Why zinc in zinc enzymes? From biological roles to DNA base-selective recognition

Abstract

Intrinsic chemical properties of the zinc(II) ion in zinc enzymes have been investigated by the model of 1 :1 Zn²⁺-macrocyclic polyamine complexes, including Zn²⁺-1,5,9-triazacyclododecane ([12]aneN₃) and 1,4,7,10-tetraazacyclododecane (cyclen). The physiologically most suitable pK a values for the Zn²⁺-bound H₂O in enzymes were illustrated by the first model Zn²⁺-[12]aneN₃ complex, which mimics the essential kinetic and thermodynamic roles of Zn²⁺ in carbonic anhydrase. The activation of proximate serine residues (in alkaline phosphatase) and activation of alcohols for hydride transfer to NAD⁺ (in alcohol dehydrogenase) were also mimicked by Zn²⁺-[12]aneN₃ complexes. The functions of two zincs in dinuclear metallophosphatases were explained by a new dinuclear Zn²⁺-cryptate. For an aldolase type II model, a Zn²⁺-cyclen derivative showed facile enolate formation from a proximate carbonyl pendant under physiological conditions. The strong anion affinities, which Zn²⁺ intrinsically possesses, were exploited into novel selective nucleobase thymine (or uracil) recognition of Zn²⁺-cyclen complexes by the strong Zn²⁺-imido anion bond formation. The Zn²⁺-aromatic-pendant cyclen complexes selectively bind to T (or U) in single- and double-stranded DNA (or RNA). Thus, Zn²⁺ complexes act like molecular zippers to break A-T pairs in DNA, which was proven by various physicochemical measurements and DNA footprinting assays. These Zn²⁺ complexes showed some relevant biochemical and biological properties such as inhibition of transcriptional factor, TATA binding protein, or strong antimicrobial activities to Gram-positive bacterial strains.