Adenosine kinase and ribokinase – the RK family of proteins

Abstract

Ribokinase (RK) and adenosine kinase (AK) catalyze the phosphorylation of ribose and adenosine to ribose-5-phosphate and AMP, respectively. Belonging to the RK family of proteins, these enzymes share a number of unique structural and functional elements. Extensive work has been carried out on many aspects of these enzymes in recent years, and we summarize the wealth of information currently available on them. The topics covered include descriptions of the primary and three-dimensional structures of AK and RK, their phylogenetic relationships, biochemical aspects of these enzymes including their reaction mechanisms and ionic requirements, and also work on certain inhibitors of these enzymes. The cellular metabolism and transport of ribose and adenosine are also briefly discussed, as well as the beneficial effects of ribose and adenosine in physiology and how these effects can be harnessed for pharmacological purposes.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…These unique features of the ADK reaction complicated the interpretation of kinetic data and both a two-site ping-pong mechanism (Chang et al, 1983) and an ordered Bi-Bi mechanism (Henderson et al, 1972;Palella et al, 1980;Mimouni et al, 1994 ) have been proposed. Information obtained from the crystal structures of human (Mathews et al, 1998) and Toxoplasma gondii (Schumacher et al, 2000) ADK have confirmed an ordered Bi-Bi mechanism and a more detailed mechanism has recently been proposed (Park and Gupta, 2008). In a first step, inorganic phosphate or an activator compound binds to a conserved NXXE motif.…”

“…In contrast, ADA is a highcapacity and high-K m enzyme, which assists in metabolic Adenosine Kinase adenosine clearance under conditions in which adenosine levels become excessive (e.g., due to pathologic activity) and the capacity of ADK is exceeded . Of note, ADK is an evolutionary ancient and highly conserved enzyme, which is directly related to bacterial ribokinases and fructokinases (Spychala et al, 1996;Park and Gupta, 2008). On the basis of these early evolutionary roots, it is not surprising that ADK has been identified in almost all living organisms that have been analyzed genetically, including microorganisms, yeasts, plants and animals, and in every tissue assayed.…”

“…At the same time the 59-hydroxyl end of adenosine is deprotonated, attacking the positive center of the g-phosphate. In a final step the g-phosphate is transferred to adenosine, and products are released in the order of ADP and AMP (Park and Gupta, 2008). Although monomer-stabilizing interaction partners have been identified in ADK from parasites (Sen et al, 2006), it remains to be determined whether similar interaction partners exist for mammalian ADK.…”

Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication

“…ADK is a ribokinase that regulates the intracellular and extracellular adenosine levels through its ability to catalyze the phosphorylation of adenosine to AMP using ATP as the phosphate donor (31). Although this enzyme is broadly expressed, it is highly expressed in the liver and pancreas (32).…”

Structures of adenosine kinase fromTrypanosoma brucei brucei

“…AK belongs to the phosphofructokinase B family of carbohydrate kinases, with two characteristic sequence motifs: the di-glycine switch close to the N-terminus and the sequence DXNGAGD close to the C-terminus (Park & Gupta, 2008). AKs of several species, including that of T. brucei rhodesiense (TbAK; Kuettel et al, 2011), have been well characterized.…”