Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 146

associated AMPK constitute a major metabolic signaling axis guiding energetics of
cell cycle, stem cell differentiation, and lineage specification; the defects in AMP
metabolic signaling could lead to cardiac malformations (Dzeja et al. 2011a ). Thus,
AK2 deficiency disrupts the mitochondrial-cytosolic-nuclear flow of energy and
the developmental metabolic information governing cell differentiation.
The mitochondrial AK2 isoform has the highest affinity (lowest Km) for AMP

μ

( M) among AMP metabolizing enzymes and is highly concentrated in the

narrow intermembrane space (Dzeja and Terzic 2009 ; Walker and Dow 1982 ).
Virtually, all the AMP reaching mitochondria is converted to ADP and channeled
into oxidative phosphorylation maintaining a low cytosolic AMP concentration. In
such a way, adenylate kinase tunes cytosolic AMP signals and guards the cellular
adenine nucleotide pool (Dzeja and Terzic 2009 ). During intense physical activity
or metabolic stress, such as ischemia, AMP concentration rises, turning on other
AMP-metabolizing enzymes, such as AMP deaminase and 5 0 -nucleotidase, produc-
ing IMP and adenosine. In this regard, a marked elevation of mitochondrial AK2
activity has been demonstrated in hypertrophy in response to increased energy
demand and the necessity to maintain the cellular adenine nucleotide pool (Seccia
et al. 1998 ).
Muscles of Ak1 knockout mice, with one less phosphotransfer chain, display
lower energetic efficiency, slower relaxation kinetics, and a faster drop in contrac-
tility upon ischemia associated with compromised myocardial-vascular crosstalk
(Dzeja et al. 2007b ; Pucar et al. 2000 , 2002 ). A mechanistic basis for thermody-
namically efficient coupling of cell energetics with cellular functions lies in the
unique property of adenylate kinase catalysis which transfers both

10

β - and

γ -phosphoryls of ATP, doubling the energetic potential of ATP as an energy-

carrying molecule (Dzeja et al. 1985 , 1998 , 2002 ; Dzeja and Terzic 2003 , 2009 ).
More recently, it was demonstrated that cytoskeleton-based cell motility can be
modulated by spatial repositioning of AK1 enzymatic activity providing local ATP
supplies and “on-site” fueling of the actomyosin-machinery (van Horssen
et al. 2009 ). Another study suggests that intracellular and extracellular adenylate
kinase play an important role in nucleotide energetic signaling, regulating actin
assembly-disassembly involved in cell movement and chemotaxis (Kuehnel
et al. 2009 ). Such integrated energetic and metabolic signaling roles place adenylate
kinase in a unique position within the cellular metabolic regulatory network.
New studies published within the past years have uncovered much wider
involvement of adenylate kinase in energy support, metabolic monitoring, and
managing cellular functions with mutations in this enzyme associated with
human diseases (Dzeja and Terzic 2009 ; Lagresle-Peyrou et al. 2009 ; Panayiotou
et al. 2011 ; van Horssen et al. 2009 ). In addition to mutations of adenylate kinase
isoform 7, AK7, gene which has been found to be associated with primary ciliary
dyskinesia which leads to chronic obstructive pulmonary disease (COPD) in
humans (Fernandez-Gonzalez et al. 2009 ), new mutations in both adenylate kinases
7 and 8, AK7 and AK8, genes were found associated with ciliary defects and
congenital hydrocephalus (Vogel et al. 2012 ). Also, recent studies have uncovered
that dysregulation of adenylate kinase AK1-, AK2-, and AK5-mediated energetic