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waiting113

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The approach to combine genes from different micro¬organisms for the production of new and interesting metabolites has become known as combinatorial biosynthesis. Recent achievements with the polyketide biosynthesis from microorganisms, especially in Streptomyces, prove the potential of combinatorial biosynthesis (Hranueli et al., 2005; Moore et al., 2005; Weber et al., 2003; Pfeifer and Khosla, 2001). It also showed that this approach can be used to improve the biosynthesis capacity of known producing microorganisms like Escherichia coli, Bacillus subtilis or Saccharomyces cerevisiae. The heterologous expression of human genes in microorganisms is well known for more than 30 years now. Fundamental work on the expression of plant genes from biosynthetic pathways, performed since the 1980s, opens a way to similar research that may even be extended in the future by directed evolution. It is now possible to combine these genes and extend the realm of combinatorial biosynthesis far beyond the polyketide biosynthesis. The diversification of products will increase dramatically when genes of very different origins are used. However there is no need to concentrate on new compounds only; there are many interesting natural products, of which the application (e.g. as a drug or fine chemical) is hampered by its availability. This problem might be solved by using alternative production systems yet to be discovered, that are based on enzymes from other biosynthetic pathways.
Nature and its huge biodiversity harbours an endless source of compounds containing unique chemical structures. Even on a species level a given biosynthetic pathway adapts through the continuous selection pressure of its surrounding. Only those compounds that are highly favorable for the producing organism are accumulated, which is a delicate balance between energy cost and physiological/ecological benefit. There are many speculations about how evolution diverges biosynthetic pathways (Pichersky and Gang, 2000). Often the result is that specific compounds are produced by specific organisms. There are certainly products that will not be produced because they cost too much energy to synthesize, their activity is not beneficial enough or the organism lacks the enzyme machinery to perform a specific chemical reaction. In other words, the biodiversity is endless and there are still possibilities to enlarge the diversity from a chemical point of view, by combining genes and products from different sources that in nature would never meet. This strategy will deliver compounds that are not influenced by selection pressures, by a habitat, or the biochemical limitations of an organism (such as compartmen¬talization or storage). These compounds can be selected for a specific pharmaceutical mode of action or an activity can be adjusted to a more specific pharmaceutical demand.
There are several pharmaceuticals on the market that are highly expensive, due to the fact that these compounds are only found in rare plants and often in extreme low concentrations. Podophyllotoxin and paclitaxel (Fig. 1) are clear examples of pharmaceuticals that can only be produced through the isolation from plants. To achieve a sustainable source of such compounds scientists all over the world have been experiment¬ing with biotechnological approaches aiming at the develop¬ment of an alternative production system. With this aim in mind, combinatorial biosynthetic strategies are expected to yield interesting alternatives in the near future. With regard to the production of podophyllotoxin it has been shown that plant cell cultures of Linum flavum L. can be used to convert deoxypodophyllotoxin, a major lignan of Anthriscus sylvestris L. into 6-methoxypodophyllotoxin (Koulman et al., 2003; Van Uden et al., 1997). The combination of the product of one species and the enzymes of another species to yield a desired product is a good example of combinatorial biosynthesis. This topic will be extensively discussed in the following subchapters.
Not only can the expression of a single gene be of interest. The reconstruction of complete biosynthetic pathways by combining genes of the desired pathway in host organisms is the current aim of actual research projects. There are many

papers describing the functional heterologous expression of single genes from biosynthetic pathways. Still in contrast the coupling of more genes and the controlled expression of genes encoding biosynthetic enzymes for metabolising precursors is a challenging approach. Thus far, the biosynthesis of flavonoids in E. coli is the only total heterologous biosynthesis of a plant compound that has been described (Miyahisa et al., 2005a,b), but promising results have been reported already for the biosynthesis of artemisinin (Martin et al., 2003; Lindahl et al., 2006; Ro et al., 2006), paclitaxel (Dejong et al., 2006) and srictosidine (Whitmer, 1999). We will discuss the biosynthesis of specific natural products in detail, and we want to give insight in the basic understanding of the concept of combinatorial biosynthesis of other natural products, which is gaining more and more interest.

