Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2022 Feb 8

PMID 35134268

Authors

Iredia D Iyamu

Jonah Z Vilseck

Ravi Yadav

Nicholas Noinaj

Rong Huang

Affiliations

Soon will be listed here.

Abstract

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate inhibitor II399, demonstrating a K of 5.9 nM in a biochemical assay and a cellular IC value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399's low nM binding affinity. Notably, II399 is 1 000-fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell-potent inhibitors for other SAM-dependent methyltransferases.

Citing Articles

Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide.

Zheng C, Li Y, Wu X, Gao L, Chen X Nutrients. 2024; 16(14).

PMID: 39064797 PMC: 11279976. DOI: 10.3390/nu16142354.

Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes.

Song Q, Wang J, Griffiths A, Lee S, Iyamu I, Huang R Am J Physiol Cell Physiol. 2023; 325(1):C29-C41.

PMID: 37212549 PMC: 10259858. DOI: 10.1152/ajpcell.00010.2023.

Nicotinamide -Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms.

Pozzi V, Campagna R, Sartini D, Emanuelli M Biomolecules. 2022; 12(9).

PMID: 36139012 PMC: 9496617. DOI: 10.3390/biom12091173.

Novel tricyclic small molecule inhibitors of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.

Ruf S, Rajagopal S, Kadnur S, Hallur M, Rani S, Kristam R Sci Rep. 2022; 12(1):15440.

PMID: 36104373 PMC: 9474883. DOI: 10.1038/s41598-022-19634-2.

References

Gao Y, van Haren M, Moret E, Rood J, Sartini D, Salvucci A . Bisubstrate Inhibitors of Nicotinamide -Methyltransferase (NNMT) with Enhanced Activity. J Med Chem. 2019; 62(14):6597-6614. PMC: 6713424. DOI: 10.1021/acs.jmedchem.9b00413. View

Kocinaj A, Chaudhury T, Uddin M, Junaid R, Ramsden D, Hondhamuni G . High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer's Disease. Mol Neurobiol. 2021; 58(4):1769-1781. PMC: 7932959. DOI: 10.1007/s12035-020-02259-9. View

Ding X, Vilseck J, Hayes R, Brooks 3rd C . Gibbs Sampler-Based λ-Dynamics and Rao-Blackwell Estimator for Alchemical Free Energy Calculation. J Chem Theory Comput. 2017; 13(6):2501-2510. PMC: 5828534. DOI: 10.1021/acs.jctc.7b00204. View

Scholfield M, Vander Zanden C, Carter M, Ho P . Halogen bonding (X-bonding): a biological perspective. Protein Sci. 2012; 22(2):139-52. PMC: 3588911. DOI: 10.1002/pro.2201. View

Mondal S, Gong X, Zhang X, Salinger A, Zheng L, Sen S . Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors. Angew Chem Int Ed Engl. 2019; 58(36):12476-12480. PMC: 6713606. DOI: 10.1002/anie.201906334. View

Jung J, Kim L, Wang X, Wu Q, Sanvoranart T, Hubert C . Nicotinamide metabolism regulates glioblastoma stem cell maintenance. JCI Insight. 2017; 2(10). PMC: 5436539. DOI: 10.1172/jci.insight.90019. View

Kraus D, Yang Q, Kong D, Banks A, Zhang L, Rodgers J . Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014; 508(7495):258-62. PMC: 4107212. DOI: 10.1038/nature13198. View

Paulini R, Trindler C, Lerner C, Brandli L, Schweizer W, Jakob-Roetne R . Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity. ChemMedChem. 2006; 1(3):340-57. DOI: 10.1002/cmdc.200500065. View

Vilseck J, Ding X, Hayes R, Brooks 3rd C . Generalizing the Discrete Gibbs Sampler-Based λ-Dynamics Approach for Multisite Sampling of Many Ligands. J Chem Theory Comput. 2021; 17(7):3895-3907. PMC: 8627277. DOI: 10.1021/acs.jctc.1c00176. View

10.

Chen D, Li L, Diaz K, Iyamu I, Yadav R, Noinaj N . Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide -Methyltransferase. J Med Chem. 2019; 62(23):10783-10797. PMC: 7296983. DOI: 10.1021/acs.jmedchem.9b01255. View

11.

Palanichamy K, Kanji S, Gordon N, Thirumoorthy K, Jacob J, Litzenberg K . NNMT Silencing Activates Tumor Suppressor PP2A, Inactivates Oncogenic STKs, and Inhibits Tumor Forming Ability. Clin Cancer Res. 2016; 23(9):2325-2334. PMC: 5413402. DOI: 10.1158/1078-0432.CCR-16-1323. View

12.

Howard E, Sanishvili R, Cachau R, Mitschler A, Chevrier B, Barth P . Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. Proteins. 2004; 55(4):792-804. DOI: 10.1002/prot.20015. View

13.

Peng Y, Sartini D, Pozzi V, Wilk D, Emanuelli M, Yee V . Structural basis of substrate recognition in human nicotinamide N-methyltransferase. Biochemistry. 2011; 50(36):7800-8. PMC: 3989893. DOI: 10.1021/bi2007614. View

14.

Iyamu I, Al-Hamashi A, Huang R . A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes. Biomolecules. 2021; 11(6). PMC: 8230315. DOI: 10.3390/biom11060854. View

15.

Chodera J, Mobley D, Shirts M, Dixon R, Branson K, Pande V . Alchemical free energy methods for drug discovery: progress and challenges. Curr Opin Struct Biol. 2011; 21(2):150-60. PMC: 3085996. DOI: 10.1016/j.sbi.2011.01.011. View

16.

van Haren M, Marechal N, Troffer-Charlier N, Cianciulli A, Sbardella G, Cavarelli J . Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1. Proc Natl Acad Sci U S A. 2017; 114(14):3625-3630. PMC: 5389282. DOI: 10.1073/pnas.1618401114. View

17.

Babault N, Allali-Hassani A, Li F, Fan J, Yue A, Ju K . Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem. 2018; 61(4):1541-1551. PMC: 5823789. DOI: 10.1021/acs.jmedchem.7b01422. View

18.

Mahmoodi N, Harijan R, Schramm V . Transition-State Analogues of Phenylethanolamine -Methyltransferase. J Am Chem Soc. 2020; 142(33):14222-14233. PMC: 7558223. DOI: 10.1021/jacs.0c05446. View

19.

Tang S, Yang T, Lin W, Chang W, Wang C, Lai M . Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells. Carcinogenesis. 2010; 32(2):138-45. DOI: 10.1093/carcin/bgq225. View

20.

Huang R, Martinez-Ferrando I, Cole P . Enhanced interrogation: emerging strategies for cell signaling inhibition. Nat Struct Mol Biol. 2010; 17(6):646-9. PMC: 3160762. DOI: 10.1038/nsmb0610-646. View