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 pKa 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.

High-Resolution Crystal Structure of the Subclass B3 Metallo-β-Lactamase BJP-1: Rational Basis for Substrate Specificity and Interaction with Sulfonamides

“…3b. The ligand has been modeled with the amide nitrogen as the bridg- (Table 2) indicate that the species bound is the anionic nitrogen of the sulfonamide, deprotonated by binding to the dinuclear zinc center (3,28), while the two sulfone oxygens behave as weaker zinc ligands. The binding of NBSA to BJP-1 is, to our knowledge, the first example of a sulfonamide bound to a dinuclear metal center in proteins.…”

A macrocyclic zinc(II) fluorophore as a detector of apoptosis

“…For instance, removal of Zn 2ϩ enhances apoptosis, whereas supplementation of Zn 2ϩ , whose mechanism is not yet understood, suppresses it (13). Furthermore, intracellular labile zinc(II) flux was observed during apoptosis by using a fluorescent Zn 2ϩ probe, Zinquin 1 (for structures of Zn A few years ago, while pursuing a model study of carbonic anhydrase, we synthesized a highly efficient macrocyclic Zn 2ϩ -selective fluorescent probe 4 (L 3 ) (18)(19)(20)(21)(22)(23)(24)(25). The structure was originally designed as a biomimetic model of the catalytic Zn 2ϩ center of carbonic anhydrase that strongly and selectively binds to dansylamide.…”

Carboxy Ester Hydrolysis Promoted by a Dicopper(II) Macrocyclic Polyamine Complex with Hydroxypropyl Pendant Groups

“…The initial rate determination was carried out according to the typical procedure previously reported by Kimura and ourselves. [4,5,9,10,18] NA and Cu II complex were mixed in the buffered solution, the UV absorption increase at 400 nm was recorded immediately and monitored generally until 2% formation of 4- All the experiments were conducted at least twice, and the tabulated data represent the average of these experiments.…”