Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 142

6.1 Adenylate Kinase Isoform Network

Adenylate kinase, a ubiquitous enzyme with a unique property to catalyze the
reaction 2ADP

ATP + AMP, is indispensable for nucleotide biosynthesis and a
sensitive reporter of the cellular energy state, translating small changes in the
balance between ATP and ADP into relative large changes in AMP concentration,
so that enzymes and metabolic sensors that are affected by AMP can respond with
high sensitivity and fidelity to stress signals (Dzeja and Terzic 2009 ; Dzeja
et al. 1998 ; Noda 1973 ; Noma 2005 ). Moreover, adenylate kinase, via a series of
spatially linked enzymatic reactions, can facilitate propagation of nucleotide
signals in the intracellular, extracellular, and mitochondrial intracristal spaces,
thus coordinating energy transfer events and the response of metabolic sensors
and nucleotide/nucleoside receptor signaling (Carrasco et al. 2001 ; Dzeja
et al. 1985 , 1998 , 2002 , 2007a , b ). A significant progress has been made in defining
dynamics of conformational transitions that are functionally important in adenylate
kinase catalysis (Daily et al. 2010 , 2012 ; Henzler-Wildman et al. 2007 ).
Distributed throughout the cell and cellular compartments, the adenylate kinase
isoform network delivers

$

β γ

-high-energy phosphoryls of ATP to ATPases and
monitors ATP/ADP metabolic imbalances (Dzeja and Terzic 2009 ). In response to
stress adenylate kinase generates AMP signals which are delivered to metabolic
sensors to adjust energy metabolism and cell functions according to changes in
physiological state and energetic environment (Dzeja and Terzic 2003 , 2009 ;
Janssen et al. 2004 ; Noma 2005 ; Pucar et al. 2002 ). Adenylate kinase-mediated
metabolic monitoring and downstream AMP signaling AK

- and

AMP
sensors (including AMPK, K-ATP, and AMP-sensitive metabolic enzymes) net-
work is increasingly recognized as a major homeostatic hub, which is critical in
regulation of diverse cellular processes (Dzeja and Terzic 2009 ; Noma 2005 ). So
far, up to nine distinct adenylate kinase isoforms and a number of subforms with
different intracellular localization and energetic-metabolic signaling roles have
been identified (Fig. 6.1 ) (Amiri et al. 2013 ; Collavin et al. 1999 ; Dzeja and Terzic
2009 ; Dzeja et al. 2011a ; Janssen et al. 2000 , 2004 ; Noma 2005 ; Panayiotou
et al. 2011 ; Ren et al. 2005 ; Ruan et al. 2002 ). The energetic signaling role of
adenylate kinase has gained particular significance after discovery that this enzyme,
through a chain of sequential reactions, facilitates the transfer and utilization of
both

! AMP !

- phosphoryls of the ATP molecule, thereby doubling the energetic
potential of ATP and cutting in half the cytosolic diffusional resistance for energy
transmission (Dzeja et al. 1985 , 1998 ). Turnover of ATP

β - and γ

-phosphoryls
can be followed by 18 O-assisted 31 P NMR, a versatile technique for measurement of
intracellular dynamics of energy metabolism (Fig. 6.1 ) (Nemutlu et al. 2012b ).
Isotope labeling studies indicate that in intact tissues the highest adenylate kinase-
catalyzed ATP

α -, β -, and γ

β -phosphoryl turnover is in the kidney, which approximates 98 % of

γ -ATP turnover, followed by the liver (80 %), the heart (15-40 %), and contracting

(10-17 %) or resting (3-5 %) skeletal muscles suggesting a centralized role of
adenylate kinase in tissue energy homeostasis (Dzeja and Terzic 2003 , 2007 , 2009 ).