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From Proteopedia
Structure of Phenylalanyl-5'-O-adenosine phosphoramidate
Structural highlights
FunctionRNAS1_BOVIN Endonuclease that catalyzes the cleavage of RNA on the 3' side of pyrimidine nucleotides. Acts on single stranded and double stranded RNA.[1] Publication Abstract from PubMedPhosphoramidates composed of an amino acid and a nucleotide analogue are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide, which can then be phosphorylated to become the pharmacologically active triphosphate. Enzymatic hydrolysis has been demonstrated, but a spontaneous chemical process may also occur. We measured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with a half-life time as short as 2.4 h for Pro-AMP in ethylimidazole-containing buffer at 37 degrees C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP. Crystal structures of Gly-AMP, Pro-AMP, betaPro-AMP and Phe-AMP bound to RNase A as crystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate, helping to explain this reactivity. Our results are significant for the design of new antiviral prodrugs. The Enzyme-Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid.,Jovanovic D, Tremmel P, Pallan PS, Egli M, Richert C Angew Chem Int Ed Engl. 2020 Nov 2;59(45):20154-20160. doi:, 10.1002/anie.202008665. Epub 2020 Sep 15. PMID:32757352[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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