Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray crystal structure of the antiviral drug foscarnet complexed to human carbonic anhydrase I.
Foscarnet (phosphonoformate trisodium salt), an antiviral used for the treatment of HIV and herpes virus infections, also acts as an activator or inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Interaction of the drug with 11 CA isozymes has been investigated kinetically, and the X-ray structure of its adduct with isoform I (hCA I-foscarnet complex) has been resolved. The first CA inhibitor possessing a phosphonate zinc-binding group is thus evidenced, together with the factors governing recognition of such small molecules by a metalloenzyme active site. Foscarnet is also a clear-cut example of modulator of an enzyme activity which can act either as an activator or inhibitor of a CA isozyme.
Temperini
Claudia
C
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Florence), Italy.
Innocenti
Alessio
A
Guerri
Annalisa
A
Scozzafava
Andrea
A
Rusconi
Stefano
S
Supuran
Claudiu T
CT
D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000737:chemistry* / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D017245:Foscarnet / Q000737:chemistry*; D006801:Humans; D063065:Organophosphonates / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D063065:Organophosphonates; D017245:Foscarnet; D024401:Carbonic Anhydrase I; D015032:Zinc