Zinc adeninates

An J, Shade CM, Chengelis-Czegan DA et al (2011) Zinc-adeninate metal-organic framework for aqueous encapsulation and sensitization of near-inlrared and visible emitting lanthanide cations. J Am Chem Soc 133 1220-1223... 

Figure 9 Structure and size of the zinc-adeninate building unit (ZABU) (a) compared with the structure and size of the basic zinc-carboxylate building unit (b) (Reproduced with permission from Macmillan Publishers Ltd Nature Communications (Ref 10), copyright (2012).)...

One example for the bulky SBU strategy was reported by Rosi s and coworkers.They synthesized a mesoMOF, Bio-MOF-100, by replacing the small 6-connected [Zn40(C00)g] octahedral building blocks with bulky zinc-adeninate 6-connected octahedral SBUs. Bio-MOF-100 with the Ics nets exhibits a high surface area of 4300 m g , low crystal densities of 0.302 g cm and large pore volume of 4.3 cm (Figures 9 and 10). 

Figure 10 Structure and function of zinc-adeninate bio-MOFs. (a) The octahedral [Zn3(ad4)J SBU taken from the crystal structure of bio-MOF-1 (CCDC deposition NUDLAA). In bio-MOF-1, each octahedral unit is linked horizontally by tetrahedral ligands...

An J, Geib SJ, Rosi NL. Cation-triggered drug release from a porous zinc-adeninate metal-organic framework. J Am Chem Soc 2009 131 8376. 

Zinc-containing alcohol dehydrogenases take up two electrons and a proton from alcohols in the form of a hydride. The hydride acceptor is usually NAD(P) (the oxidized form of nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative, NADPH). Several liver alcohol dehydrogenases have been structurally characterized, and Pig. 17.8 shows the environment around the catalytic Zn center and the bound NADH cofactor. 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

So far 18 different members of HDACs have been discovered in humans and classified into four classes based on their homology to yeast histone deacetylases [33]. Class I includes four different subtypes (HDACl, 2, 3, 8), class II contains six subtypes tvhich are divided into two subclasses class Ila with subtypes HDAC4, 5, 7, 9 and class Ilb with HDAC6, 10. Class I and class II HDAC share significant structural homology, especially within the highly conserved catalytic domains. HDACs 6 and 10 are unique as they have two catalytic domains. HDACll is referred to as class IV. While the activity of class I, II and IV HDACs depends on a zinc based catalysis mechanism, the class III enzymes, also called sirtuins, require nicotinamide adenine dinucleotide as a cofactor for their catalysis. 

The class III deacetylases, named sirtuins, are structurally and functionally different from other HDACs. In contrast to the zinc-dependent deacetylation of classic HDACs, sirtuins depend on NAD" to carry out catalytic reactions. A variety of sirtuin crystal structures have been published over the past few years. The structures of human Sirt2 and SirtS as well as several bacterial Sir2 proteins could be derived, whereas no 3D structure is available for Sirtl and the other subtypes [69]. All solved sirtuin structures contain a conserved 270-amino-acid catalytic domain with variable N- and C-termini. The structure of the catalytic domain consists of a large classic Rossmann fold and a small zinc binding domain. The interface between the large and the small subdomain is commonly subdivided into A, B and C pockets. This division is based on the interaction of adenine (A), ribose (B) and nicotinamide (C) which are parts of the NAD" cofactor. (Figure 3.5) Whereas the interaction of adenine and... 

Although zinc itself is not redox-active, some class I enzymes containing zinc in their active sites are known. The most prominent are probably alcohol dehydrogenase and copper-zinc superoxide dismutase (Cu,Zn-SOD). AU have in common that the redox-active agent is another transition-metal ion (copper in Cu,Zn-SOD) or a cofactor such as nicotinamide adenine dinucleotide (NAD+/NADH). The Zn(II) ion affects the redox reaction only in an indirect manner, but is nevCTtheless essential and cannot be regarded simply as a structural factor. 

Alcohol dehydrogenases (ADH EC 1.1.1.1), for which several X-ray structures are available ", catalyze the biological oxidation of primary and secondary alcohols via the formal transfer of a hydride anion to the oxidized form of nicotinamide adenine dinucleotide (NAD ), coupled with the release of a proton. Liver alcohol dehydrogenase (LADH) consists of two similar subunits, each of which contains two zinc sites, but only one site within each subunit is catalytically active. The catalytic zinc is coordinated in a distorted tetrahedral manner to a histidine residue, two cysteine residues and a water molecule. The remaining zinc is coordinated tetrahedrally to four cysteine residues and plays only a structural role . 

