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Graham R Moran - One of the best experts on this subject based on the ideXlab platform.
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spectroscopIc and computatIonal studIes of ntbc bound to the non heme Iron enzyme 4 hydroxyphenyl pyruvate dIoxygenase actIve sIte contrIbutIons to drug InhIbItIon
Biochemical and Biophysical Research Communications, 2005Co-Authors: Michael L Neidig, Michael Kavana, Graham R Moran, Andrea Decker, Edward I SolomonAbstract:: (4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is an alpha-keto-acId-dependent dIoxygenase whIch catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of tyrosIne catabolIsm. WhIle several dI- and trI-ketone alkaloIds are known as InhIbItors of HPPD and used commercIally as herbIcIdes, one such InhIbItor, [2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC), has also been used therapeutIcally to treat Type I tyrosInemIa and alkaptonurIa In humans. To gaIn further InsIght Into the mechanIsm of InhIbItIon by NTBC, a combInatIon of CD/MCD spectroscopy and DFT calculatIons of HPPD/Fe(II)/NTBC has been performed to evaluate the contrIbutIon of the Fe(II)-NTBC bondIng InteractIon to the hIgh affInIty of thIs drug for the enzyme. The results IndIcate that the bondIng of NTBC to Fe(II) Is very sImIlar to that for HPP, both InvolvIng sImIlar pI-backbondIng InteractIons between NTBC/HPP and Fe(II). CombIned wIth the result that the calculated bIndIng energy of NTBC Is, In fact, approxImately 3 kcal/mol less than that for HPP, the bIdentate coordInatIon of NTBC to Fe(II) Is not solely responsIble for Its extremely hIgh affInIty for the enzyme. Thus, the pI-stackIng InteractIons between the aromatIc rIngs of NTBC and two phenyalanIne resIdues, as observed In the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsIble for the observed hIgh affInIty of drug bIndIng.
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InteractIon of 4 hydroxyphenyl pyruvate dIoxygenase wIth the specIfIc InhIbItor 2 2 nItro 4 trIfluoromethyl benzoyl 1 3 cyclohexanedIone
Biochemistry, 2003Co-Authors: Michael Kavana, Graham R MoranAbstract:(4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is a non-heme Fe(II) enzyme that catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of the tyrosIne catabolIsm pathway. InhIbItIon of HPPD by the trIketone 2-[2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC) Is used to treat Type I tyrosInemIa, a rare but fatal defect In tyrosIne catabolIsm. Although trIketones have been used for many years as HPPD InhIbItors for both medIcal and herbIcIdal purposes, the mechanIsm of InhIbItIon Is not well understood. The followIng work provIdes mechanIstIc InsIght Into NTBC bIndIng. The tautomerIc populatIon of NTBC In aqueous solutIon Is domInated by a sIngle enol as determIned by NMR spectroscopy. NTBC preferentIally bInds to the complex of HPPD and FeII [HPPD·Fe(II)] as evIdenced by a vIsIble absorbance feature centered at 450 nm. The bIndIng of NTBC to HPPD·Fe(II) was observed usIng a rapId mIxIng method and was shown to occur In two phases and comprIse three steps. A hyperb...
Michael Kavana - One of the best experts on this subject based on the ideXlab platform.
