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10.1021/bi3015482 http://scihub22266oqcxt.onion/10.1021/bi3015482 C4059518!4059518 !23351038     free     free     free Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\23351038 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Biochemistry 2013 ; 52 (9 ): 1594-602 Nephropedia Template TP {{tp|p=23351038 |t=2013. Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor |pdf=|usr=}}{{23351038 }} gab.com Text Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor JO: Biochemistry http://www.kidney.de/pget.php?&tw=1&pmid=23351038 #FOAvip Oxygen homeostasis plays a critical role in angiogenesis, erythropoiesis, and cell metabolism. Oxygen homeostasis is set by the hypoxia inducible factor-1? (HIF-1?) pathway, which is controlled by factor inhibiting HIF-1? (FIH). FIH is a non-heme Fe(II), ?-ketoglutarate (?KG)-dependent dioxygenase that inhibits HIF-1? by hydroxylating the C-terminal transactivation domain (CTAD) of HIF-1? at HIF-Asn(803). A tight coupling between CTAD binding and O2 activation is essential for hypoxia sensing, making changes in the coordination geometry of Fe(II) upon CTAD encounter a crucial feature of this enzyme. Although the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by causing the Fe(II) cofactor to release an aquo ligand, experimental evidence of this has been absent. More broadly, this proposed coordination change at Fe(II) has not been observed during steady-state turnover in any ?KG oxygenase to date. In this work, solvent isotope effects (SIEs) were used as a direct mechanistic probe of substrate-triggered aquo release in FIH, as inverse SIEs (SIE < 1) are signatures for pre-equilibrium aquo release from metal ions. Our mechanistic studies of FIH have revealed inverse solvent isotope effects in the steady-state rate constants at limiting concentrations of CTAD or ?KG [(D2O)kcat/KM(CTAD) = 0.40 ± 0.07, and (D2O)kcat/KM(?KG) = 0.32 ± 0.08], providing direct evidence of aquo release during steady-state turnover. Furthermore, the SIE at saturating concentrations of CTAD and ?KG was inverse ((D2O)kcat = 0.51 ± 0.07), indicating that aquo release occurs after CTAD binds. The inverse kinetic SIEs observed in the steady state for FIH can be explained by a strong Fe-OH2 bond. The stable Fe-OH2 bond plays an important part in FIH's regulatory role over O2 homeostasis in humans and points toward a strategy for tightly coupling O2 activation with CTAD hydroxylation that relies on substrate triggering. Twit Text FOAVip Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor ????Biochemistry http://www.kidney.de/pget.php?&tw=1&pmid=23351038 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=23351038 #FOAvip English Wikipedia <ref>{{Cite pmid|23351038 }}</ref> Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor #MMPMID23351038 Hangasky JA ; Saban E ; Knapp MJ Biochemistry 2013[Mar]; 52 (9 ): 1594-602 PMID23351038 show ga Oxygen homeostasis plays a critical role in angiogenesis, erythropoiesis, and cell metabolism. Oxygen homeostasis is set by the hypoxia inducible factor-1? (HIF-1?) pathway, which is controlled by factor inhibiting HIF-1? (FIH). FIH is a non-heme Fe(II), ?-ketoglutarate (?KG)-dependent dioxygenase that inhibits HIF-1? by hydroxylating the C-terminal transactivation domain (CTAD) of HIF-1? at HIF-Asn(803). A tight coupling between CTAD binding and O2 activation is essential for hypoxia sensing, making changes in the coordination geometry of Fe(II) upon CTAD encounter a crucial feature of this enzyme. Although the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by causing the Fe(II) cofactor to release an aquo ligand, experimental evidence of this has been absent. More broadly, this proposed coordination change at Fe(II) has not been observed during steady-state turnover in any ?KG oxygenase to date. In this work, solvent isotope effects (SIEs) were used as a direct mechanistic probe of substrate-triggered aquo release in FIH, as inverse SIEs (SIE < 1) are signatures for pre-equilibrium aquo release from metal ions. Our mechanistic studies of FIH have revealed inverse solvent isotope effects in the steady-state rate constants at limiting concentrations of CTAD or ?KG [(D2O)kcat/KM(CTAD) = 0.40 ± 0.07, and (D2O)kcat/KM(?KG) = 0.32 ± 0.08], providing direct evidence of aquo release during steady-state turnover. Furthermore, the SIE at saturating concentrations of CTAD and ?KG was inverse ((D2O)kcat = 0.51 ± 0.07), indicating that aquo release occurs after CTAD binds. The inverse kinetic SIEs observed in the steady state for FIH can be explained by a strong Fe-OH2 bond. The stable Fe-OH2 bond plays an important part in FIH's regulatory role over O2 homeostasis in humans and points toward a strategy for tightly coupling O2 activation with CTAD hydroxylation that relies on substrate triggering. |Amino Acid Sequence [MESH] |Deuterium Oxide/*metabolism [MESH] |Humans [MESH] |Hypoxia-Inducible Factor 1, alpha Subunit/chemistry/*metabolism [MESH] |Ketoglutaric Acids/*metabolism [MESH] |Kinetics [MESH] |Mixed Function Oxygenases/chemistry/*metabolism [MESH] |Molecular Sequence Data [MESH] |Oxygen/metabolism [MESH] |Protein Structure, Tertiary [MESH] |Repressor Proteins/chemistry/*metabolism [MESH]Inverse solvent isotope effects arising from substrate triggering in t(epmc).pdf DeepDyve Pubget Overpricing