Novel natural products, engineering

Understanding the molecular genetics of plant natural product pathways facilitates the engineering of these pathways for plant improvement and human benefit (see Chapter by Halkier et al). This chapter focuses attention on the need to start applying genomics technology to exotic species for development of biotech crops with novel natural products and with improved pest resistance and increased nutritional value. 

Engineering of novel natural products by enzymatic modifications of core skeletons is another method where molecular tools are used to produce a range of novel products with enhanced/modified bioactivity. This is mainly carried out because the distribution of many of these compounds are either restricted or they accumulate at low levels, which is insufficient for large-scale extraction... 

Researchers have started using biosynthetic genes to alter the structure of natural compounds by genetic engineering or to combine genes from different biosynthetic pathways. This new technology named combinatorial biosynthesis results in the formation of novel natural products. 

Shen, B., Liu, W. and Nonaka, K. (2003) Enediyne natural products biosynthesis and prospect towards engineering novel antitumor agents. Current Medicinal Chemistry, 10, 2317. 

Du, L., Sanchez, C. andShen, B. (2001) Hybrid peptide—polyketide natural products biosynthesis and prospects toward engineering novel molecules. Metabolic Engineering, 3 (1), 78—95. 

Figure 13.5 Metabolic engineering of oxime-derived natural products in Arabidopsis plants. Up- and downregulation of endogenous as well as exogenous CYP79s provides a powerful tool for alteration of the glucosinolate profiles and introduction of novel glucosinolates, as well as for engineering oxime-derived natural products.

The novel horizons in natural product chemistry are a consequence of advances in mass spectrometry instrumentation. Current applications comprise the elucidation of natural products as part of total extract mixtures in samples of interest to environmental chemists, archaelogists, paleobotanists, geologists, oceanographers, atmospheric chemists, forensic chemists and engineers. The list of applications is expected to expand and some examples are discussed in this chapter. 

Motivated by the value of these natural products, there has been much research focused on developing guidelines for engineering polyketide synthases to generate natural and novel polyketides [445,446], Additionally, manipulation of the biosynthetic pathways of microbial polyketides through engineering permits the biosynthesis of bioactive polyketides not generated naturally [447,448],... 

Shen B, Liu W, Nonaka K (2003) Enediyne Natural Products Biosynthesis and Prospect Towards Engineering Novel Antitumor Agents. Curr Med Chem 10 2317... 

The discovery of PKSs has led to the emergence of new horizons for the engineered biosynthesis of complex natural product-like molecules. The goals of this chapter are twofold. First, we will summarize our understanding of these systems at a molecular level, and the techniques that have emerged to dissect and manipulate these systems. Second, we will present selected examples of how PKSs can be engineered to synthesize novel biomolecules, and the pharmacological implications of such manipulation. Hopefully it will become clear that, al-... 

Despite this limitation, in vitro biosynthesis using purified biocatalysts promises to be a simple and inexpensive means to access a wealth of complex natural product structures under clean and controlled conditions. The versatility of this technology can be significantly enhanced by the application of genetic engineering to create novel proteins. 

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