Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents.
l-Nucleoside analogs are a new class of clinically active antiviral and anticancer agents. The phosphorylation of these analogs from diphosphate to triphosphate metabolites is crucial for their biological action. We studied the role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the metabolism of l-nucleoside analogs, using small interfering RNAs to down-regulate the amount of this enzyme in HelaS3 and 2.2.15 cells, chosen as models for studying the impact of the enzyme on the anticancer and antihepatitis B virus activities of these analogs. Decrease in the expression of 3-phosphoglycerate kinase led to a corresponding decrease in the formation of the triphosphate metabolites of l-nucleoside analogs (but not d-nucleoside analogs), resulting in detrimental effects on their activity. The enzyme is important for generating as well as maintaining the steady state levels of l-nucleotides in the cells, thereby playing a key role in the activity of l-nucleoside analogs against human immunodeficiency virus, hepatitis B virus, and cancer. This study also indicates a structure-based distinction in the metabolism of l- and d-nucleoside analogs, disputing the classic notion that nucleoside diphosphate kinases are responsible for the phosphorylation of all classes of nucleoside analog diphosphates.
Krishnan
Preethi
P
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Gullen
Elizabeth A
EA
Lam
Wing
W
Dutschman
Ginger E
GE
Grill
Susan P
SP
Cheng
Yung-Chi
YC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006367:HeLa Cells; D006509:Hepatitis B / Q000188:drug therapy; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy; D010735:Phosphoglycerate Kinase / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D034741:RNA, Small Interfering; D010735:Phosphoglycerate Kinase