A number of zinc and cadmium complexes of adenine (82),554,555 adenine N-oxide,556 guanine,557 inosine,558 cytidine559 and other nucleosides560 have been studied. The structure of (9-methyladenine)ZnCl2 is polymeric each zinc ion is tetrahedrally coordinated to two chlorine atoms (Zn—Cl = 2.22 A), and to N-l and N-7 of neighbouring adenine moieties (Zn— N = 2.05A).561 A structural study of the related cadmium complex, CdCl2(DMSO)L (L = 9-methyladenine), has shown the complex to form a one-dimensional polymer. 2... 

NADH Nicotineamide adenine dinucleotide reduced form. EDTA Ethylenediamine tetraacetic acid. RSH Mercaptoethanol. ZnTPP Zinc tetraphenylporphyrin. ZnTMPyP Zinc tetrakis(4-methylpyridyl)porphyrin. ZnTPPS Zinc tetraphenylporphyrin tetrasulfomate. 

The alcohol dehydrogenases are zinc metalloenzymes which can oxidize a wide variety of alcohols to their corresponding aldehydes or ketones using nicotinamide adenine dinucleotide (NAD+) as coenzyme. These reactions are readily reversible so that carbonyl compounds may be reduced by NADH. 

With the development of the cross coupling methodology, many 6-C-substituted purines have been prepared in the past decade. Thus, 6 halopurine derivatives react with arylmagnesium halides,25 alkyl(aryl)zinc or tin reagents,26 trialkylaluminum,27 or alkylcuprates28 to give the 6-alkylpurine derivatives. Also a reverse approach based on the reaction of purine-6-zinc iodide with aryl or vinyl halides has recently been described.29 For the synthesis of 6-arylpurines, an alternative approach makes use of radical photochemical reactions of adenine derivatives with aromatic compounds,30 but this method is very unselective and for substituted benzenes, mixtures of ortho-, meta-, and para substituted derivatives were obtained. 

Nucleobases and nucleosides are common motifs for hydrogen-bonded supramolecular arrays. Ng et al. first reported a series of phthalocyanine-nucleobase conjugates [64], The tetra-adenine phthalocyanine 64 was prepared by standard <9-alkylation of zinc(II) tetrahydroxyphthalocyanine with 9-(2-bromoethyl)adenine in the presence of K2CO3. The fluorescence of 64 is quenched substantially upon addition of thymine-substituted 9,10-anthraquinone 65, and the rate is much faster compared with that for the situation when the unsubstituted 9,10-anthraquinone is used as the quencher. These results suggest that 64 forms a supramolecular complex with 65 through the Watson-Crick base-pairing interactions. 

The sulfur can be reductively removed by one of the many methods utilized for sulfur heterocycles. For the fused pyrimidine (703) zinc in acetic acid can be used (64JOC2135). In the 7-formylamino analogue (704), however, Raney nickel in aqueous ethanol was the best reagent for the reductive cyclization to form adenines (705) (78JOC960). It has been pointed out that nucleophilic substitution at C-7 in the [l,2,5]thiadiazolo[3,4-d]pyrimidine system easily takes place. This makes the compounds (704) readily available as key substances in this convenient approach to the synthesis of 9-substituted adenine derivatives. 

Figure 21-2. Metabolism of homocysteine. BHMT, betaineihomocysteine methyl-transferase CBS, cystathionine P-synthase Cob, cobalamin CTH, cystathionine y-lyase DHF, dihydrofolate DMG, dimethylglycine FAD, flavin adenine dinucleotide MAT, methionine adenosyltransferase 5-MTHF, 5-methyltetrahydrofolate 5,10-MTHF, 5,10-methylenetetrahydrofolate MTHFR, methylenetetrahydrofolate reductase MS, methionine synthase MTRR, methionine synthase reductase MTs, methyl transferases PLE pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase SAM, 5-adenosylmethionine SHMT, serine hydroxymethyltransferase THF, tetrahydrofolate Zn, zinc.

The crystal structure of a zinc chloride adenine adduct namely (adenine)2 ZnCl4 H20 contains adenine cations which exist in the unusual N(7)// form (81AX(A)C63) analogous to the structure found in purine crystals (65AX573). 

A novel class of nucleic acid mimics has been described which possess two ethylenediamine moieties for intermolecular metal co-ordination (25). In the presence of Zn + ions and template DNA, the analogues (25) form relatively stable structures, stabilised by the co-ordination of adjacent chelating moieties with zinc ions. It was shown that with an oligothymidine template and the adenine derivative of (25) that a 2 1 complex was formed, which showed a biphasic melting transition. Short RNA duplexes (3-4 bp) are considerably stabilised if both termini of the duplexes are bridged by non-nucleotidic linkers. For example, the pairing of rGAA with rUUC in such a cyclic system exhibits a Tm of 36°C in IM salt solution. 

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