Identification of a cellularly active SIRT6 allosteric activator

Huang, Zhimin; Zhao, Junxing; Deng, Wei; Chen, Yuanchang; Shang, Jialin; Song, Kun; Zhang, Lenan; Wang, C.; Lu, Shaoyong; Yang, Xiuyan; He, Bin; Min, Jinrong; Hu, Hao; Tan, Mengyao; Xu, Jianrong; Zhang, Q.; Zhong, Jie; Sun, Xian-He; Mao, Zhiyong; Lin, Hou-Wen; Xiao, Mingzhe; Chin, Y. Eugene; Jiang, Hualiang; Xu, Ying; Chen, G.; Zhang, Jun

doi:10.1038/s41589-018-0150-0

Cited by 198 publications

(200 citation statements)

References 52 publications

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“…Therefore, we cannot rule out the possibility that the ornithine cyclodeaminase activity of AgrE requires another unknown factor(s). For example, SIRT6, a deacetylase with a Rossmann fold, contains an independent site for an allosteric activator (20).…”

Section: Resultsmentioning

confidence: 99%

Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena

Lee

Rhee

2020

Journal of Biological Chemistry

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In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.

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Section: Resultsmentioning

confidence: 99%

Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena

Lee

Rhee

2020

Journal of Biological Chemistry

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“…However, the Δ G pred value is comparable to its analogue Amox (Kong et al, ). The relative rigid molecule structures with fewer flexible bonds in N ‐Des and Amox introduce less entropy loss upon the binding, and the omission of entropy term may lead to the underestimation of binding free energy for this kind of molecules (Chen et al, ; Hou, Wang, Li, & Wang, ; Hou, Wang, Li, & Wang, ; Huang et al, ; Jiang et al, ; Lu, Shen, & Zhang, ; Sun et al, ; Sun, Li, Shen, et al, ; Sun, Li, Tian, Xu, & Hou, ; Wang et al, ; Xu, Sun, Li, Wang, & Hou, ). The non‐polar energy contributions (Δ E vdw + Δ G SA ) are the primary favorable terms in the binding free energy and determine the binding affinities of the studied compounds (Table ).…”

Section: Resultsmentioning

confidence: 99%

Identify old drugs as selective bacterial β‐GUS inhibitors by structural‐based virtual screening and bio‐evaluations

Zhou

Piao

et al. 2020

Chem Biol Drug Des

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Irinotecan (CPT‐11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose‐dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. The bacterial β‐glucuronidase (β‐GUS) plays pivotal role in CPT‐11‐induced diarrhea (CID) via activating the non‐toxic SN‐38G to toxic SN‐38 inside intestine. By using structural‐based virtual screening, three old drugs (N‐Desmethylclozapine, Aspartame, and Gemifloxacin) were firstly identified as selective bacterial β‐GUS inhibitors. The IC50 values of the compounds in the enzyme‐based and cell‐based assays range from 0.0389 to 3.6040 and 0.0105 to 5.3730 μM, respectively. The compounds also showed good selectivity against mammalian β‐GUS and no significant cytotoxicity in bacteria. Molecular docking and molecular dynamics simulations were performed to further investigate the binding modes of compounds with bacterial β‐GUS. Binding free energy decomposition revealed that the compounds formed strong interactions with E413 in catalytic trail from primary monomer and F365′ on the bacterial loop from the other monomer of bacterial β‐GUS, explaining the selectivity against mammalian β‐GUS. The old drugs identified here may be used as bacterial β‐GUS inhibitors for CID or other bacterial β‐GUS‐related disorders.

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“…The dinucleotide such as FAD, NAD and NADP can bind in the domain [26]. There is a long hydrophobic-channel pocket that binds the small molecules [27].Probing potential inhibitors has become essential for the development of cancer drug design [4,28,29]. Several potential inhibitors of SIRT6 have been reported, such as Compound 9 [3,30], trichostatin A [23] and inhibitors with a salicylate-linked structure [31].…”

mentioning

confidence: 99%

“…The dinucleotide such as FAD, NAD and NADP can bind in the domain [26]. There is a long hydrophobic-channel pocket that binds the small molecules [27].…”

mentioning

confidence: 99%

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Zhao

Zhu

Wang

et al. 2020

IJMS

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Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues-Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6.Our study provides a new potential way to explore potential inhibitors from TCMS.Int. J. Mol. Sci. 2020, 21, 2601 2 of 15 cancers and rectal adenocarcinoma, according to the Cancer Genome Atlas database [17]. Crystal structure of SIRT6 (PDB code 3K35) [23,24] includes the hydrophobic channel, the Rossman fold and the small domain shown in Figure S1A [25]. The Rossman fold is one of the most common and widely distributed super-secondary structures. The dinucleotide such as FAD, NAD and NADP can bind in the domain [26]. There is a long hydrophobic-channel pocket that binds the small molecules [27].Probing potential inhibitors has become essential for the development of cancer drug design [4,28,29]. Several potential inhibitors of SIRT6 have been reported, such as Compound 9 [3,30], trichostatin A [23] and inhibitors with a salicylate-linked structure [31]. Parenti et al. synthesized three (SYN17739303, BAS13555470 or Compound 9 and BAS00417531) potential inhibitors for SIRT6 [30]. Interestingly we found that the three inhibitors have similar chemical structure. The structures of these inhibitors can give insight into the direction of the design of improved inhibitors. However, the mechanism of interactions between the inhibitors and SIRT6 is still elusive. The relationship between the interactions and the bioactivity of SIRT6 is also not clear.Small molecules from herbs have many advantages as inhibitors. For example, herbal medicine has low toxicity and can be easily absorbed and easily expelled from the body. In this investigation, we therefore sought to probe structure-based inhibitors similar to Compound 9 [30] from Traditional Chinese Medicines (TCMS). Scutellarin is one compound of Scutellaria baicalensis Georgi, named Huang Qin in TCMS. It has been reported that ...

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Identification of a cellularly active SIRT6 allosteric activator

Cited by 198 publications

References 52 publications

Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena

Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena

Identify old drugs as selective bacterial β‐GUS inhibitors by structural‐based virtual screening and bio‐evaluations

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

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