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Suramin mediated SIRT5 oligomerization (582.6)
Author(s) -
Yu Junru,
Leedahl Travis,
Singh Raushan,
Mueller Dustin,
Nyren Erin,
Mallik Sanku,
Srivastava D.K.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.582.6
Subject(s) - suramin , nad+ kinase , sirtuin , biochemistry , chemistry , enzyme , nicotinamide adenine dinucleotide , receptor
Silent information regulator2 (sir2) proteins, or sirtuins, are nicotinamide adenine dinucleotide dependent lysine deacetylase. There are 7 human sirtuins, which have linked to a broad range of biological functions including aging, metabolism, cell cycle and apoptosis, and are considered as therapeutic targets. SIRT5 is the only enzyme that also possesses NAD+ dependent desuccinylase activity, which is important for modulating the urea cycle. Crystallization data shows that the binding of a sirtuin inhibitor, suramin, with SIRT5 leads to protein dimerization. Here we describe the detailed binding and inhibition mechanism of suramin to SIRT5. We also did comparative study with half suramin, which binds to SIRT5 with lower affinity. The data suggest that suramin bridging leads to dimerization of SIRT5 and improves the binding affinity. SIRT5 oligomerization state varies accordingly to the change of suramin/SIRT5 ratio. Our kinetic data also shows that suramin competes with both the succinylated lysine and NAD+, which explains the discrepancy between the binding affinity (2.5µM) and inhibition constant (40µM). The overall study may provide insight for the rational design of more potent inhibitors against sirtuins.