bims-sikglu 2024-04-14 papers

Issue of 2024‒04‒14
two papers selected by
Dipsikha Biswas, Københavns Universitet and Maria Madrazo i Montoya, Københavns Universitet

Biochem J. 2024 Apr 09. pii: BCJ20240082. [Epub ahead of print]

AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.

Simon A Hawley, Fiona M Russell, D Grahame Hardie.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2β2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.

Keywords: ADP; AMP; AMPK; CBS repeats; LKB1; adenine nucleotides

DOI: https://doi.org/10.1042/BCJ20240082

Adv Pharm Bull. 2024 Mar;14(1): 120-131

AMPK Signaling Pathway as a Potential Therapeutic Target for Parkinson's Disease.

Seyed Zanyar Athari, Fereshteh Farajdokht, Rana Keyhanmanesh, Gisou Mohaddes.

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the loss of dopaminergic neurons. Genetic factors, inflammatory responses, oxidative stress, metabolic disorders, cytotoxic factors, and mitochondrial dysfunction are all involved in neuronal death in neurodegenerative diseases. The risk of PD can be higher in aging individuals due to decreased mitochondrial function, energy metabolism, and AMP-activated protein kinase (AMPK) function. The potential of AMPK to regulate neurodegenerative disorders lies in its ability to enhance antioxidant capacity, reduce oxidative stress, improve mitochondrial function, decrease mitophagy and macroautophagy, and inhibit inflammation. In addition, it has been shown that modulating the catalytic activity of AMPK can protect the nervous system. This article reviews the mechanisms by which AMPK activation can modulate PD.

Keywords: AMPK; Inflammation; Oxidative stress; Parkinson's disease; α-Synuclein

DOI: https://doi.org/10.34172/apb.2024.013