Molecular Characterization of Human Tryptophan Hydroxylase 2 (hTPH2)

人色氨酸羟化酶 2 (hTPH2) 的分子表征

基本信息

批准号：
7901201
负责人：
KENT E VRANA
金额：
$ 6.79万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901201
关键词：
Active Sites Address Amino Acid Substitution Amino Acids Anabolism Area Aromatic Amino Acids Base Sequence Biochemical Biogenic Amines Biological Assay Catecholamines Cell Culture Techniques Code Crystallography Data Development Disease Enzymatic Biochemistry Enzyme Stability Enzymes Functional RNA Funding Genes Genetic Polymorphism Goals Grant Health Human Image Kinetics Knowledge Laboratories Mammalian Cell Maps Mental Health Mental disorders Mixed Function Oxygenases Modeling Molecular Molecular Models Mutagenesis Mutation N-terminal Nervous system structure Neuraxis PC12 Cells Peripheral Phenylalanine Phosphorylation Site Positioning Attribute Publishing Recombinant Proteins Recording of previous events Regulation Research Personnel Role Seminal Serotonin Silent Mutation Site Structure Structure-Activity Relationship Substance abuse problem TDO2 gene Testing Time Tryptophan Tryptophan 5-monooxygenase Tyrosine Tyrosine 3-Monooxygenase Variant Work base depression design enzyme activity gene discovery human tryptophan hydroxylase 2 inhibitor/antagonist insight molecular modeling mutant novel programs research study

项目摘要

DESCRIPTION (provided by applicant): Tryptophan hydroxylase (TPH) catalyzes the initial and rate-limiting step in the biosynthesis of serotonin. As such, it has been implicated in a variety of mental health disorders. One of the goals of this long-standing R01 has been to better understand this pivotal enzyme. However, in the midst of the preceding cycle, other investigators (and current collaborators) made the seminal discovery of a new variant of this enzyme (encoded by a separate gene) that is responsible for central nervous system serotonin synthesis - TPH2. Given that the work in this field had to this point focused on the peripheral enzyme (now termed TPH1), and given the importance of CNS serotonin to health and disease, we propose shifting the emphasis of this upcoming renewal period to better understanding this novel and pivotal enzyme. Virtually nothing is known about the structure, function, and enzymology of hTPH2. Partnering with the discoverers of this new enzyme, we have established important new characterization studies on the human TPH2 (hTPH2). We are strongly positioned to pursue three specific aims in the present proposal. Specific Aim 1 will characterize the functional consequences of naturally-occurring polymorphisms in the hTPH2 gene. In the few short years since discovery of the TPH2 gene, seven different coding region polymorphisms have been described. Little is known concerning the consequences of these amino acid substitutions and this aim will address this gap in our knowledge. Aim 2 will use data we have obtained from tyrosine hydroxylase and hTPH1 to map the active site of hTPH2. These biochemical studies will provide important functional insights into this novel and important enzyme. Specific Aim 3 will explore the regulation of hTPH2 by its N-terminal regulatory domain. These experiments will contribute to our knowledge of the dynamic regulation of serotonin biosynthesis in health and disease. The novel hTPH2 gene was first described three years ago. Its discovery resolves several important discprepancies in the field of serotonin biosynthese. However, we must establish a deeper understanding of this pivotal enzyme to better appreciate its role in health and disease and to provide a basis for potential development of novel pharmacotherapeutics.

描述（由申请人提供）：色氨酸羟化酶（TPH）催化5-羟色胺生物合成的初始和限制步骤。因此，它与各种心理健康障碍有关。这个长期存在的R01的目标之一就是更好地了解这种关键酶。但是，在上一个周期的中间，其他研究人员（和当前的合作者）的开创性发现了该酶的新变体（由单独的基因编码），该酶负责中枢神经系统5-羟色胺合成-TPH2。鉴于该领域的工作必须集中在外围酶（现称为TPH1）上，并且考虑到中枢神经系统5-羟色胺对健康和疾病的重要性，我们提出了改变这一即将到来的更新时期的重点，以更好地理解这一小说和可笑的酶。实际上，HTPH2的结构，功能和酶学几乎一无所知。与这种新酶的发现者合作，我们已经建立了有关人类TPH2（HTPH2）的重要新特征研究。在本提案中，我们有力地追求三个具体目标。特定的目标1将表征HTPH2基因中自然出现多态性的功能后果。在发现TPH2基因以来的短短几年中，已经描述了七个不同的编码区多态性。关于这些氨基酸取代的后果知之甚少，这一目标将在我们的知识中解决这一差距。 AIM 2将使用我们从酪氨酸羟化酶和HTPH1获得的数据来绘制HTPH2的活性位点。这些生化研究将为这种新颖而重要的酶提供重要的功能见解。具体目标3将探索其N末端调节域对HTPH2的调节。这些实验将有助于我们了解健康和疾病中5-羟色胺生物合成的动态调节。新颖的HTPH2基因是三年前首次描述的。它的发现解决了5-羟色胺生物合成领域的几个重要疾病。但是，我们必须对这种关键酶建立更深入的了解，以更好地欣赏其在健康和疾病中的作用，并为新型药物治疗的潜在发展提供基础。