Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 144

The highest total adenylate kinase activity is in skeletal muscle followed by heart,
brain, kidney, and liver (Borglund et al. 1978 ), suggesting that flux and enzyme
activity are independent parameters. Therefore, functional activity imposed meta-
bolic flux cannot be predicted from activity measurements or from model
calculations (Nemutlu et al. 2012b ).
Three major isoforms, AK1, AK2, and AK3 are localized in the cytosol, the
mitochondrial intermembrane space, and the matrix, facilitating transcellular nucle-
otide exchange (Dzeja et al. 1985 ; Noda 1973 ). The existence of the whole family
of adenylate kinases with different expression profiles, substrate specificities, and
kinetic properties provides evidence of specialized functions in specific cellular
processes (Panayiotou et al. 2011 ). The major cytosolic isoform AK1 is expressed
at high levels in skeletal muscle, brain, and heart, whereas AK2 is expressed in the
mitochondrial intermembrane space of tissues rich in mitochondria like liver,
kidney, heart, and skeletal muscle. AK3 is located in the mitochondrial matrix,
with high expression levels in the liver, heart, and skeletal muscle. Tissue specific
adenylate kinase isoforms AK4 and AK5, with preferential localization in mito-
chondrial matrix and cytosol, respectively, have been cloned (Miyoshi et al. 2009 ;
Noma 2005 ; Panayiotou et al. 2010 ; Van Rompay et al. 1999 ; Yoneda et al. 1998 ).
AK4 contains an N-terminal mitochondrial import sequence and is expressed at low
levels in brain, kidney, liver, and heart tissues (Panayiotou et al. 2010 ). AK5 is
mostly cytosolic or both cytosolic and nuclear depending on the transcript variants.
With two separate active functional domains, AK5 is expressed almost exclusively
in brain, although there is evidence that it exists in other tissues too (Solaroli
et al. 2009 ; Van Rompay et al. 1999 ). AK4 protein levels are increased in cultured
cells exposed to hypoxia and in animal models of neurodegenerative diseases (Liu
et al. 2009 ). Although AK4 might be enzymatically less active, it retains nucleotide
binding capability, interacts with the mitochondrial ADP/ATP translocator, and
serves a stress responsive function, promoting cell survival and proliferation (Liu
et al. 2009 ). Both AK4 and AK3 are among hypoxia-inducible factor 1 (HIF-1)
regulated genes promoting cell survival (Hu et al. 2006 ; Semenza 2000 ). AK5 is
detected in human pancreatic beta-cells and implicated in the regulation of the
K-ATP channel (Stanojevic et al. 2008 ), while appearance of autoantibodies to
AK5 in refractory limbic encephalitis patients carrying poor prognosis (Tuzun
et al. 2007 ).
More recently,

the existence of an additional AK1 gene product, the

p53-inducible membrane-bound myristoylated AK1 , has been reported and

implicated in p53-dependent cell cycle arrest and nucleotide exchange in the
submembrane space (Collavin et al. 1999 ; Janssen et al. 2004 ; Ruan et al. 2002 ).
In this context, the gene encoding AK1 is downregulated during tumor develop-
ment, which could be associated with lower AK1

β

β levels and cell cycle

disturbances (Vasseur et al. 2005 ). AK1 also has been demonstrated to be

associated with the nuclear envelope (Janssen et al. 2004 ) and proteome studies
identify AK1

β

in epithelium microvilli (Bonilha et al. 2004 ), suggesting a role in
energy support of nuclear and epithelia transport processes.

β