Arthur Kornberg

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We have switched the focus of our research from DNA replication to an entirely new subject: inorganic polyphosphate (poly P). Poly P is a linear polymer of many tens or hundreds of orthophosphate (Pi) residues linked by high-energy, phosphoanhydride bonds. Likely a prominent precursor in prebiotic evolution, poly P is now found in volcanic condensates, deep-oceanic steam vents and in every living thing-bacteria, fungi, protozoa, plants and mammals. Ignored in textbooks and dismissed as a "molecular fossil," our mission is to bring this molecule back to life and demonstrate that poly P is truly a "molecule for many reasons."

Numerous and varied biological functions are performed by poly P depending on the need and where it is needed-the species, cell, and subcellular compartment. Among these functions are: reservoirs of energy and phosphate, chelation of metals (e.g., Mn2+, Ca2+), buffer against alkali, capsule of bacteria, competence for bacterial transformation, ecological disposal of pollutant phosphate, and, of great interest, physiologic adjustments to growth, development, stress and deprivation.

Our approach is to discover the enzymes for the synthesis and utilization of poly P in bacteria, yeast and animal cells. These enzymes will reveal novel mechanisms and insights and when purified will open the route of reverse genetics: the peptide sequence leads to the gene and thereby the means to knock it out and overexpress it. By manipulating expression of the gene and the cellular levels of its product, phenotypes are created which provide clues to metabolic functions. Most immediate and decisive, the enzymes provide unique and invaluable reagents for analytic and preparative work.

Among the several current directions are:

DNA entry into cells: The mechanism whereby the inclusion of poly P in a membrane complex enables a cell to become competent to take up DNA and then genetically transformed.

Survival in the stationary phase: The basis for poly P regulation of cellular responses to stresses and adjustments for survival in the stationary phase of culture growth and development. In view of the universality and complexity of basic biochemical mechanisms, it would be surprising if some of the variety of poly P functions already observed in microorganisms did not apply to aspects of human growth and development, to aging and to the aberrations of disease.

Regulation of development: Developmental changes in microorganisms-fruiting body and spore formation in Myxobacteria (e.g., M. xanthus), sporulation in bacteria (e.g., Bacillus) and fungi, and heterocyst formation in cyanobacteria (e.g., Anabaena)-occur in response to starvation of one or another nutrient. In view of the involvement of poly P in the stationary stage of E. coli, poly P may well participate in other instances of cellular adjustments to deprivation.

Kornberg, A. (Nov. 1996) Essay for the Electronic Nobel Museum: "Basic Research, The Lifeline of Medicine."

Kumble, K., Ahn, A. and Kornberg, A. (1996) "Phosphohistidyl active sites in polyphosphate kinase of Escherichia coli." PNAS 93, 14391-14395.

Kumble, K. and Kornberg, A. (1996) "Endopolyphosphatases for Long Chain Inorganic Polyphosphate in Yeast and Mammals." J.Biol.Chem. 271, 27146-27151.

Kuroda, A. and Kornberg, A. (1997) "Polyphosphate kinase as a nucleoside diphosphate kinase in Escherichia coli and Pseudomonas aeruginosa" PNAS, 94, 439-442.

Kuroda, A. , Murphy, H., Cashel, M. and Kornberg, A. (1997) "Guanosine Tetra- and Pentaphosphate Promote Accumulation of Inorganic Polyphosphate in Escherichia coli" J.Biol.Chem. 272, 21240-21243.

Shiba, T., Tsutsumi, K., Yano, H., Ihara, Y., Kameda, A., Tanaka, K., Takahashi, H., Munekata, M., Rao, N. and Kornberg, A. (1997) "Inorganic polyphosphate and the induction of rpoS expression." PNAS, 94, 11210-11215.

Kornberg, A. (1997) An Essay for TIBS: "Centenary of the Birth of Modern Biochemistry." (Printed in August, 1997).

Kornberg, A. (1997) Commentary: "Science and Medicine at the Millennium." Biochemical and Molecular Medicine, 61, 121-126; Academic Press.

Severo Ochoa article for Proceedings of the American Philosophical Society, 141, 479-491.

Kornberg, A. (1997) "The NIH Did It" - Editorial in Science magazine 278, 1863.

Kornberg, A. (1997) - "Centenary of the Birth of Modern Biochemistry" December 1997 FASEB Journal, 11, 1209-1214.

Kornberg, A. (1997) "Science and medicine at the millennium" - Brazilian Journal of Medical and Biological Research ( September 1997) 30, 1379-1386.

Kim, H.-Y., Schlictman, D., Shankar, S., Xie, Z., Chakrabarty, A.M. and Kornberg, A. (1998) "Alginate, Inorganic polyphosphate, GTP and ppGpp synthesis coregulated in Pseudomonas aeruginosa: Implications for stationary phase survival and synthesis of RNA/DNA precursors." Molecular Microbiology, 27, 717-725.

Ault-Richi, D., Fraley, C. D., Tzeng, C.-M. and Kornberg, A. (1998) "Novel Assay Reveals Multiple Pathways Regulating Stress-induced Accumulations of Inorganic Polyphosphate in Escherichia coli/"J. of Bacteriology, 180, 1841-1847.

Tzeng, C.-M. and Kornberg, A. (1998) "Polyphosphate Kinase is Highly Conserved in Many Bacterial Pathogens." Molecular Microbiology, 29, 381-382.

Rao, N. N., Liu, S. and Kornberg, A. (1998) "Inorganic Polyphosphate in Escherichia coli. I. The Phosphate Regulon and the Stringent Response." J. of Bacteriology, 180, 2186-2193.