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Structure and Function of Tryptophan Hydroyylase

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abstract
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, and is a member of a family of enzymes known as aromatic amino acid hydroxylases (AAAH). Studies into the regulation, structure, and function of TPH have lagged behind those of the other AAAH. In the absence of an experimentally-determined crystal structure, we generated a hypothetical model of human TPH using multiple sequence alignment homology-based molecular modeling of the other AAAH. We then performed site-directed mutagenesis to identify functional domains within the TPH protein, and to validate the hypothetical model. Our studies demonstrated that tyrosine 235 plays a role in tryptophan substrate interactions in the active site, and that serine 58 and serine 260 are substrates for Ca2+/calmodulin-dependent protein kinase II. Additional studies analyzed a coding region polymorphism in human TPH, a subtle valine to isoleucine substitution at residue 177 (V177I). Our studies suggest that this residue is involved in the optimal orientation of the tryptophan substrate binding pocket in the TPH active site. These studies have added to our understanding of the structure and function of TPH.Using this type of information, novel TPH-specific pharmacotherapies may be developed for use in the treatment of serotonergic disorders in human health and disease.
subject
hydroxylase
phenylalanine
serotonin
tryptophan
tyrosine
contributor
Jiang, George Chih-Thai (author)
George_Chih-Thai_Jiang@alumni.wfu.edu (authorEmail)
Linda C. McPhail (committee chair)
Leslie B. Poole (committee member)
Mark O. Lively (committee member)
William E. Sonntag (committee member)
Kent E. Vrana (committee member)
creator
Jiang, George Chih-Thai
date
2008-09-28T10:52:09Z (accessioned)
2010-06-18T18:57:22Z (accessioned)
2004-12-21 (available)
2008-09-28T10:52:09Z (available)
2010-06-18T18:57:22Z (available)
2003 (issued)
degree
null (defenseDate)
Molecular Genetics (discipline)
Wake Forest University (grantor)
MS (level)
identifier
jianggct_05_2003.pdf
http://hdl.handle.net/10339/14689 (uri)
migration
etd-05302003-110429 (oldETDId)
rights
Release the entire work for access only to the Wake Forest University system for one year from the date of approval. After one year, release the entire work for access worldwide, unless I send notification to delay release. (accessRights)
I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Wake Forest University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. (license)
title
Structure and Function of Tryptophan Hydroyylase

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