Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates.
作者： James D. Vasta , Ronald T. Raines
DOI: 10.1016/J.BMC.2015.05.003
关键词: Hypoxia-inducible factors 、 Hydroxyproline 、 Proline 、 Biochemistry 、 Isozyme 、 Chemistry 、 Prolyl-Hydroxylase Inhibitors 、 Endoplasmic reticulum 、 Procollagen-proline dioxygenase 、 Hypoxia-Inducible Factor-Proline Dioxygenases
摘要: Collagen is the most abundant protein in animals. A variety of indications are associated with overproduction collagen, including fibrotic diseases and cancer metastasis. The stability collagen relies on posttranslational modification proline residues to form (2S,4R)-4-hydroxyproline. This catalyzed by prolyl 4-hydroxylases (CP4Hs), which Fe(II)- α-ketoglutarate (AKG)-dependent dioxygenases located lumen endoplasmic reticulum. Human CP4Hs validated targets for treatment both metastatic breast cancer. Herein, we report 2,2′-bipyridinedicarboxylates as inhibitors a human CP4H. Although capable inhibition via iron sequestration, 4,5′- 5,5′-dicarboxylates were found be potent competitive CP4H, 5,5′-dicarboxylate was selective its inhibitory activity. Our findings clarify strategy developing CP4H clinical utility.
sci-hub.se 参考文章(35)
V Günzler, H M Hanauske-Abel, R Myllylä, J Mohr, K I Kivirikko, Time-dependent inactivation of chick-embryo prolyl 4-hydroxylase by coumalic acid. Evidence for a syncatalytic mechanism. Biochemical Journal. ,vol. 242, pp. 163- 169 ,(1987) , 10.1042/BJ2420163
Neil J. Hales, John F. Beattie, Novel inhibitors of prolyl 4-hydroxylase. 5. The intriguing structure-activity relationships seen with 2,2'-bipyridine and its 5,5'-dicarboxylic acid derivatives Journal of Medicinal Chemistry. ,vol. 36, pp. 3853- 3858 ,(1993) , 10.1021/JM00076A014
J. Myllyharju, Characterization of the iron- and 2-oxoglutarate-binding sites of human prolyl 4-hydroxylase The EMBO Journal. ,vol. 16, pp. 1173- 1180 ,(1997) , 10.1093/EMBOJ/16.6.1173
Elizabeth A. Kersteen, Joshua J. Higgin, Ronald T. Raines, Production of human prolyl 4-hydroxylase in Escherichia coli Protein Expression and Purification. ,vol. 38, pp. 279- 291 ,(2004) , 10.1016/J.PEP.2004.09.008
Richard A. Berg, Darwin J. Prockop, The thermal transition of a non-hydroxylated form of collagen. Evidence for a role for hydroxyproline in stabilizing the triple-helix of collagen Biochemical and Biophysical Research Communications. ,vol. 52, pp. 115- 120 ,(1973) , 10.1016/0006-291X(73)90961-3
J Myllyharju, Collagens, modifying enzymes and their mutations in humans, flies and worms Trends in Genetics. ,vol. 20, pp. 33- 43 ,(2004) , 10.1016/J.TIG.2003.11.004
Joel Rosenbloom, Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies Annals of Internal Medicine. ,vol. 152, pp. 159- 166 ,(2010) , 10.7326/0003-4819-152-3-201002020-00007
Robert I. Dowell, Elizabeth M. Hadley, Novel inhibitors of prolyl 4-hydroxylase Journal of Medicinal Chemistry. ,vol. 35, pp. 800- 804 ,(1992) , 10.1021/JM00083A001
Louis-Charles Campeau, Sophie Rousseaux, Keith Fagnou, A solution to the 2-pyridyl organometallic cross-coupling problem: regioselective catalytic direct arylation of pyridine N-oxides. Journal of the American Chemical Society. ,vol. 127, pp. 18020- 18021 ,(2005) , 10.1021/JA056800X
Johanna Myllyharju, Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets Annals of Medicine. ,vol. 40, pp. 402- 417 ,(2008) , 10.1080/07853890801986594