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Interactions of non-heme ferrous active sites with substrates :Structure/function correlations for phenylalanine hydroxylase and bleomycin.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Interactions of non-heme ferrous active sites with substrates :
Reminder of title:	Structure/function correlations for phenylalanine hydroxylase and bleomycin.
Author:	Kemsley, Jyllian Nicole.
Description:	148 p.
Notes:	Adviser: Edward I. Solomon.
Notes:	Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1239.
Contained By:	Dissertation Abstracts International64-03B.
Subject:	Chemistry, Inorganic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3085198
ISBN:	0496330055

Interactions of non-heme ferrous active sites with substrates :Structure/function correlations for phenylalanine hydroxylase and bleomycin.
Kemsley, Jyllian Nicole.

Interactions of non-heme ferrous active sites with substrates :Structure/function correlations for phenylalanine hydroxylase and bleomycin. [electronic resource] - 148 p.

Adviser: Edward I. Solomon.

Thesis (Ph.D.)--Stanford University, 2003.

Investigation of Fe(II)PAH indicates that binding either substrate, phenylalanine or pterin, does not greatly affect the six-coordinate ferrous active site. Binding of both cosubstrates results in loss of a metal ligand, directly implicating the iron in the hydroxylation mechanism. Studies of two PAH mutants related to phenylketonuria, Arg158Gln and Glu280Lys, show that only the Arg158Gln mutant loses a ligand upon binding of both cosubstrates. This indicates that the first step of the reaction mechanism is formation of a peroxy-pterin species, which subsequently reacts with the ferrous site if the pterin is properly oriented in the active site pocket.

ISBN: 0496330055Subjects--Topical Terms:

197298
Chemistry, Inorganic.

Interactions of non-heme ferrous active sites with substrates :Structure/function correlations for phenylalanine hydroxylase and bleomycin.
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245 1 0 $a Interactions of non-heme ferrous active sites with substrates : $b Structure/function correlations for phenylalanine hydroxylase and bleomycin. $h [electronic resource]
300 $a 148 p.
500 $a Adviser: Edward I. Solomon.
500 $a Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1239.
502 $a Thesis (Ph.D.)--Stanford University, 2003.
520 # $a Investigation of Fe(II)PAH indicates that binding either substrate, phenylalanine or pterin, does not greatly affect the six-coordinate ferrous active site. Binding of both cosubstrates results in loss of a metal ligand, directly implicating the iron in the hydroxylation mechanism. Studies of two PAH mutants related to phenylketonuria, Arg158Gln and Glu280Lys, show that only the Arg158Gln mutant loses a ligand upon binding of both cosubstrates. This indicates that the first step of the reaction mechanism is formation of a peroxy-pterin species, which subsequently reacts with the ferrous site if the pterin is properly oriented in the active site pocket.
520 # $a Mononuclear non-heme ferrous active sites are involved in a variety of biological systems and catalyze a wide range of biological functions requiring dioxygen. Two of these systems are phenylalanine hydroxylase (PAH), a pterin-dependent enzyme that catalyzes the hydroxylation of phenylalanine, and bleomycin (BLM), an antibiotic that catalyzes DNA cleavage. Most previous studies have involved metals or oxidation states not used in vivo. This dissertation focuses on the use of magnetic circular dichroism spectroscopy to probe the catalytically active ferrous complexes of these systems and provide insight into their reaction mechanisms.
520 # $a Studies of Fe(II)BLM and its interaction with its substrate, DNA, show that the active site is significantly perturbed upon DNA binding. This effect is not dependent on the presence of a preferred cleavage sequence. Parallel work on BLM structural derivatives indicate that Fe(II)iso-PEPLM forms the same DNA-bound species as Fe(II)BLM. In contrast, Fe(II)DP-PEPLM forms a different species. These results are consistent with a model in which the beta-aminoalanine primary amine is an iron ligand and the mannose carbamoyl provides either a ligand to the metal or significant second-sphere effects on the ferrous site; intercalation of the bithiazole tail into the DNA double helix likely brings the metal-bound complex close enough to the minor groove to create steric interactions, removing the sugar groups from interaction with the ferrous site. That the Fe(II) active site is perturbed by DNA regardless of sequence may indicate that different reaction coordinates are active depending on drug orientation relative to the helix structure.
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650 # 0 $a Chemistry, Inorganic. $3 197298
650 # 0 $a Chemistry, Biochemistry. $3 226900
710 0 # $a Stanford University. $3 212607
773 0 # $g 64-03B. $t Dissertation Abstracts International
790 $a 0212
790 1 0 $a Solomon, Edward I., $e advisor
791 $a Ph.D.
792 $a 2003
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