Sunday, August 30, 2009

Understand the Basics of Metabolic Engineering

A powerful new approach to product development is the creative application of fermentation technology and molecular biology for "metabolic engineering." Examples of metabolic engineering for heterologous-protein production include deletion of proteases that eliminate product and production of factors that facilitate product maturation and secretion. For protein production on an industrial scale, metabolic engineering could be useful in shifting metabolic flow toward a desired product, creating arrays of enzymatic activities for synthesis of novel structures, and accelerating rate-limiting steps. Metabolic engineering has recently been used to increase the efficiency of nutrient assimilation (increasing the growth rate), improve the efficiency of ATP production (decreasing nutrient demands), and reduce the production of inhibitory end products (increasing final cell densities).

Central to molecular modification of multigene pathways, such as those involved in antibiotic production, is the development of new vectors and transformation procedures and other tools of molecular biology. Another important discovery in metabolic engineering is the isolation of positive-control genes that regulate production of secondary metabolites. Positive regulators have been found in biosynthetic gene clusters for actinorhodin, bialophos, streptomycin, and undecylprodigiosin, all of which are Streptomyces products.

Genes encoding the converting enzymes D-amino acid oxidase and cephalosporin acylase were cloned from Fusarium and Pseudomonas, respectively, into the fungus Acremonium chrysogenum. Expression of this "artificial" antibiotic biosynthetic pathway was confirmed by analysis of transformants that synthesized and secreted detectable amounts of 7- aminocephalosporanic acid.

In addition to classical mutation, new tools have become available for genetic manipulation of important producers of natural products, such as Streptomyces. The ability to clone and manipulate biosynthetic genes for antibiotic production, regulatory genes for improved synthesis, and genes from primary metabolic pathways that contribute to secondary biosynthetic pathways can facilitate construction of strains that have substantially altered metabolic properties. In addition, the cloning of heterologous genes into bacterial hosts has generated strains that can produce compounds that are foreign and even
Deleterious to cell physiology.

Tags: Bio Technology, Bio Genetics, Bio Process Engineering

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