Biosynthesis of Heme and Chlorophyll Precursors

血红素和叶绿素前体的生物合成

• 批准号: 9808578
• 负责人: Samuel Beale
• 金额: $ 30万
• 依托单位: Brown University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9808578&HistoricalAwards=false
• 关键词: Biosynthesis; Heme; Chlorophyll; Precursors

BealeTetrapyrrole pigments comprise a family of biomolecules including hemes, chlorophylls, bilins, and vitamin B12- These pigments function as essential components in the processes of respiration and photosynthesis, and also exist as cofactors in other important enzyme reactions. All tetrapyrroles arise from a branched biosynthetic pathway that has (-aminolevulinic acid (ALA) as its first universal committed intermediate. The long-term goals of this project are to determine the structures, mechanisms of action, and regulation of the enzymes that catalyze ALA formation and metabolism in plants and algae, and to understand how ALA formation controls the photosynthetic pigment content of these organisms. Recent progress has exploited the unique genetic and biochemical potentials of the unicellular alga Chlamydomonas reinhardtii toward achieving these goals. Three Chlamydomonas genes, gtr, gsa, and alad, that encode enzymes which catalyze the first three steps of tetrapyrrole biosynthesis (glutamyl-tRNA reductase, glutamate 1-semialdehyde aminotransferase, and ALA dehydratase, respectively) have been cloned from Chlamydomonas. It is planned to express the cloned gtr gene which catalyzes the key, initial step of ALA formation, to obtain sufficient quantities of its product to be used for characterization of its physical and kinetic properties, cofactor content and requirements, reaction mechanism, possible interactions with other enzymes, and regulation of activity by allosteric effectors.The importance of understanding the biosynthesis of ALA lies in its position as the initial universal metabolite in the diversion of cellular metabolites toward tetrapyrrole end products, and therefore the likely exercise of metabolic control over cellular pigment content by regulation of ALA formation. Moreover, the fact that ALA biosynthesis in all plants and most bacteria differs from that in animals suggests that it may be possible to develop herbicides and antibiotics that specifically target steps in the ALA biosynthetic pathway, and which are nontoxic to animals. Rational progress in this area will require a thorough knowledge of the five-carbon ALA biosynthetic pathway. Although herbicide and antibiotic development are not objectives of the proposed research, they serve to illustrate aspects of the potential longer-term significance of this research for human welfare.

Beale四吡咯色素包括一个生物分子家族，包括血红素、叶绿素、胆色素和维生素B12。这些色素在呼吸和光合作用过程中起重要作用，也作为其他重要酶反应的辅助因子存在。所有的四吡咯都来自一个分支的生物合成途径，该途径具有α-氨基乙酰丙酸（ALA）作为其第一个通用的定向中间体。该项目的长期目标是确定植物和藻类中催化ALA形成和代谢的酶的结构，作用机制和调节，并了解ALA形成如何控制这些生物体的光合色素含量。最近的进展已经利用了单细胞衣藻的独特的遗传和生化潜力来实现这些目标。已从衣原体中克隆了三个衣原体基因gtr、gsa和alad，它们编码催化四吡咯生物合成的前三步的酶（分别为谷氨酰-tRNA还原酶、谷氨酸1-半醛氨基转移酶和ALA脱氢酶）。计划表达催化ALA形成的关键初始步骤的克隆gtr基因，以获得足够量的其产物，用于表征其物理和动力学性质、辅因子含量和要求、反应机制、与其他酶的可能相互作用，了解ALA生物合成的重要性在于它作为生物合成中最初的通用代谢物的地位，细胞代谢物转向四吡咯终产物，因此可能通过调节ALA形成对细胞色素含量进行代谢控制。此外，ALA在所有植物和大多数细菌中的生物合成与动物中的生物合成不同的事实表明，有可能开发出专门针对ALA生物合成途径中的步骤的除草剂和抗生素，并且对动物无毒。这一领域的合理进展将需要对五碳ALA生物合成途径的透彻了解。虽然除草剂和抗生素的开发不是拟议研究的目标，但它们有助于说明这项研究对人类福利的潜在长期意义。