3MO7

Crystal structure of human orotidine 5'-monophosphate decarboxylase covalently modified by 2'-fluoro-6-iodo-UMP

Summary for 3MO7

• Entry DOI: 10.2210/pdb3mo7/pdb
• Related: 2EAW 2P1F 3BGG 3BGJ 3BKO 3G3D
• Descriptor: Uridine 5'-monophosphate synthase, 2'-deoxy-2'-fluorouridine 5'-(dihydrogen phosphate), GLYCEROL, ... (4 entities in total)
• Functional Keywords: ump synthase, orotidine 5'-monophosphate decarboxylase, 2'-fluoro-6-iodo-ump, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 30890.43

Authors

Liu, Y.,Kotra, L.P.,Pai, E.F. (deposition date: 2010-04-22, release date: 2011-04-06, Last modification date: 2024-10-30)

Primary citation

Lewis, M.,Meza-Avina, M.E.,Wei, L.,Crandall, I.E.,Bello, A.M.,Poduch, E.,Liu, Y.,Paige, C.J.,Kain, K.C.,Pai, E.F.,Kotra, L.P.
Novel interactions of fluorinated nucleotide derivatives targeting orotidine 5'-monophosphate decarboxylase.
J.Med.Chem., 54:2891-2901, 2011

PubMed Abstract: Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 ± 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations.

PubMed: 21417464
DOI: 10.1021/jm101642g

Experimental method

X-RAY DIFFRACTION (1.35 Å)