7329-79-5Relevant articles and documents
Purine nucleoside phosphorylase-catalyzed, phosphate-independent hydrolysis of 2-amino-6-mercapto-7-methylpurine ribonucleoside
Cheng, Jianming,Farutin, Victor,Wu, Zhijun,Jacob-Mosier, Gayatry,Riley, Brad,Hakimi, Ryan,Cordes, Eugene H.
, p. 307 - 325 (1999)
In the presence of 1 mM phosphate, 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) is a well-behaved substrate for calf spleen purine nucleoside phosphorylase (PNP). In the absence of phosphate, calf spleen PNP catalyzes a slow hydrolysis of MESG, which is accompanied by inactivation of the enzyme, analogous to the previously observed PNP-catalyzed hydrolysis of inosine and guanosine with formation, in the former case, of a stable PNP·hypoxanthine complex (P.C. Kline and V.L. Schramm (1992) Biochemistry 31, 5964-5973). Qualitative and semiquantitative features of calf spleen PNP- catalyzed hydrolysis of MESG are accounted for by the following model. First, in the absence of phosphate and at pH 7.4, the enzyme exists as an equilibrium mixture of monomer and trimer with a dissociation constant for the trimer of 3 x 1014 M2. Second, a stoichiometric reaction between three molecules of MESG and the PNP trimer results in the formation of a stable PNP·purinethiol complex. Third, the PNP·purinethiol complex initially formed with the monomeric enzyme partitions between product release and formation of a stable complex with 55 turnovers per inactivation event. Fourth, the stable PNP·purinethiol complexes are rapidly dissociated by phosphate to regenerate active enzyme. This dissociation is accompanied by an increase in absorbance at 356 nm consistent with a pK(a) for the purinethiol base on the enzyme of 8.1, compared to a corresponding value of 8.8 in aqueous solution.
Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE
Veleti, Sri Kumar,Lindenberger, Jared J.,Ronning, Donald R.,Sucheck, Steven J.
, p. 1404 - 1411 (2014/03/21)
The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. GlgE is a Mycobacterium tuberculosis (Mtb) encoded maltosyltransferase involved in α-glucan biosynthesis. Deletion of GlgE in Mtb results in the accumulation of M1P within cells leading to rapid death of the organism. To inhibit GlgE a maltose-C-phosphonate (MCP) 13 was designed to act as an isosteric non-hydrolysable mimic of M1P. MCP 13, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step in transforming maltose to the desired product. MCP 13 inhibited Mtb GlgE with an IC50 = 230 ± 24 μM determined using a coupled enzyme assay which measures orthophosphate release. The requirement of M1P for the assay necessitated the development of an expedited synthetic route to M1P from an intermediate used in the MCP 13 synthesis. In conclusion, we designed a substrate analogue of M1P that is the first to exhibit Mtb GlgE inhibition.
Synthesis and evaluation of l-rhamnose 1C-phosphonates as nucleotidylyltransferase inhibitors
Loranger, Matthew W.,Forget, Stephanie M.,McCormick, Nicole E.,Syvitski, Raymond T.,Jakeman, David L.
, p. 9822 - 9833 (2013/10/22)
We report the synthesis of a series of phosphonates and ketosephosphonates possessing an l-rhamnose scaffold with varying degrees of fluorination. These compounds were evaluated as potential inhibitors of α-d-glucose 1-phosphate thymidylyltransferase (Cps2L), the first enzyme in Streptococcus pneumoniae l-rhamnose biosynthesis, and a novel antibiotic target. Enzyme-substrate and enzyme-inhibitor binding experiments were performed using water-ligand observed binding via gradient spectroscopy (WaterLOGSY) NMR for known sugar nucleotide substrates and selected phosphonate analogues. IC 50 values were measured and Ki values were calculated for inhibitors. New insights were gained into the binding promiscuity of enzymes within the prokaryotic l-rhamnose biosynthetic pathway (Cps2L, RmlB-D) and into the mechanism of inhibition for the most potent inhibitor in the series, l-rhamnose 1C-phosphonate.
Nucleotidylation of unsaturated carbasugar in validamycin biosynthesis
Yang, Jongtae,Xu, Hui,Zhang, Yirong,Bai, Linquan,Deng, Zixin,Mahmud, Taifo
experimental part, p. 438 - 449 (2011/03/17)
Validamycin A is a member of microbial-derived C7N-aminocyclitol family of natural products that is widely used as crop protectant and the precursor of the antidiabetic drug voglibose. Its biosynthetic gene clusters have been identified in seve
