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indicating developing energy deficits. However, minor decreases in ATP levels lead
to more pronounced relative increases in free ADP and even more in AMP due to
the adenylate kinase (AK) reaction (Fig. 11.13 ). Under these conditions, AK uses
two ADP to regenerate ATP and AMP, thus increasing AMP concentrations from
the sub-micromolar range under resting conditions to the lower micromolar range
(Frederich and Balschi 2002 ). To lesser extent, AMP levels also depend on
pyrophosphates (cleaving the
β
-phosphate bond of ATP) and the activity of AMP
degradation pathways [AMP-deaminase and 5 0 -nucleotidase, whose inhibition may
be useful to activate AMPK (Kulkarni et al. 2011 )]. As a consequence, a decrease in
ATP levels by only 10 % translates into a 10- to 100-fold increase in AMP, making
AMP an ideal second messenger of energy stress (Fig. 11.13 , upper left). Regula-
tion of AMPK activation by the balance between ATP, ADP, and AMP
concentrations resembles to what was put forward by Atkinson 40 years ago as
“energy charge” regulation (Xiao et al. 2011 ; Oakhill et al. 2011 ; Atkinson 1968 ;
Hardie and Hawley 2001 ).
The molecular basis of allosteric AMPK activation is not yet fully understood,
but certainly involves multiple interconnected mechanisms. The nucleotide ratios
are sensed at the
-subunit binding sites (sites 1, 3, and 4), which possess high
affinity for AMP and ADP, but less for ATP in its major, Mg 2+ -complexed form.
AMP or ADP binding to AMPK has several consequences: (1) it makes
γ
α
-Thr172 a
better substrate for phosphorylation, (2) it protects P-
-Thr172 from dephosphory-
lation, and (3), only in case of AMP, it exerts direct allosteric activation of AMPK
(Xiao et al. 2011 ; Oakhill et al. 2011 ; Davies et al. 1995 ; Suter et al. 2006 ). All these
effects require close communication between the AMP-binding
α
γ
- and the catalytic
α
-subunit. The three adenylate binding sites participate differentially in these
mechanisms. Diverging models have been proposed that involve different structural
elements of the
-subunit (Xiao et al. 2011 ; Chen et al. 2013a ). We and our
collaborators have proposed that all these mechanisms involve an AMP-
(or ADP)- induced conformational switch within the full-length AMPK complex
that is not seen in the X-ray structures of AMPK core complexes solved so far
(Chen et al. 2009 , 2012 ; Riek et al. 2008 ; Zhu et al. 2011 ).
α
11.5.4.3 Other Covalent and Non-Covalent Regulations
An increasing number of additional secondary protein modifications adds to the
complex scheme of AMPK activation. Myristoylation at Gly2 in the
-subunit
increases the sensitivity of AMPK for allosteric activation and promotes Thr172
phosphorylation (Oakhill et al. 2010 ). Acetylation of
β
-subunits is determined by
the reciprocal actions of the acetylase p300 and the histone deacetylase 1. AMPK
deacetylation promotes its activation via LKB1 interaction (Lin et al. 2012 ). LKB1
itself is also regulated by acetylation, since deacetylated LKB1 shifts from nucleus
to the cytosol, where it forms active complexes with STRAD (Lan et al. 2008 ).
Thus, acetylation is a potentially important factor for activating the LKB1-AMPK
pathway (Ruderman et al. 2010 ), but its role in the heart has not been examined so
α
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