopedia of Food Microbiology, 1999

Adenylate Kinase

Adenylate kinase (AK) is a constitutively expressed enzyme which comprises about 0.1% of cell protein. It catalyses the equilibrium reaction:

Equation 1Mg2+ATP+AMPADP+Mg2+ADP

where ATP, ADP and AMP are the adenosine tri-, di- and monophosphates respectively.

In vivo the reaction serves to maintain the balance of adenylates in the cell, usually proceeding to the right to rephosphorylate the AMP which is produced by various phosphatase reactions. The ADP formed can then be further phosphorylated to ATP. However, by adding an excess of ADP the reaction in vitro can be driven in the opposite direction. This generates ATP which can then be measured using the luciferin/luciferase reaction:

Equation 22ADPMg2ATP+AMP

Equation 3ATP+LH2+EMg2LH2AMPE+PPi

Equation 4LH2AMPE+O2L+CO2+AMP+Light

where LH2 is luciferin, E is luciferase, PPi is inorganic pyrophosphate and L is oxyluciferin.

Adenylate kinase (ATP: AMP phosphotransferase, EC 2.7.4.3) is found in virtually all eukaryotic and prokaryotic cells, the exception being some sulphur bacteria in which AMP-sulphate is used instead of ATP for energy transfer. In eukaryotes it is predominantly found in the space between the inner and outer mitochondrial membranes and in Gram-negative bacteria in the periplasmic space. It is the only enzyme produced by cells for the purpose of rephosphorylating AMP to ADP and, as such, is essential for life. (Exceptionally, other kinases may have limited nonspecific AK activity which can allow very limited growth in cells in which the gene for AK has been deleted.) It is a stable protein with a relatively long intracellular lifetime. The molecular mass of AK is 20–25kDa. In bacteria it is usually made up of 214 or 217 amino acids. Typical AK equilibrium ([ADP]2/[ATP]·[AMP]) and Michaelis (Km for ADP) constants are 2.26 and 1.58mmol l−1 respectively.

A medium-sized bacterium contains about 10−21 moles of AK in comparison with about 10−18 moles of ATP, so there is approximately 1 molecule of AK for every 1000 molecules of ATP. The enzyme has a turnover number of around 40 000, which means that with just 1 min incubation it can generate 40 times more ATP for bioluminescent signal production than would be possible from the ATP naturally present on its own. The amplification reaction requires only a single substrate and provides a linear increase in the amount of ATP over time. In theory, if a count of 103 cells is taken as the limit of detection for a conventional ATP assay, an AK assay with a 25 min incubation should allow single bacterial cells to be detected. Raised backgrounds from contaminating ATP and AK prevent this from being easily achieved, but it has been demonstrated.

From an operator's viewpoint there is very little difference between the two assays (Fig. 1). By premixing the ADP with a detergent-based extractant, the extraction and amplification steps needed in the AK assay can be performed simultaneously. The only variation between the two assays may be an extended incubation time (of about 5 min) for the AK assay.

Adenylate Kinase - an overview (1)

Figure 1. Comparison of (A) ATP-based and (B) AK-based bioluminescent assays.

Kinases other than AK, such as pyruvate kinase, could potentially be used as ATP-generating cell markers. Several have been tried, but none has been found to give results comparable with AK. One reason for this is that all of the other kinases require two substrates: a phosphate donor and ADP. Obtaining a high degree of purity in the reagents is consequently made more difficult. Adenylate kinase uses two ADP molecules with one as the phosphate acceptor and the other as the phosphate donor. The AK approach thus has a unique advantage in terms of simplicity. Other reasons for the greater usefulness of AK over other kinases include its enzymatic properties (it has a high turnover number), its characteristics as a protein (it is very small for an enzyme and is particularly robust) and the critical nature of its metabolic function.

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Other Hereditary Red Blood Cell Disorders

Bertil Glader, in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013

72.2.3 Adenylate Kinase Deficiency

Adenylate kinase (AK) reversibly catalyzes the interconversion of adenine nucleotides and thereby salvages adenosine monophosphate (AMP) generated in a variety of RBC reactions. Hereditary nonspherocytic hemolytic anemia has been reported in 11 families with erythrocyte AK deficiency (38,62,77,82,83). In most cases AK deficiency is associated with moderate to severe hemolytic anemia. In some cases there also is psychomotor impairment (83,84).

In one report, there was congenital hemolytic anemia and a marked reduction in erythrocyte AK activity in one patient, although the proband’s brother, who was hematologically normal, also had no detectable erythrocyte AK activity (85). The significance of this observation is not known. The AK enzyme has been studied at a molecular level in almost all cases, and each family has its own unique mutation, predominantly a missense mutation.

