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5-Aminolevulinate Synthase and Heme Biosynthesis

5-氨基乙酰丙酸合酶和血红素生物合成

基本信息

批准号：
7008477
负责人：
GLORIA C. FERREIRA
金额：
$ 18.54万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-15 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7008477
关键词：
5 aminolevulinate synthase X ray crystallography active sites catalyst chemical kinetics cofactor conformation enzyme activity enzyme biosynthesis enzyme mechanism enzyme substrate molecular dynamics myelin proteolipid porphyrin biosynthesis protein structure function spectrometry transaminases

项目摘要

DESCRIPTION (provided by applicant): 5-Aminolevulinate synthase (ALAS), a pyridoxal 5'-phosphate (PLP)-dependent enzyme of the alpha-oxoaminesynthase family, catalyzes the first and regulatory step of the mammalian heme biosynthetic pathway. Mutations in the gene encoding the erythroid ALAS isoform cause X-linked sideroblastic anemia (XLSA), an erythropoietic disorder resulting in increased tissue iron levels. The prospect of developing pyridoxine-based therapies of universal efficacy for XLSA relies on the knowledge of the mechanism of ALAS, the cofactor-binding pocket (PLP-fold) and their relationship. It is the design of the active site, entailing the PLP cofactor-protein interaction, that discriminates one type of reaction among the wide gamut of PLP-dependent enzyme-catalyzed reactions. Recent studies in the P.I.'s laboratory on the architecture of the active site and mechanism of ALAS (1996-2002)set the stage for the following 3 hypotheses to be tested: 1. Modulation of the PLP cofactor chemistry controls the enzymatic mechanism of ALAS. 2. Substrate specificity of ALAS can be acquired through minor modifications of the protein scaffold for the ctoxoaminesynthase family of PLP-dependent enzymes, which possesses the same general PLP-binding fold and chemistry of catalysis. 3. The distinct catalytic chemistries of ALAS and glutamate l-semialdehyde aminomutase (GSA-AT), two PLP-dependent enzymes which both produce 5-aminolevulinate (ALA) and play crucial roles in the two natural ALA biosynthetic pathways (e.g., in animals and plants), can be generated by "evolution" of a primary protein scaffold. The proposed studies provide a new strategy to establish structure/function relationships within ALAS and other alpha-oxoamine synthase enzymes. Further, the proposed studies provide a novel approach to understanding how shuffling protein structural domains changes function and how enzyme active sites evolve; this strategy promises to be a key particularly for determining the function of unidentified genes in the human genome.

描述（由申请人提供）：

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional asymmetry for the active sites of linked 5-aminolevulinate synthase and 8-amino-7-oxononanoate synthase.

连接的 5-氨基乙酰丙酸合酶和 8-氨基-7-氧壬酸合酶活性位点的功能不对称。

DOI：
10.1016/j.abb.2011.05.002
发表时间：
2011
期刊：
Archives of biochemistry and biophysics
影响因子：
3.9
作者：
Turbeville,TracyD;Zhang,Junshun;Adams,WChristopher;Hunter,GregoryA;Ferreira,GloriaC
通讯作者：
Ferreira,GloriaC

Conversion of 5-aminolevulinate synthase into a more active enzyme by linking the two subunits: spectroscopic and kinetic properties.

通过连接两个亚基将 5-氨基乙酰丙酸合酶转化为活性更高的酶：光谱和动力学特性。