AGK 2

AGK 2 is a potent and selective inhibitor of sirtuin 2 with IC50 value of 3.5 μM [1].

Sirtuin 2 (SIRT2) is a NAD-dependent deacetylase and is involved in cell cycle regulation through α-tubulin deacetylation. SIRT2 plays an important role in neuroprotective effects and the pathogenesis and development of cancer [1] [2] [3].

AGK 2 is a potent and selective SIRT2 inhibitor. AGK 2 inhibited SIRT2 with IC50 value of 3.5 μM and slightly inhibited SIRT1 and 3 at concentrations over 40 μM. AGK 2 increased acetylation of tubulin heterodimers from bovine brain. In HeLa cells expressing SIRT2-myc, AGK2 effectively inhibited SIRT2-myc activity. AGK2 also dose-dependently increased acetylated tubulin. In H4 cells transfected with α-Syn, AGK2 dose-dependently reduced α-Syn-mediated toxicity. In primary midbrain cultures transduced with lentivirus encoding α-SynA53T, AGK2 rescued dorsomedial neurons in a dose-dependent way [1]. In primary rat astrocytes, AGK-2 (35 μM) significantly inhibited astrocyte viability and proliferation and also inhibited astrocyte activation induced by beta amyloid 1-42 (Aβ 1-42). Also, AGK2 significantly inhibited the increase of iNOS and COX-2 induced by Aβ 1-42 [2]. In glioblastoma multiforme cancer stem cells (GBM CSCs), AGK-2 exhibited good antiproliferative activity [3].

References:
[1].  Outeiro TF, Kontopoulos E, Altmann SM, et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science, 2007, 317(5837): 516-519.
[2].  Scuderi C, Stecca C, Bronzuoli MR, et al. Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer's disease. Front Pharmacol, 2014, 5: 89.
[3].  Rotili D, Tarantino D, Nebbioso A, et al. Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells. J Med Chem, 2012, 55(24): 10937-10947.

Cloning of the guanylate kinase homologues AGK-1 and AGK-2 from Arabidopsis thaliana and characterization of AGK-1.[Pubmed:10632732]

Eur J Biochem. 2000 Jan;267(2):606-15.

Guanylate kinase is an essential enzyme for nucleotide metabolism, phosphorylating GMP to GDP or dGMP to dGDP. The low molecular mass cytosolic forms of guanylate kinase are implicated primarily in the regulation of the supply of guanine nucleotides to cell signalling pathways. The high molecular mass and membrane-associated forms of guanylate kinase homologues, notably found in neuronal tissues, are assigned roles in cell junction organization and transmembrane regulation. Here, we describe the first plant guanylate kinase-encoding genes, AGK1 and AGK2, from Arabidopsis thaliana. The nucleotide sequences of their genomic and cDNA clones predict proteins that carry N-terminal and C-terminal extensions of the guanylate kinase-like domain. The amino acid sequences of this domain share 46-52% identity with guanylate kinases from yeast, Escherichia coli, human, mouse and Caenorhabditis elegans. Arabidopsis guanylate kinases (AGKs) exhibit a high degree of conservation of active site residues and sequence motifs in common with other nucleoside monophosphate kinases, which suggests overall structural similarity of the plant proteins. Although bacterially expressed AGK-1 is enzymatically much less active than yeast guanylate kinase, its kinase domain is shown to complement yeast GUK1 recessive lethal mutations. AGKs are expressed ubiquitously in plant tissues with highest transcriptional activity detected in roots. The identification of AGKs provides new perspectives for understanding the role of guanylate kinases in plant cell signalling pathways.

Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.[Pubmed:17588900]

Science. 2007 Jul 27;317(5837):516-9.

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.

AGK2 is a selective SIRT2 inhibitor with IC50 of 3.5 μM. AGK2 can also inhibit SIRT1 and SIRT3 with IC50 of 30 and 91 μM, respectively.

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