AChE inhibitors and substrates

As was mentioned above, AChE hydrolysizes the neurotransmitter , producing group. directly binds catalytic (via its nucleophilic Oγ atom). , O-(1,2,2-trimethylpropyl) methylphosphonofluoridate (fluorine atom is colored violet and phosphorus atom is colored darkmagenta), is one of the most toxic OPs. Soman inhibits AChE by to catalytic Ser200, . This process implicates nucleophilic attack of the Ser200 nucleophilic Oγ atom on the phosphorus atom of soman, with concomitant departure of its fluoride atom. After that AChE catalyzes the of the soman or other OP. This causes irreversible inhibition of AChE, "aged" soman/AChE conjugate can not be reactivated. However, before “aging”, at the step of , AChE can be by nucleophiles, such as pralidoxime (2-PAM), resulting in of the phosphonyl adduct from Ser200 Oγ. At the (2wfz) the catalytic His440 forms hydrogen bonds with Ser200 Oγ and Glu327 Oε1 via its Nε2 and Nδ1 nitrogens, respectively. The O2 atom of soman is within hydrogen bonding distance of His440 Nε2. Soman O1 mimicks carbonyl oxygen of ACh. A water molecule 1001 interacting with soman O2 is represented as a red ball. The active site residues of the nonaged soman/TcAChE are colored yellow. The O2 atom of the (2wg0) forms a salt bridge with His440 Nε2. The active site residues of the aged soman/TcAChE are colored pink. of the structures of the nonaged (2wfz) and aged (2wg0) conjugates reveals a small, but important, change within the active site - the imidazole ring of His440 is tilted back to a native-like conformation after dealkylation. The water molecule 1001, which interacts with soman O2 in the nonaged crystal structure, is not within hydrogen bonding distance of O2 in the aged crystal structure. 2-PAM binds poorly to the nonaged phosphonylated enzyme (its electron density was not found) and binds in an after soman aging to TcAChE (2wg1).

To understand the basis for irreversible inhibition, the obtained by reaction of TcAChE with soman was solved by X-ray crystallography to 2.2Å resolution (1som). The highest positive difference density peak corresponded to the OP phosphorus and was located within covalent bonding distance of the active-site serine (S200). The are within hydrogen-bonding distance of four potential donors from catalytic subsites of the enzyme, suggesting that electrostatic forces significantly stabilize the aged enzyme. The methyl group of soman occupies the , bounded by Trp233, Phe288, and Phe290.

Sarin, O-isopropylmethylphosponofluoridate, is an other toxic OP compound. It is also inhibits AChE by covalent binding to the catalytic Ser200. The active sites of aged (1cfj) and aged soman-TcAChE (1som and 2wg0) are almost identical and provided structural models for the negatively charged, tetrahedral intermediate that occurs during deacylation with the ACh. There are four hydrogen bond donors (red dotted lines) to the anionic phosphonyl oxygen atoms: the backbone amide nitrogen atoms of Ala201, Gly118, and Gly119, as well as His440 Nε2. The sarin methyl carbon (colored cyan) is within non-bonded contact distances (black dotted lines) of Phe288 and Phe290 in the acyl binding pocket.

, diisopropylphosphorofluoridate, is an other toxic OP nerve agent. It is also inhibits AChE by covalent binding to the catalytic Ser200. As in the case with soman (1som) and sarin (1cfj), there are four hydrogen bond donors (dotted lines) to the anionic phosphonyl oxygen atoms: the backbone amide nitrogen atoms of Ala201, Gly118, and Gly119, as well as His440 Nε2 at the of aged DFP-TcAChE (2dfp). Phosphorylation with DFP caused an unexpected distortion in the main chain of a loop that includes residues F288 and F290 of the TcAChE acyl binding pocket. F288 and F290 move significantly in the DFP-TcAChE structure (lime), in comparison to their positions in the native enzyme (2ace). This is the first major conformational change reported in the active site of any AChE−ligand complex, and it offers a structural explanation for the substrate selectivity of AChE.

From Proteopedia

Contents

AChE substrate

AChE monovalent inhibitors

Organophosphorus acid anhydride nerve agents

Treatment of Alzheimer's disease

AChE bivalent inhibitors

Selected 3D Structures of AChE

Additional Resources

References

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