Ferrer J-L, Austin M B, Stewart C, Noel J P
Institut de Biologie Structurale, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Université Joseph Fourier, Groupe Synchrotron, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France.
Plant Physiol Biochem. 2008 Mar;46(3):356-70. doi: 10.1016/j.plaphy.2007.12.009. Epub 2007 Dec 31.
As a major component of plant specialized metabolism, phenylpropanoid biosynthetic pathways provide anthocyanins for pigmentation, flavonoids such as flavones for protection against UV photodamage, various flavonoid and isoflavonoid inducers of Rhizobium nodulation genes, polymeric lignin for structural support and assorted antimicrobial phytoalexins. As constituents of plant-rich diets and an assortment of herbal medicinal agents, the phenylpropanoids exhibit measurable cancer chemopreventive, antimitotic, estrogenic, antimalarial, antioxidant and antiasthmatic activities. The health benefits of consuming red wine, which contains significant amounts of 3,4',5-trihydroxystilbene (resveratrol) and other phenylpropanoids, highlight the increasing awareness in the medical community and the public at large as to the potential dietary importance of these plant derived compounds. As recently as a decade ago, little was known about the three-dimensional structure of the enzymes involved in these highly branched biosynthetic pathways. Ten years ago, we initiated X-ray crystallographic analyses of key enzymes of this pathway, complemented by biochemical and enzyme engineering studies. We first investigated chalcone synthase (CHS), the entry point of the flavonoid pathway, and its close relative stilbene synthase (STS). Work soon followed on the O-methyl transferases (OMTs) involved in modifications of chalcone, isoflavonoids and metabolic precursors of lignin. More recently, our groups and others have extended the range of phenylpropanoid pathway structural investigations to include the upstream enzymes responsible for the initial recruitment of phenylalanine and tyrosine, as well as a number of reductases, acyltransferases and ancillary tailoring enzymes of phenylpropanoid-derived metabolites. These structure-function studies collectively provide a comprehensive view of an important aspect of phenylpropanoid metabolism. More specifically, these atomic resolution insights into the architecture and mechanistic underpinnings of phenylpropanoid metabolizing enzymes contribute to our understanding of the emergence and on-going evolution of specialized phenylpropanoid products, and underscore the molecular basis of metabolic biodiversity at the chemical level. Finally, the detailed knowledge of the structure, function and evolution of these enzymes of specialized metabolism provide a set of experimental templates for the enzyme and metabolic engineering of production platforms for diverse novel compounds with desirable dietary and medicinal properties.
作为植物次生代谢的主要组成部分，苯丙烷生物合成途径可提供用于色素沉着的花青素、用于抵御紫外线光损伤的黄酮类化合物（如黄酮）、多种诱导根瘤菌结瘤基因的黄酮类和异黄酮类化合物、用于结构支撑的聚合木质素以及各种抗菌植物抗毒素。作为富含植物的饮食成分和各类草药制剂，苯丙烷类化合物具有显著的癌症化学预防、抗有丝分裂、雌激素、抗疟疾、抗氧化和抗哮喘活性。饮用红酒对健康有益，红酒中含有大量的3,4',5-三羟基芪（白藜芦醇）和其他苯丙烷类化合物，这凸显了医学界和广大公众对这些植物衍生化合物潜在饮食重要性的认识不断提高。就在十年前，人们对这些高度分支的生物合成途径中所涉及酶的三维结构还知之甚少。十年前，我们启动了对该途径关键酶的X射线晶体学分析，并辅以生化和酶工程研究。我们首先研究了黄酮类途径的起始点查尔酮合酶（CHS）及其近亲芪合酶（STS）。随后很快开展了对参与查尔酮、异黄酮和木质素代谢前体修饰的O-甲基转移酶（OMT）的研究。最近，我们团队及其他团队将苯丙烷途径结构研究的范围扩大到包括负责苯丙氨酸和酪氨酸初始招募的上游酶，以及一些苯丙烷衍生代谢物的还原酶、酰基转移酶和辅助修饰酶。这些结构-功能研究共同提供了苯丙烷代谢一个重要方面的全面视图。更具体地说，这些对苯丙烷代谢酶的结构和作用机制基础的原子分辨率见解有助于我们理解特定苯丙烷产物的出现和持续进化，并强调了化学层面代谢生物多样性的分子基础。最后，这些次生代谢酶的结构、功能和进化的详细知识为生产具有理想饮食和药用特性的各种新型化合物的酶和代谢工程提供了一组实验模板。
