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SCIENCE CHINA Life Sciences, Volume 60, Issue 3: 249-256(2017) https://doi.org/10.1007/s11427-016-0060-7

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

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  • ReceivedMar 21, 2016
  • AcceptedMay 23, 2016
  • PublishedNov 17, 2016

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.


Funded by

Chun hui of Ministry of Education Project(Z2015120)

National Natural Science Foundation of China(81502989)

China Postdoctoral Science Foundation Funded Project(2015M570789)


Acknowledgment

This work was supported by the Chun hui of Ministry of Education Project (Z2015120), the National Natural Science Foundation of China (81502989), and the China Postdoctoral Science Foundation Funded Project (2015M570789).


Open access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


Interest statement

The author(s) declare that they have no conflict of interest.


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  • Figure 1

    Phylogenetic tree of human HDAC family based on the similarity of their amino acid sequences. The HDAC family consists of four classes (Class I, II, III, and IV, shown in different colors). Class I, II, and IV HDACs are zinc2+-dependent deacetylases, while class III HDACs are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, called sirtuins.

  • Figure 2

    The overall structure of SIRT5.

  • Figure 3

    Bioinformatics analyses revealed that SIRT5 has a similar overall domain organization and fold to SIRT1, SIRT2, and SIRT3, but different to SIRT6 especially in zinc-binding domain and catalytic site. A, Comparative analysis of SIRT5 with SIRT1, SIRT2, and SIRT3. The catalytic sites of these sirtuins are highlighted in yellow. B, Comparing SIRT5 with SIRT6. SIRT5 is shown in yellow, and SIRT6 is highlighted in blue.

  • Figure 4

    An example of the succinyl-K9 peptide-NAD+ ternary crystal structure (PDB code: 3RIY).

  • Figure 5

    The known peptide inhibitors of SIRT5.

  • Figure 6

    The known small-molecule inhibitors of SIRT5.

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