2. Definition of combinatorial biosynthesis

The definition of combinatorial biosynthesis has been changed and is still changing because of the rapid developments in molecular biological techniques and innovative strategies applied in this research area. From the past, combinatorial biosynthesis is defined on the metabolic level, using different precursors or further modification of a structural scaffold.
The concept of combinatorial biosynthesis has been introduced from the work with polyketides and oligopeptides. These natural products were model compounds showing that repeated use of the same type of reaction with different precursors like acetyl-CoA units or amino acids can lead to a combined biosynthetic product. The finished peptide or polyketide scaffold can be posttranslational structurally modified. Also this step has been accepted as part of combinatorial biosynthesis. An important example of combi¬natorial biosynthesis on the metabolic level is the development erythromycin analogues (Peiru et al., 2005; Rodriguez and McDaniel, 2001), which are impossibly obtained by synthetic organic chemistry. The scope of combinatorial biosynthesis and the number of structural variants, which can be generated by manipulation of biosynthetic modules, is limited by the specificity of different domains and modules for initiating, extending and terminating the growing chain of the polyketide or the nonribosomal peptide, or even by combinations thereof. To date, combinatorial biosynthesis of natural products has to be defined wider, not focussing the metabolic level only. With the current knowledge of molecular biology, it has become possible to combine genes (thus also the resulting enzymes) and products of different organisms. This can yield a further diversification of both chemical and natural product libraries. Because these strategies have also become known as combinatorial biosynthesis, we define combinatorial biosynth¬esis as the approach to combine genes from different organisms to produce bioactive compounds.
Current research in this field still focuses mainly on the polyketide biosynthesis in microorganisms. But a careful examination of the literature on plant biotechnology reveals that several studies have already been carried out in the past twenty years that can now be called combinatorial biosynthesisas we use the new definition. Due to the strategy of combinatorial chemistry at the beginning of the eighties, which uses a random approach to synthesize novel polymeric or oligomeric chemical entities from uniform monomers (e.g. amino acids), the term combinatorial biosynthesis since the 1990s suggested a random approach and combination of genes in the polyketide or terpenoid biosynthetic pathways using also biosynthetic monomers (e.g. isoprenes, acetyl and propionyl units) from natural origin. Today, we would like to add to this definition the possibility to have directed and controlled combination of genes to produce a desired single compound. At the moment combinatorial biosynthesis of plant secondary metabolites focuses on the reconstruction of the basic pathways into microbial hosts. This review gives a survey of the use of genes and products from plants in combination with genes and products from other organisms. It emphasizes the potential of plant combinatorial biosynthesis for drug discovery and its future importance for pharmaceutical sciences.

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由于分子生物学技术以及这个研究领域所应用的全新策略的迅速发展，组合生物合成学的定义已经并且还将不断改变。过去，组合生物学的定义局限在代谢水平——使用不同的前体或者对一个结构骨架进行进一步的修饰。组合生物学的概念是从有关聚酮化合物和寡肽的工作中引用出来的。这些天然产品是模板化合物，由它们可以看到：利用不同的前体——例如乙酰辅酶A或氨基酸——重复进行相同类型的反应，可以生成一种混合的生物合成产品。最终得到的肽或聚酮骨架可以在结构上进行翻译后修饰。而且这一步骤可以作为组合分子合成学的一个部分。代谢水平的组合分子合成学中一个重要的例子就是红霉素相似物的开发，而这一工作是有机合成所无法完成的。组合生物合成学的范围以及通过操纵生物合成模板所得到的结构变异体的数量，局限于开始、延伸和终止聚酮或非核糖肽段链增长的不同区域和模板的专一性甚至及其化合作用。迄今为止，天然产品组合生物合成学的定义更加宽泛，不再只关注代谢水平了。利用分子生物学中的最新知识，有可能结合基因（以此方式还能结合相应的酶）和不同生物体的产物。这就会带来化学产物和天然产品的进一步多样化。因为这些技术最为组合生物合成学的一部分，也已经受到认可，我们就把组合生物合成学定义为：将不同生物体的基因进行组合，来生产具有生物活性的化合物。最近这个领域的研究工作仍然主要放在微生物体内聚酮的生物合成上面。但是我们仔细查阅了植物生物技术的文献后发现几项二十年前的研究工作如今也可被称为我们所最新定义的组合生物合成学。二十世纪八十年代初的化学组合学技术利用随机方法，由统一的单体（如氨基酸）合成全新的多聚或低聚化学体；二十世纪九十年代，组合生物合成学这一术语是指一种随机方法，或者是聚酮或类萜的生物合成途径中的基因组合——这一途径利用了同样由天然来源进行生物合成所得到的单体（例如异戊二烯、乙酰和丙酰单位）”。如今，我们还可以在这一定义中加入如下内容：对基因进行直接组合并对此过程加以控制，从而生产出所需的单一化合物的可能性。此刻，植物二级代谢产物的组合生物合成学致力于重组到生物宿主中的基础路径。这篇评论概括叙述了利用植物基因或者产品跟其他生物体的基因和产品进行组合，并强调了植物组合生物合成学在药物研发中的潜力以及未来在药剂学中的重要性。

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3楼2008-01-17 08:48:34

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从组合不同微生物基因来生产新代谢产物的途径称为组合生物合成。近来，从微生物尤其是链霉菌，生物合成聚酮化合物的进展，证实了组合生物合成的潜力。(Hranueli et al., 2005; Moore et al., 2005; Weber et al., 2003; Pfeifer and Khosla, 2001). 它也表明此种途径能够用于提升已知源型微生物，如大肠杆菌，枯草杆菌或者酿酒酵母菌的生物合成能力。人类基因在微生物的外源表达已经数为人知30多年。从八几年开始的从生物合成途径来表达植物基因的基础工作，打开了一个类似的研究方法，甚至可能在未来得到更大范围的应用。现在有可能组合这些基因，而且组合生物合成的领域，将远远不止限于聚酮化合物的生物合成。当极为不同的源性基因得到应用时，产品的多样化将戏剧性地剧增。但没有必要只关注于新的化合物。还有许多人们感兴趣的天然产物，其可利用性阻碍了它们的应用（如作为药物或者精细化工品）。这个问题可能通过应用其它基于其它生物合成途径的酶的生产体系来解决，而这种生产体系还需要进行探索。

[ Last edited by redanqi999 on 2008-1-17 at 09:21 ]

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