Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

Abstract

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylases, which regulate important biological processes ranging from apoptosis, age-associated pathophysiologies, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. Very recently, sirtuin 5 (SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase, demalonylase and deglutarylase activities, and it was also found to be associated with several human diseases such as cancer, Alzheimer's disease, and Parkinson's disease. In this review, we for the first time summarized the structure characteristics, known peptide and small-molecule inhibitors of SIRT5, extracted some clues from current available information and introduced some feasible, practical in silico methods, which might be useful in further efforts to develop new SIRT5 inhibitors.Sirtuin, SIRT5 inhibitor, crystal structure, small-molecule inhibitors, computer-aided drug design Citation:Yang, L., Ma, X., He, Y., Yuan, C., Chen, Q., Li, G., and Chen, X. (2017). Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci China Life Sci 60, 249-256.

Mitochondrial sirtuins in the rat adrenal gland: location within the glands of males and females, hormonal and developmental regulation of gene expressions

“…This is not a phenomenon specific for adrenal cortex parenchymal cells. A similar high Sirt5 gene reactivity to various factors is also observed in other cell types [11]. However, it should be stressed that the role of this sirtuin in the regulation of steroidogenesis is still to be clarified.…”

“…Be as it might, these findings are still to be explored. It is all the more interesting that the latest data associate Sirt5 gene expression disorders with such diseases as cancer, Alzheimer's disease, or Parkinson's disease [11].…”

“…The least known is the Sirt5 function. It has been suggested that this Sirt isoform modulates numerous acyl modifications and glutarylation in both mitochondrial and extra-mitochondrial compartments [10,11].…”

SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy

“…SIRT3, the major deacetylase of metabolic targets in mitochondria, promotes mitochondrial networking and function by activating the fusion factor OPA1 [ 37 ]. In the case of SIRT5, an enzyme with demalonylase, deglutarylase, and desuccinylase activities [ 38 , 39 ] that regulates ammonia detoxification, mitochondrial size was increased and mitophagy decreased upon SIRT5 overexpression [ 40 ]. Lastly, overexpression of SIRT4 was linked to the regulation of mitochondrial dynamics via inhibition of ERK-mediated phosphorylation of the pro-fission factor DRP1, therefore inhibiting its activity and hence mitochondrial fission [ 41 ].…”

SIRT5 as a biomarker for response to anthracycline-taxane-based neoadjuvant chemotherapy in triple-negative breast cancer

“…Therefore, in the present study, we extracted gene expression data on 64 TNBC patients (with pCR and non-pCR to NAC) from the GSE41998 dataset of Gene Expression Omnibus (GEO), and identified five core genes that were closely associated with the pCR of TNBC patients, namely NOL7, GFER, COMMD4, sirtuin 5 (SIRT5) and SRC, via a genetic algorithm-support vector machine (GA-SVM)-based method. SIRT5 is a member of the sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD + )-dependent deacetylases that participate in various biological processes, including the regulation of metabolism, cell division, aging and oxidative stress (7). In recent years, studies have evaluated the potential roles of SIRTs in different cancer types (8)(9)(10).…”