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Primary T-Cell Immunodeficiencies

Chaim M. Roifman, in Clinical Immunology (Fifth Edition), 2019

AK2 Deficiency (Reticular Dysgenesis)

Adenylate kinase-2 (AK2) deficiency, also known as reticular dysgenesis (OMIM #267500), is a profound inherited immune deficiency characterized by severe lymphopenia and marrow failure. The disorder has an autosomal recessive pattern of inheritance and is caused by mutations in the AK2 gene.17,18 Mitochondrial AK2 catalyzes the reversible phosphorylation between nucleoside triphosphates and monophosphates. AK2 defects are associated with impaired mitochondrial energy metabolism and leukocyte differentiation. Patients suffer repeated bacterial, viral, and fungal infections and have bilateral sensorineural deafness.17 Patients present in infancy with profound neutropenia and lymphopenia, the thymus is dystrophic, and TRECs are undetectable. Diagnosis is confirmed by genetic analysis. Bone marrow reconstitution can be achieved with HSCT and remains the most effective modality of treatment.

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The Temporal Lobe

Christian G. Bien, in Handbook of Clinical Neurology, 2022

Pathophysiology

AK5 is an intracellular protein. The CSF proteomic profile of five patients and one neuropathologic study suggested apoptosis pathways and innate/adaptive immune responses compatible with a destructive T cell pathology (Muñiz-Castrillo et al., 2021). There is an association with HLA-B*08.01 (Muñiz-Castrillo et al., 2021). The IgG subclass frequencies of AK5 abs were: IgG1 (9/9)>IgG2 (8/9), IgG4 (8/9)>IgG3 (4/9) (Muñiz-Castrillo et al., 2021).

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Molecular Classification of Primary Immunodeficiencies of T Lymphocytes

William A. Comrie, Michael J. Lenardo, in Advances in Immunology, 2018

3.13.2 AK2

Adenylate kinase 2 (AK2) catalyzes the conversion of ADP to ATP and AMP, and is thus crucial for the de novo biogenesis of AMP (Noma, 2005). Biallelic LOF mutations in AK2 causes reticular dysgenesis, a severe SCID phenotype with absence of granulocytes, severe lymphocyte deficiency, hypoplasia of the thymus and lymph nodes caused by an early arrest in myeloid lineage development and lymphoid maturation with loss of almost all major immune cellular subsets (OMIM 267500) (Lagresle-Peyrou et al., 2009; Pannicke et al., 2009). This was traced back to an increase in spontaneous apoptosis related to defects in mitochondrial function, oxidative phosphorylation, and ROS production due to altered homeostasis of ADP, ATP, and AMP (Six et al., 2015).

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Protein Kinases in Drug Discovery

T.A. Tavella, ... E. Bilsland, in Advances in Protein Chemistry and Structural Biology, 2021

4.4 Potential Adenylate kinase 1 inhibitors

The Adenylate kinase (AK) is a housekeeping enzyme involved in energy metabolism via catalysis of the nucleotide exchange reaction 2ADP↔ATP+AMP. The unique delivery of γ- and β-phosphoryl groups to ATP, doubling its energetic potential, promoted by AK enzyme, plays a major role in several cellular processes like hormone secretion, endocytosis, cellular motility and nuclear transport, besides ubiquitous participation in energetic metabolic signaling pathways (Dzeja & Terzic, 2009). The search for AK inhibitors ended as fast as it started, with a collection of synthetic inhibitors arising in the 70s (Feldhaus, Frohlich, Goody, Isakov, & Schirmer, 1975). The knockdown of AK in tumor cells overexpressing AK2 can impair multiple processes intrinsic for cancer cells proliferation and metastasis, like migration, invasion, and apoptosis (Klepinin et al., 2020). Although there are nine members of AK family expressed in humans (K1–K9), four of them involved in cancer metabolism, this number varies depending on the organism. While Plasmodium and Schistosoma have two known variants of the gene and additional putative AKs (Ma et al., 2012), Trypanosomatids have an impressive high number of genes coding Adenylate kinases (Pereira, Bouvier, De Los Milagros Cámara, & Miranda, 2011). Here we present the potential AK1 inhibitors proposed by HIP results (Fig. 6).

Adenylate Kinase - an overview (2)

Fig. 6. Potential Adenylate kinase 1 inhibitors proposed by HIP results.

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TOTAL VIABLE COUNTS | Specific Techniques

Michael G. Williams, Frank F. Busta, in Encyclopedia of Food Microbiology, 1999

See also:

ADENYLATE KINASE; ATP BIOLUMINESCENCE | Application in Meat Industry; ATP BIOLUMINESCENCE | Application in Dairy Industry; ATP BIOLUMINESCENCE | Application in Beverage Microbiology; ELECTRICAL TECHNIQUES | Food Spoilage Flora and TVC; NATIONAL LEGISLATION, GUIDELINES & STANDARDS GOVERNING MICROBIOLOGY | European Union; NATIONAL LEGISLATION, GUIDELINES & STANDARDS GOVERNING MICROBIOLOGY | Japan; RAPID METHODS FOR FOOD HYGIENE INSPECTION; SAMPLING REGIMES & STATISTICAL EVALUATION OF MICROBIOLOGICAL RESULTS; TOTAL VIABLE COUNTS | Pour Plate Technique; TOTAL VIABLE COUNTS | Spread Plate Technique; TOTAL VIABLE COUNTS | MPN; TOTAL VIABLE COUNTS | Metabolic Activity Tests; TOTAL VIABLE COUNTS | Microscopy; ULTRASONIC IMAGING.

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