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• W1995239780 abstract "Nitric oxide synthase (NOS) catalyzes the conversion of l-arginine to l-citrulline through the intermediate Nω-hydroxy-l-arginine (NHA), producing nitric oxide, an important mammalian signaling molecule. Several disease states are associated with improper regulation of nitric oxide production, making NOS a therapeutic target. The first step of the NOS reaction has been well-characterized and is presumed to proceed through a compound I heme species, analogous to the cytochrome P450 mechanism. The second step, however, is enzymatically unprecedented and is thought to occur via a ferric peroxo heme species. To gain insight into the details of this unique second step, we report here the synthesis of NHA analogues bearing guanidinium methyl or ethyl substitutions and their investigation as either inhibitors of or alternate substrates for NOS. Radiolabeling studies reveal that Nω-methoxy-l-arginine, an alternative NOS substrate, produces citrulline, nitric oxide, and methanol. On the basis of these results, we propose a mechanism for the second step of NOS catalysis in which a methylated nitric oxide species is released and is further metabolized by NOS. Crystal structures of our NHA analogues bound to nNOS have been determined, revealing the presence of an active site water molecule only in the presence of singly methylated analogues. Bulkier analogues displace this active site water molecule; a different mechanism is proposed in the absence of the water molecule. Our results provide new insights into the steric and stereochemical tolerance of the NOS active site and substrate capabilities of NOS." @default.
• W1995239780 created "2016-06-24" @default.
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• W1995239780 date "2013-04-26" @default.
• W1995239780 modified "2023-10-04" @default.
• W1995239780 title "Methylated <i>N</i>^ω-Hydroxy-<scp>l</scp>-arginine Analogues as Mechanistic Probes for the Second Step of the Nitric Oxide Synthase-Catalyzed Reaction" @default.
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• W1995239780 doi "https://doi.org/10.1021/bi301571v" @default.
• W1995239780 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3678535" @default.
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