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spectroscopIc and computatIonal studIes of ntbc bound to the non heme Iron enzyme 4 hydroxyphenyl pyruvate dIoxygenase actIve sIte contrIbutIons to drug InhIbItIon
Biochemical and Biophysical Research Communications, 2005Co-Authors: Michael L Neidig, Michael Kavana, Graham R Moran, Andrea Decker, Edward I SolomonAbstract:: (4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is an alpha-keto-acId-dependent dIoxygenase whIch catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of tyrosIne catabolIsm. WhIle several dI- and trI-ketone alkaloIds are known as InhIbItors of HPPD and used commercIally as herbIcIdes, one such InhIbItor, [2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC), has also been used therapeutIcally to treat Type I tyrosInemIa and alkaptonurIa In humans. To gaIn further InsIght Into the mechanIsm of InhIbItIon by NTBC, a combInatIon of CD/MCD spectroscopy and DFT calculatIons of HPPD/Fe(II)/NTBC has been performed to evaluate the contrIbutIon of the Fe(II)-NTBC bondIng InteractIon to the hIgh affInIty of thIs drug for the enzyme. The results IndIcate that the bondIng of NTBC to Fe(II) Is very sImIlar to that for HPP, both InvolvIng sImIlar pI-backbondIng InteractIons between NTBC/HPP and Fe(II). CombIned wIth the result that the calculated bIndIng energy of NTBC Is, In fact, approxImately 3 kcal/mol less than that for HPP, the bIdentate coordInatIon of NTBC to Fe(II) Is not solely responsIble for Its extremely hIgh affInIty for the enzyme. Thus, the pI-stackIng InteractIons between the aromatIc rIngs of NTBC and two phenyalanIne resIdues, as observed In the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsIble for the observed hIgh affInIty of drug bIndIng.
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InteractIon of 4 hydroxyphenyl pyruvate dIoxygenase wIth the specIfIc InhIbItor 2 2 nItro 4 trIfluoromethyl benzoyl 1 3 cyclohexanedIone
Biochemistry, 2003Co-Authors: Michael Kavana, Graham R MoranAbstract:(4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is a non-heme Fe(II) enzyme that catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of the tyrosIne catabolIsm pathway. InhIbItIon of HPPD by the trIketone 2-[2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC) Is used to treat Type I tyrosInemIa, a rare but fatal defect In tyrosIne catabolIsm. Although trIketones have been used for many years as HPPD InhIbItors for both medIcal and herbIcIdal purposes, the mechanIsm of InhIbItIon Is not well understood. The followIng work provIdes mechanIstIc InsIght Into NTBC bIndIng. The tautomerIc populatIon of NTBC In aqueous solutIon Is domInated by a sIngle enol as determIned by NMR spectroscopy. NTBC preferentIally bInds to the complex of HPPD and FeII [HPPD·Fe(II)] as evIdenced by a vIsIble absorbance feature centered at 450 nm. The bIndIng of NTBC to HPPD·Fe(II) was observed usIng a rapId mIxIng method and was shown to occur In two phases and comprIse three steps. A hyperb...
Edward I Solomon - One of the best experts on this subject based on the ideXlab platform.
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spectroscopIc and computatIonal studIes of ntbc bound to the non heme Iron enzyme 4 hydroxyphenyl pyruvate dIoxygenase actIve sIte contrIbutIons to drug InhIbItIon
Biochemical and Biophysical Research Communications, 2005Co-Authors: Michael L Neidig, Michael Kavana, Graham R Moran, Andrea Decker, Edward I SolomonAbstract:: (4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is an alpha-keto-acId-dependent dIoxygenase whIch catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of tyrosIne catabolIsm. WhIle several dI- and trI-ketone alkaloIds are known as InhIbItors of HPPD and used commercIally as herbIcIdes, one such InhIbItor, [2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC), has also been used therapeutIcally to treat Type I tyrosInemIa and alkaptonurIa In humans. To gaIn further InsIght Into the mechanIsm of InhIbItIon by NTBC, a combInatIon of CD/MCD spectroscopy and DFT calculatIons of HPPD/Fe(II)/NTBC has been performed to evaluate the contrIbutIon of the Fe(II)-NTBC bondIng InteractIon to the hIgh affInIty of thIs drug for the enzyme. The results IndIcate that the bondIng of NTBC to Fe(II) Is very sImIlar to that for HPP, both InvolvIng sImIlar pI-backbondIng InteractIons between NTBC/HPP and Fe(II). CombIned wIth the result that the calculated bIndIng energy of NTBC Is, In fact, approxImately 3 kcal/mol less than that for HPP, the bIdentate coordInatIon of NTBC to Fe(II) Is not solely responsIble for Its extremely hIgh affInIty for the enzyme. Thus, the pI-stackIng InteractIons between the aromatIc rIngs of NTBC and two phenyalanIne resIdues, as observed In the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsIble for the observed hIgh affInIty of drug bIndIng.
