Complexes of Bacterial Nicotinate Mononucleotide Adenylyltransferase with Inhibitors: Implication for Structure-based Drug Design and Improvement

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Jun 29

PMID 20578699

Citations 15

Authors

Nian Huang

Rohit Kolhatkar

Yvonne Eyobo

Leonardo Sorci

Irina Rodionova

Andrei L Osterman

Alexander D MacKerell

Hong Zhang

Affiliations

Soon will be listed here.

Abstract

Bacterial nicotinate mononucleotide adenylyltransferase encoded by the essential gene nadD plays a central role in the synthesis of the redox cofactor NAD(+). The NadD enzyme is conserved in the majority of bacterial species and has been recognized as a novel target for developing new and potentially broad-spectrum antibacterial therapeutics. Here we report the crystal structures of Bacillus anthracis NadD in complex with three NadD inhibitors, including two analogues synthesized in the present study. These structures revealed a common binding site shared by different classes of NadD inhibitors and explored the chemical environment surrounding this site. The structural data obtained here also showed that the subtle changes in ligand structure can lead to significant changes in the binding mode, information that will be useful for future structure-based optimization and design of high affinity inhibitors.

Citing Articles

Synthesis, Biological, and Computational Evaluations of Conformationally Restricted NAD-Mimics as Discriminant Inhibitors of Human NMN-Adenylyltransferase Isozymes.

Matteucci F, Ferrati M, Spinozzi E, Piergentili A, Del Bello F, Giorgioni G Pharmaceuticals (Basel). 2024; 17(6).

PMID: 38931406 PMC: 11207052. DOI: 10.3390/ph17060739.

Inhibitors of NAD Production in Cancer Treatment: State of the Art and Perspectives.

Ghanem M, Caffa I, Monacelli F, Nencioni A Int J Mol Sci. 2024; 25(4).

PMID: 38396769 PMC: 10889166. DOI: 10.3390/ijms25042092.

First series of -alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation.

Pypec M, Jouffret L, Taillefumier C, Roy O Beilstein J Org Chem. 2022; 18:845-854.

PMID: 35923157 PMC: 9296984. DOI: 10.3762/bjoc.18.85.

In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c).

Cloete R, Shahbaaz M, Grobbelaar M, Sampson S, Christoffels A PLoS One. 2021; 16(11):e0259348.

PMID: 34727137 PMC: 8562812. DOI: 10.1371/journal.pone.0259348.

The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors.

Rohde K, Sorci L Front Microbiol. 2021; 11:634640.

PMID: 33584600 PMC: 7873932. DOI: 10.3389/fmicb.2020.634640.

References

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

Osterman A, Gerdes S . Comparative approach to analysis of gene essentiality. Methods Mol Biol. 2008; 416:459-66. DOI: 10.1007/978-1-59745-321-9_31. View

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

Begley T, Kinsland C, Mehl R, Osterman A, Dorrestein P . The biosynthesis of nicotinamide adenine dinucleotides in bacteria. Vitam Horm. 2001; 61:103-19. DOI: 10.1016/s0083-6729(01)61003-3. View

Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S . Structure and function of nicotinamide mononucleotide adenylyltransferase. Curr Med Chem. 2004; 11(7):873-85. DOI: 10.2174/0929867043455666. View

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

Osterman A, Begley T . A subsystems-based approach to the identification of drug targets in bacterial pathogens. Prog Drug Res. 2007; 64:131, 133-70. DOI: 10.1007/978-3-7643-7567-6_6. View

Han S, Forman M, Loulakis P, Rosner M, Xie Z, Wang H . Crystal structure of nicotinic acid mononucleotide adenylyltransferase from Staphyloccocus aureus: structural basis for NaAD interaction in functional dimer. J Mol Biol. 2006; 360(4):814-25. DOI: 10.1016/j.jmb.2006.05.055. View

Zhang H, Zhou T, Kurnasov O, Cheek S, Grishin N, Osterman A . Crystal structures of E. coli nicotinate mononucleotide adenylyltransferase and its complex with deamido-NAD. Structure. 2002; 10(1):69-79. DOI: 10.1016/s0969-2126(01)00693-1. View

10.

McDevitt D, Rosenberg M . Exploiting genomics to discover new antibiotics. Trends Microbiol. 2001; 9(12):611-7. DOI: 10.1016/s0966-842x(01)02235-1. View

11.

Sorci L, Pan Y, Eyobo Y, Rodionova I, Huang N, Kurnasov O . Targeting NAD biosynthesis in bacterial pathogens: Structure-based development of inhibitors of nicotinate mononucleotide adenylyltransferase NadD. Chem Biol. 2009; 16(8):849-61. PMC: 2770502. DOI: 10.1016/j.chembiol.2009.07.006. View

12.

Wright G, Sutherland A . New strategies for combating multidrug-resistant bacteria. Trends Mol Med. 2007; 13(6):260-7. DOI: 10.1016/j.molmed.2007.04.004. View

13.

Adams P, Gopal K, Grosse-Kunstleve R, Hung L, Ioerger T, McCoy A . Recent developments in the PHENIX software for automated crystallographic structure determination. J Synchrotron Radiat. 2003; 11(Pt 1):53-5. DOI: 10.1107/s0909049503024130. View

14.

Olland A, Underwood K, Czerwinski R, Lo M, Aulabaugh A, Bard J . Identification, characterization, and crystal structure of Bacillus subtilis nicotinic acid mononucleotide adenylyltransferase. J Biol Chem. 2001; 277(5):3698-707. DOI: 10.1074/jbc.M109670200. View

15.

Cogan E, Birrell G, Griffith O . A robotics-based automated assay for inorganic and organic phosphates. Anal Biochem. 1999; 271(1):29-35. DOI: 10.1006/abio.1999.4100. View

16.

Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P . Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis. Biochemistry. 2007; 46(16):4912-22. DOI: 10.1021/bi6023379. View

17.

Tong L, Lee S, Denu J . Hydrolase regulates NAD+ metabolites and modulates cellular redox. J Biol Chem. 2009; 284(17):11256-66. PMC: 2670130. DOI: 10.1074/jbc.M809790200. View

18.

Dorman S, Chaisson R . From magic bullets back to the magic mountain: the rise of extensively drug-resistant tuberculosis. Nat Med. 2007; 13(3):295-8. DOI: 10.1038/nm0307-295. View

19.

Zhou T, Kurnasov O, Tomchick D, Binns D, Grishin N, Marquez V . Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin. J Biol Chem. 2002; 277(15):13148-54. DOI: 10.1074/jbc.M111469200. View

20.

Gerdes S, Edwards R, Kubal M, Fonstein M, Stevens R, Osterman A . Essential genes on metabolic maps. Curr Opin Biotechnol. 2006; 17(5):448-56. DOI: 10.1016/j.copbio.2006.08.006. View