An expanded role for microbial physiology in metabolic engineering and functional genomics: moving towards systems biology.

Microbial physiology has traditionally played a very important role in both fundamental research and in industrial applications of microorganisms. The classical approach in microbial physiology has been to analyze the role of individual components (genes or proteins) in the overall cell function. With the progress in molecular biology it has become possible to optimize industrial fermentations through introduction of directed genetic modification - an approach referred to as metabolic engineering. Furthermore, as a consequence of large sequencing programs the complete genomic sequence has become available for an increasing number of microorganisms. This has resulted in substantial research efforts in assigning function to all identified open reading frames - referred to as functional genomics. In both metabolic engineering and functional genomics there is a trend towards application of a macroscopic view on cell function, and this leads to an expanded role of the classical approach applied in microbial physiology. With the increased understanding of the molecular mechanisms it is envisaged that in the future it will be possible to describe the interaction between all the components in the system (the cell), also at the quantitative level, and this is the goal of systems biology. Clearly this will have a significant impact on microbial physiology as well as on metabolic engineering.

[1]  J. Nielsen,et al.  Metabolic Engineering of Saccharomyces cerevisiae , 2000, Microbiology and Molecular Biology Reviews.

[2]  M. Reuss,et al.  In VivoDynamics of the Pentose Phosphate Pathway inSaccharomyces cerevisiae , 1999 .

[3]  L. Gautier,et al.  Comparative Genomics of Listeria Species , 2001, Science.

[4]  J. Bailey,et al.  Toward a science of metabolic engineering , 1991, Science.

[5]  James R. Knight,et al.  A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae , 2000, Nature.

[6]  E. Papoutsakis Express together and conquer , 1998, Nature Biotechnology.

[7]  D. Botstein,et al.  Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF , 2001, Nature.

[8]  Barbara M. Bakker,et al.  In Vivo Analysis of the Mechanisms for Oxidation of Cytosolic NADH by Saccharomyces cerevisiaeMitochondria , 2000, Journal of bacteriology.

[9]  Ute Roessner,et al.  Simultaneous analysis of metabolites in potato tuber by gas chromatography-mass spectrometry. , 2000 .

[10]  Roger E Bumgarner,et al.  Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. , 2001, Science.

[11]  J. Pronk,et al.  Steady-state and transient-state analysis of growth and metabolite production in a Saccharomyces cerevisiae strain with reduced pyruvate-decarboxylase activity. , 1999, Biotechnology and bioengineering.

[12]  J. Nielsen,et al.  Quantitative analysis of Penicillium chrysogenum Wis54-1255 transformants overexpressing the penicillin biosynthetic genes. , 2001, Biotechnology and bioengineering.

[13]  B. Palsson,et al.  Saccharomyces cerevisiae phenotypes can be predicted by using constraint-based analysis of a genome-scale reconstructed metabolic network , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B O Palsson,et al.  Metabolic modeling of microbial strains in silico. , 2001, Trends in biochemical sciences.

[15]  James E. Bailey,et al.  Lessons from metabolic engineering for functional genomics and drug discovery , 1999, Nature Biotechnology.

[16]  C. Scazzocchio,et al.  Carbon catabolite repression in Aspergillus nidulans: a review , 1995 .

[17]  J. Pronk,et al.  The Saccharomyces cerevisiae ICL2 Gene Encodes a Mitochondrial 2-Methylisocitrate Lyase Involved in Propionyl-Coenzyme A Metabolism , 2000, Journal of bacteriology.

[18]  Jens Nielsen,et al.  Increasing galactose consumption by Saccharomyces cerevisiae through metabolic engineering of the GAL gene regulatory network , 2000, Nature Biotechnology.

[19]  J. Gancedo Yeast Carbon Catabolite Repression , 1998, Microbiology and Molecular Biology Reviews.

[20]  D. Cove,et al.  Nitrogen metabolite repression in Aspergillus nidulans , 1973, Molecular and General Genetics MGG.

[21]  B. Palsson,et al.  The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Reuss,et al.  In vivo dynamics of the pentose phosphate pathway in Saccharomyces cerevisiae. , 1999, Metabolic engineering.

[23]  D. Kell,et al.  A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations , 2001, Nature Biotechnology.

[24]  J. Nielsen,et al.  Network Identification and Flux Quantification in the Central Metabolism of Saccharomyces cerevisiae under Different Conditions of Glucose Repression , 2001, Journal of bacteriology.

[25]  Mark Johnston,et al.  Function and Regulation of Yeast Hexose Transporters , 1999, Microbiology and Molecular Biology Reviews.

[26]  M. Reuss,et al.  In vivo analysis of metabolic dynamics in Saccharomyces cerevisiae: II. Mathematical model. , 1997, Biotechnology and bioengineering.

[27]  M. Reuss,et al.  In vivo analysis of metabolic dynamics in Saccharomyces cerevisiae : I. Experimental observations. , 1997, Biotechnology and bioengineering.

[28]  Kaspar von Meyenburg,et al.  Katabolit-Repression und der Sprossungszyklus von Saccharomyces cerevisiae , 1969 .

[29]  W. Wiechert 13C metabolic flux analysis. , 2001, Metabolic engineering.

[30]  J. Nielsen,et al.  Physiological characterisation of recombinant Aspergillus nidulans strains with different creA genotypes expressing A. oryzae alpha-amylase. , 2002, Journal of biotechnology.

[31]  B. Palsson The challenges of in silico biology , 2000, Nature Biotechnology.

[32]  R. Schoenfeld,et al.  Comparative Genomics of Listeria Species , 1976 .

[33]  J. Kelly,et al.  Null alleles of creA, the regulator of carbon catabolite repression in Aspergillus nidulans. , 1997, Fungal genetics and biology : FG & B.

[34]  U. Sauer,et al.  Central carbon metabolism of Saccharomyces cerevisiae explored by biosynthetic fractional (13)C labeling of common amino acids. , 2001, European journal of biochemistry.

[35]  B. Palsson,et al.  Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. , 2003, Genome research.

[36]  J. Nielsen,et al.  Glucose control in Saccharomyces cerevisiae: the role of Mig1 in metabolic functions. , 1998, Microbiology.

[37]  J. Kelly,et al.  Cloning of the creA gene from Aspergillus nidulans: a gene involved in carbon catabolite repression , 1989, Current Genetics.

[38]  Jens Nielsen,et al.  Identification of Enzymes and Quantification of Metabolic Fluxes in the Wild Type and in a Recombinant Aspergillus oryzae Strain , 1999, Applied and Environmental Microbiology.

[39]  J. Pronk,et al.  Regulation of pyruvate metabolism in chemostat cultures of Kluyveromyces lactis CBS 2359 , 2000, Yeast.

[40]  J. Kelly,et al.  Analysis of the creA gene, a regulator of carbon catabolite repression in Aspergillus nidulans , 1991, Molecular and cellular biology.

[41]  R. Brent,et al.  Modelling cellular behaviour , 2001, Nature.

[42]  J J Heijnen,et al.  Energetics of growth and penicillin production in a high-producing strain of Penicillium chrysogenum. , 2001, Biotechnology and bioengineering.