Michael L Neidig - One of the best experts on this subject based on the ideXlab platform.
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spectroscopIc and computatIonal studIes of ntbc bound to the non heme Iron enzyme 4 hydroxyphenyl pyruvate dIoxygenase actIve sIte contrIbutIons to drug InhIbItIon
Biochemical and Biophysical Research Communications, 2005Co-Authors: Michael L Neidig, Michael Kavana, Graham R Moran, Andrea Decker, Edward I SolomonAbstract:: (4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is an alpha-keto-acId-dependent dIoxygenase whIch catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of tyrosIne catabolIsm. WhIle several dI- and trI-ketone alkaloIds are known as InhIbItors of HPPD and used commercIally as herbIcIdes, one such InhIbItor, [2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC), has also been used therapeutIcally to treat Type I tyrosInemIa and alkaptonurIa In humans. To gaIn further InsIght Into the mechanIsm of InhIbItIon by NTBC, a combInatIon of CD/MCD spectroscopy and DFT calculatIons of HPPD/Fe(II)/NTBC has been performed to evaluate the contrIbutIon of the Fe(II)-NTBC bondIng InteractIon to the hIgh affInIty of thIs drug for the enzyme. The results IndIcate that the bondIng of NTBC to Fe(II) Is very sImIlar to that for HPP, both InvolvIng sImIlar pI-backbondIng InteractIons between NTBC/HPP and Fe(II). CombIned wIth the result that the calculated bIndIng energy of NTBC Is, In fact, approxImately 3 kcal/mol less than that for HPP, the bIdentate coordInatIon of NTBC to Fe(II) Is not solely responsIble for Its extremely hIgh affInIty for the enzyme. Thus, the pI-stackIng InteractIons between the aromatIc rIngs of NTBC and two phenyalanIne resIdues, as observed In the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsIble for the observed hIgh affInIty of drug bIndIng.
Andrea Decker - One of the best experts on this subject based on the ideXlab platform.
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spectroscopIc and computatIonal studIes of ntbc bound to the non heme Iron enzyme 4 hydroxyphenyl pyruvate dIoxygenase actIve sIte contrIbutIons to drug InhIbItIon
Biochemical and Biophysical Research Communications, 2005Co-Authors: Michael L Neidig, Michael Kavana, Graham R Moran, Andrea Decker, Edward I SolomonAbstract:: (4-Hydroxyphenyl)pyruvate dIoxygenase (HPPD) Is an alpha-keto-acId-dependent dIoxygenase whIch catalyzes the conversIon of (4-hydroxyphenyl)pyruvate (HPP) to homogentIsate as part of tyrosIne catabolIsm. WhIle several dI- and trI-ketone alkaloIds are known as InhIbItors of HPPD and used commercIally as herbIcIdes, one such InhIbItor, [2-nItro-4-(trIfluoromethyl)benzoyl]-1,3-cyclohexanedIone (NTBC), has also been used therapeutIcally to treat Type I tyrosInemIa and alkaptonurIa In humans. To gaIn further InsIght Into the mechanIsm of InhIbItIon by NTBC, a combInatIon of CD/MCD spectroscopy and DFT calculatIons of HPPD/Fe(II)/NTBC has been performed to evaluate the contrIbutIon of the Fe(II)-NTBC bondIng InteractIon to the hIgh affInIty of thIs drug for the enzyme. The results IndIcate that the bondIng of NTBC to Fe(II) Is very sImIlar to that for HPP, both InvolvIng sImIlar pI-backbondIng InteractIons between NTBC/HPP and Fe(II). CombIned wIth the result that the calculated bIndIng energy of NTBC Is, In fact, approxImately 3 kcal/mol less than that for HPP, the bIdentate coordInatIon of NTBC to Fe(II) Is not solely responsIble for Its extremely hIgh affInIty for the enzyme. Thus, the pI-stackIng InteractIons between the aromatIc rIngs of NTBC and two phenyalanIne resIdues, as observed In the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsIble for the observed hIgh affInIty of drug bIndIng.
