17298-58-7Relevant articles and documents
Deamination of 6-aminodeoxyfutalosine in menaquinone biosynthesis by distantly related enzymes
Goble, Alissa M.,Toro, Rafael,Li, Xu,Ornelas, Argentina,Fan, Hao,Eswaramoorthy, Subramaniam,Patskovsky, Yury,Hillerich, Brandan,Seidel, Ron,Sali, Andrej,Shoichet, Brian K.,Almo, Steven C.,Swaminathan, Subramanyam,Tanner, Martin E.,Raushel, Frank M.
, p. 6525 - 6536 (2013/10/01)
Proteins of unknown function belonging to cog1816 and cog0402 were characterized. Sav2595 from Steptomyces avermitilis MA-4680, Acel0264 from Acidothermus cellulolyticus 11B, Nis0429 from Nitratiruptor sp. SB155-2 and Dr0824 from Deinococcus radiodurans R1 were cloned, purified, and their substrate profiles determined. These enzymes were previously incorrectly annotated as adenosine deaminases or chlorohydrolases. It was shown here that these enzymes actually deaminate 6-aminodeoxyfutalosine. The deamination of 6-aminodeoxyfutalosine is part of an alternative menaquinone biosynthetic pathway that involves the formation of futalosine. 6-Aminodeoxyfutalosine is deaminated by these enzymes with catalytic efficiencies greater than 10 5 M-1 s-1, Km values of 0.9-6.0 μM, and kcat values of 1.2-8.6 s-1. Adenosine, 2′-deoxyadenosine, thiomethyladenosine, and S-adenosylhomocysteine are deaminated at least an order of magnitude slower than 6-aminodeoxyfutalosine. The crystal structure of Nis0429 was determined and the substrate, 6-aminodeoxyfutalosine, was positioned in the active site on the basis of the presence of adventitiously bound benzoic acid. In this model, Ser-145 interacts with the carboxylate moiety of the substrate. The structure of Dr0824 was also determined, but a collapsed active site pocket prevented docking of substrates. A computational model of Sav2595 was built on the basis of the crystal structure of adenosine deaminase and substrates were docked. The model predicted a conserved arginine after β-strand 1 to be partially responsible for the substrate specificity of Sav2595.
Synthesis of 5′-methylthio coformycins: Specific inhibitors for malarial adenosine deaminase
Tyler, Peter C.,Taylor, Erika A.,Froehlich, Richard F. G.,Schramm, Vern L.
, p. 6872 - 6879 (2008/02/10)
Transition state theory suggests that enzymatic rate acceleration (k cat/knon) is related to the stabilization of the transition state for a given reaction. Chemically stable analogues of a transition state complex are predicted to convert catalytic energy into binding energy. Because transition state stabilization is a function of catalytic efficiency, differences in substrate specificity can be exploited in the design of tight-binding transition state analogue inhibitors. Coformycin and 2′-deoxycoformycin are natural product transition state analogue inhibitors of adenosine deaminases (ADAs). These compounds mimic the tetrahedral geometry of the ADA transition state and bind with picomolar dissociation constants to enzymes from bovine, human, and protozoan sources. The purine salvage pathway in malaria parasites is unique in that Plasmodium falciparum ADA (PfADA) catalyzes the deamination of both adenosine and 5′-3 methylthioadenosine. In contrast, neither human adenosine deaminase (HsADA) nor the bovine enzyme (BtADA) can deaminate 5′-methylthioadenosine. 5′-Methylthiocoformycin and 5′-methylthio-2′-deoxycoformycin were synthesized to be specific transition state mimics of the P. falciparum enzyme. These analogues inhibited PfADA with dissociation constants of 430 and 790 pM, respectively. Remarkably, they gave no detectable inhibition of the human and bovine enzymes. Adenosine deamination is involved in the essential pathway of purine salvage in P. falciparum, and prior studies have shown that inhibition of purine salvage results in parasite death. Inhibitors of HsADA are known to be toxic to humans, and the availability of parasite-specific ADA inhibitors may prevent this side-effect. The potent and P. falciparum-specti'ic inhibitors described here have potential for development as antimalarials without inhibition of host ADA.
Nucleic acid related compounds. 82. Conversions of adenosine to inosine 5'-thioether derivatives with Aspergillus oryzae adenosine deaminase or alkyl nitrites. Substrate and inhibitory activities of inosine 5'-thioether derivatives with purine nucleoside
Wnuk,Stoeckler,Robins
, p. 389 - 403 (2007/10/02)
Adenosine derivatives lacking a 5'-hydroxyl group seldom act as alternative substrates of adenosine deaminases from calf intestine and other mammalian sources. A deaminase from Aspergillus oryzae deaminated adenosine 5'-thioether derivatives cleanly and m
