STRUCTURAL AND MECHANISTIC STUDY OF SIROHEME SYNTHASE

西罗血红素合成酶的结构和机理研究

• 批准号: 2518213
• 负责人: HEIDI L SCHUBERT
• 金额: $ 2.14万
• 依托单位: UNIVERSITY OF YORK
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2518213
• 关键词: X ray crystallography; active sites; cofactor; enzyme mechanism; enzyme structure; enzyme substrate; metalloporphyrins; methyltransferase; site directed mutagenesis

Tetrapyrrolic cofactors participate in many critical cellular functions such as respiration (heme), photosynthesis (chlorophyll), sulfite and nitrite reduction (siroheme) and mammalian methionine synthesis (vitamin B12). In humans, a vitamin B12 deficiency contributes to the disease pernicious anemia, and the inappropriate build up of heme precursors causes various types of skin and blood disorders called porphyrias. The complex biosynthetic pathways of these cofactors start with common precursors, and branch at various stages of modification, with the longest and most complex pathway belonging to vitamin Bl2 (Scott, 1993; Battersby, 1994). One multifunctional enzyme participates at the crossroads of vitamin Bl2 and siroheme biosynthesis, siroheme synthase. This enzyme is responsible for three separate enzymatic reactions, porphyrin ring methylation, dyhdrogenation, and iron chelation. The three dimensional structure of siroheme synthase will be solved by X-ray diffraction techniques. Substrate and cofactor complexes will provide a detailed view of the critical interactions necessary for ligand binding. The catalytic mechanism will be probed by site directed mutagenesis to determine the function of residues identified in the structure to hold critical positions around the active sites.

四吡咯辅因子参与许多关键细胞功能 例如呼吸作用（血红素）、光合作用（叶绿素）、亚硫酸盐 亚硝酸盐还原（siroheme）和哺乳动物蛋氨酸合成（维生素 B12）。在人类中，维生素B12缺乏会导致这种疾病。 恶性贫血和血红素前体的不适当积累 导致各种皮肤和血液疾病，称为卟啉症。的 这些辅因子的复杂生物合成途径始于共同的 前体，和分支在不同阶段的修改，最长的 和属于维生素B12的最复杂的途径（Scott，1993;巴特斯比， 1994年）。一种多功能酶参与了 维生素B12与西罗血红素生物合成、西罗血红素合成酶。这种酶 负责三个独立的酶促反应，卟啉环 甲基化、脱氢和铁螯合。三维 西罗血红素合酶的结构将通过X射线衍射来解决 技术.底物和辅因子复合物将提供详细的视图 配体结合所必需的关键相互作用。催化 将通过定点突变来探索机制，以确定 在结构中鉴定的残基的功能， 活动场地周围的位置。