Huperzine A Complexed with Acetylcholinesterase

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3D Structure of Huperzine A Complexed with Acetylcholinesterase (1vot) (see also AChE inhibitors and substrates (Part II))

Background

Huperzine A (HupA), discovered by Chinese scientists from 1980s, has been proved to be a powerful, highly specific, and reversible inhibitor of acetylcholinesterase (AChE). It is a novel alkaloid originally isolated from the Traditional Chinese medicine [1] Qian Ceng Ta which is produced from the whole plant of the club moss Huperzia serrata.

Qian Ceng Ta has been used for over 1000 years in China for treatment of contusions, strains, swellings, schizophrenia and myasthenia gravis. Shuangyiping[2], a tablet form of HupA produced from the extracts of Huperzia serrata, was developed in 1996 as a new drug for symptomatic treatment of Alzheimer’s disease in China. Compared with the other three FDA-approved drugs for the treatment of Alzheimer’s disease, Donepezil (Aricept, 1eve), Rivastigmine (Exelon, 1gqr), Galanthamine (Reminyl, 1dx6), HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action.

The structure of HupA shows some similarity to other known AChE inhibitors and substrates. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties.

Structure

The crystal structure of the complex of Torpedo californica AChE (TcAChE) with HupA at 2.5 Å resolution (pdb code 1vot) was determined in 1997 and it shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. The active site of TcAChE was found to be buried at the bottom of a deep and narrow gorge, lined by 14 aromatic residues (colored darkmagenta). The TcAChE natural substrate acetylcholine (ACh) directly binds Ser200 within the catalytic triad (Ser200, His440, and Glu327). The residues Trp84 and Phe330 are also important in the ligand recognition. HupA also binds to TcAChE at this active site, but its observed orientation is almost orthogonal in comparison to ACh. The principal interactions of HupA with TcAChE are including: a direct hydrogen bond with Tyr130 and HBs with Glu199 and Gly117 (colored orange) through a water molecule as a linker at the bottom of the gorge; cation-π interactions between the amino group of HupA and Trp84 and Phe330 (colored lime) with the distance between the nitrogen and the centroid of the aromatic rings of 4.8 and 4.7 Å, respectively; at the top of the gorge, hydrogen bonds (HBs) through two water molecules as linkers formed between the amino group of HupA and Tyr70, Asp72, Ser81, Asn85 and Tyr121 (colored magenta). An unusually short (~3.0 Å) C-H→O HB has been seen between the ethylidene methyl group of HupA and the main chain oxygen of His440 (colored crimson).

Additional Resources

For additional information, see: Alzheimer's Disease

Huperzine A complexed with AChE (PDP code 1vot)

Drag the structure with the mouse to rotate

Reference

Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A., Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL, Nat. Struct. Biol. 1997 Jan;4(1):57-63. PMID:8989325

Huperzine A from Huperzia species-An ethnopharmacolgical review., Ma X, Tan C, Zhu D, Gang D, Xiao P, J. Ethnopharmacol. 2007 Aug;113(1):15-34. PMID:17644292

Created with the participation of Yechun Xu, Joel L. Sussman, David Canner, Jaime Prilusky, Eran Hodis.

Proteopedia Page Contributors and Editors (what is this?)

Joel L. Sussman, Alexander Berchansky, Michal Harel, Jaime Prilusky

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