Kegg Pathway: Cyanoamino acid metabolism

J Am Chem Soc. 2005 May 25; 127(20): 7346-58
Glaser R, Wu H, Lewis M

Effects are discussed of the anisotropic DNA environment on nitrosative guanine deamination based on results of an ab initio study of the aggregate 3 formed by guaninediazonium ion 1 and cytosine 2. Within 3, the protonation of 2 by 1 is fast and exothermic and forms 6, an aggregate between betaine 4 (2-diazonium-9H-purin-6-olate) and cytosinium ion 5. Electronic structure analysis of 4 shows that this betaine is not mesoionic; only the negative charge is delocalized in the pi-system while the positive charge resides in the sigma-system. Potential energy surface exploration shows that both dediazoniation and ring-opening of betaine 4 in aggregate 6 are fast and exothermic and lead irreversibly to E-11, the aggregate between (E)-5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole E-10 and 5. The computed pair binding energies for 3, 6, and E-11 greatly exceed the GC pair binding energy. While 1 can be a highly reactive intermediate in reactions of the "free nucleobase" (or its nucleoside and nucleotide), the cyanoimine 10 emerges as the key intermediate in nitrosative guanine deamination in ds-DNA and ds-oligonucleotides. In essence, the complementary nucleobase cytosine provides base catalysis and switches the sequence of deprotonation and dediazoniation. It is argued that this environment-induced switch causes entirely different reaction paths to products as compared to the respective "free nucleobase" chemistry, and the complete consistency is demonstrated of this mechanistic model with all known experimental results. Products might form directly from 10 by addition and ring closure, or their formation might involve water catalysis via 5-Cyanoamino-4-imidazolecarboxylic acid 12 and/or 5-carbodiimidyl-4-imidazolecarboxylic acid 13. The pyrimidine ring-opened intermediates 10, 12, and 13 can account for the formations of xanthosine, the pH dependency and the environment dependency of oxanosine formation, the formation of the classical cross-link dG(N(2)())-to-dG(C2), including the known sequence specificity of its formation, and the formation of the structure-isomeric cross-link dG(N1)-to-dG(C2).

J Am Chem Soc. 2004 Aug 18; 126(32): 9960-9
Rayat S, Majumdar P, Tipton P, Glaser R

The nitrosative deaminations (37 degrees C, NaNO2, NaAc buffer, pH 3.7) of guanosine 1r in (18O)water (97.6%) and of [6-18O]-1r in normal water were studied. [6-(18)O]-1r was prepared from 2-amino-6-chloropurine riboside using adenosine deaminase. The reaction products xanthosine 3r and oxanosine 4r were separated by HPLC and characterized by LC/MS analysis and 13C NMR spectroscopy. The 18O-isotopic shifts on the 13C NMR signals were measured and allowed the identification of all isotopomers formed. The results show that oxanosine is formed via 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole, 5, and its 1,4-addition product 5-Cyanoamino-4-imidazolecarboxylic acid, 6. This hydration of 5 to 6 leads to aromatization and greatly dominates over water addition to the cyanoimino group of 5 to form 5-guanidinyliden-4-oxomethylene-4,5-dihydroimidazole, 7. 5-Guanidinyl-4-imidazolecarboxylic acid, 8, the product of water addition to 6, is not involved.

Eur J Pharmacol. 1998 Feb 26; 344(1): 45-8
Muck S, Weber AA, Schrör K

The present study describes the platelet-inhibitory effects of terbogrel (5-hexenoic acid, 6-[3-[[(Cyanoamino)[(1,1-dimethylethyl)amino]methylene]amino]pheny l]-6-(3-pyridinyl)-, (epsilon)-), a novel combined thromboxane A2 synthase inhibitor and thromboxane A2 receptor antagonist. Terbogrel concentration-dependently inhibited collagen (0.6 microg/ml)- and U46619 (11alpha,9alpha-epoxymethano-15(S)-hydroxy-prosta-5Z,+ ++13E-dienoic acid) (1 microM)-induced aggregation and thromboxane synthesis of washed human platelets. In this system, terbogrel exhibited an equipotent (IC50 of about 10 nM) activity as thromboxane A2 synthase inhibitor and thromboxane A2 receptor antagonist. In addition, the compound favoured prostacyclin synthesis in cultured vascular smooth muscle cells by increasing the transfer of platelet-derived prostaglandin endoperoxides. Terbogrel appears to be a compound with an equipotent molar potency as thromboxane A2 synthase inhibitor and receptor antagonist.

Hoppe Seylers Z Physiol Chem. 1984 Feb; 365(2): 137-42
Fridrich E, Müller O

(2-Amino-5, 6-dimethylbenzimidazolyl)-cobamide (III) is transformed to (2-hydroxy-5, 6-dimethylbenzimidazolyl) cobamide (IV) by nitrous acid. Exchange of the NH2-group by hydrogen with nitrous acid/hypophosphorous acid yields vitamin B12 (I). This reaction completes a cycle vitamin B12 (I)----[carboxy(2-Cyanoamino-4,5-dimethylphenyl)amino]cobamide+ ++ (II)----(2-amino-5,6-dimethylbenzimidazolyl)cobamide (III)----vitamin B12 (I), which allows chemical 14C-labelling of vitamin B12. In this procedure cyanogen bromide, which is necessary for the first step, was labelled with [14C] cyanide. By the following reactions a vitamin B12 was formed in which C-2 of the 5, 6-dimethylbenzimidazole moiety is labelled.

Biochim Biophys Acta. 1971 Aug 20; 242(2): 473-83
Ressler C, Koga T