Professor and Chair of Chemistry

Ph.D., 1987, University of Southampton

Postdoctoral Fellowship (1987-1989) University of Washington 

Email: reynoldsk@pdx.edu
Phone: 503-725-3886

Curriculum Vitae

Research

One of our major research areas is centered around microorganisms that produce secondary metabolites or natural products. These compounds find widespread use including antibiotics, immunosuppressants, anticancer agents, and antiparasitic agents. The carbon skeleton core of many of these compounds areproduced by polyketide synthases (PKSs).  We are studying these complex fascinating biosynthetic processes at both the genetic and enzymatic level.  Acombination of genetic techniques, including molecular breeding and in vivo recombination, are being used to generate engineered microorganisms in which the natural biosynthetic process of interest has been diverted, in some cases through the use of catalytically efficient hybrid PKSs.  In combination with chemoenzymatic approaches and precursor-directed mutasynthesis we are producing a wide range of new natural products with various of biological activities.  Currently we are interested in  phoslactomycin and fostriecin (antitumor agents), hygromycin A and pikromycin (antibacterial agents) and prodiginines (red pigmented compounds withinteresting immunosuppressant and antitumor activites). We also study the primary metabolic pathways which provide the necessary precursors for assembling natural products.   We have shown that manipulation of these processes affect the ratio and yields of natural product in a fermentation process.  Currently we deciphering the importance of competing precursor pathways in mutagenized industrial strains under fermentation conditions which produce high titers of the natural product.  We are also utilizing these strains as super hosts for heterologous expression of natural product biosynthetic processes where fermentation yields from the native microorganism are a limiting factor. 

Our second area of research interest is the pathway of plant and bacterial fatty acid biosynthesis, catalyzed by type II fatty acid synthases (FASs). The unique features of this pathway, and of enzyme specific to this process have attracted considerable interest as both targets for both antibiotic development and engineering altered oil composition in bacteria and transgenic plants. 3-Ketoacyl ACP synthase III (KASIII) initiates fatty acid biosynthesis in this process by catalyzing a condensation between an acyl CoA and a malonyl ACP substrate. We are actively investigating differentKASIII enzymes from Staphylococci aureus, Escherichia coli, and Mycobacterium tuberculosis (the organism that causes tuberculosis) and Plasmodial falciparum (the parasite responsible for malaria). We are using mutagenesis, molecular modeling, kinetic analyses and X-ray diffraction to probe the mechanism and varying substrate specificities of these enzymes. We have crystallized and solved the structure of the M. tuberculosis KASIII, believed to play a critical role in initiating mycolate biosynthesis in this pathogenic microorganism. We have designed and synthesized several series of selective synthetic KASIII inhibitors and are using techniques such as molecular modeling and X-ray crystallography with a long term goal of developing these into a new generation of antimalarial, antibacterial and antituberculosis drugs.

Representative Publications (2002-)

55.       Yoon, Y. J., Beck, B., Kim B. S., Kang, H. Y, Reynolds, K. A. and Sherman, D. H., Generation of multiple bioactive macrolides by hybrid polyketide synthases in Streptomyces venezuelae. Chem & Biol., 9(2):203-14, 2002

56.       He, X., and Reynolds, K. A.  Purification characterization and identification of Novel Inhibitors of the b-ketoacyl acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob. Chemother., 46, 1310-1318, , 2002.

57.       Cropp, T. A., Kim, B. S., Beck, B. J., Yoon, Y. J., Sherman, D. H., and Reynolds, K. A., Recent developments in the production of novel polyketides by combinatorial biosynthesis.  Biotechnology and Genetic Engineering Reviews, 19, 159-172, 2002.

58.       Kim, B. S., Cropp, T. A., Sherman, D. H., and Reynolds, K. A. An unexpected interaction between the modular polyketide synthases, erythromycin DEBS1 and pikromycin PikAIV, leads to efficient triketide lactone synthesis, Biochemistry, 41,2002, 10827-10833.

59.       Beck B. J., Yoon Y. J., Reynolds K.A.,and  Sherman D.H.  The hidden steps of domain skipping. Macrolactone ring size determination in the pikromycin modularpolyketide synthase, Chem & Biol., 9(5), 575-83, 2002.

60.       Florova, G., Kazanina, G., and Reynolds, K. A.  Enzymes involved in fatty acid and polyketide biosynthesis in Streptomyces glaucescens: The role of FabH, FabD and their acyl carrier protein specificity. Biochemistry, 41, 2002, 10462-10471.

61.   Kim, B. S, Cropp, T. A., Beck, B. J., Sherman, D. H., and Reynolds, K. A. Biochemical Evidence for anEditing Role of Thioesterase II in the Biosynthesis of the Polyketide Pikromycin, J. Biol. Chem. 277, 48028-34, 2002.

62.       Prigge, S. T, He, X, Gerena, L., Waters,N. C. and Reynolds, K. A. The initiation steps of a type II fatty acid biosynthetic system in Plasmodium falciparum are catalyzed by pfACP, pfMCAT and pfKASIII.  Biochemistry. 42,2003, 1160-1169

63.       Beck, B. J., Aldrich, C. C., Fecik, R. A., Reynolds, K. A., and Sherman, D. H., Iterative Chain Elongation by a Pikromycin Monomodular Polyketide Synthase. J Amer. Chem. Soc.125, 2003, 4682-4683. 

64.       Habib, E. S., and Reynolds, K. A., Biosynthetic origin of the antibiotic hygromycin A, Antimicrob. Agents Chemother., 47, 2003, 2065-2071.

65.       Palaniappan, N, Kim, B.S., Sekiyama, Y, Osada, H, and Reynolds, K. A. Enhancement and selective production of phoslactomycin B, a protein phosphatase IIa inhibitor, through identification and engineering of the corresponding biosynthetic gene cluster. J. Biol. Chem., 278, 2003, 35552-35557.

66.       Brown, M. S., Akopiants, K., Resceck, D.  M.,, McAthur, H.  A. I., McCormick, E, and Reynolds, K. A. , Biosynthetic Origins of the Natural Product Thiolactomycin, a Unique and Selective Inhibitor of Type II Dissociated Fatty Acid Synthetases. J. Amer. Chem. Soc. 125, 2003, 10166-10167.

67.       Sekiyama Y., Palaniappan, N., Reynolds, K. A. and Osada, H., Biosynthesis of phoslactomycins: Cyclohexanecarboxylic acid as the starter unit,Tetrahedron, 59, 2003, 7465-7471. 

68.       Beck, B., Aldrich, C. A., Fecik, R. A., Reynolds, K. A., and Sherman, D. H., Substrate recognition and channeling activities of monomodules from the Pikromycin PolyketideSynthase" J. Amer. Chem. Soc. 125, 2003, 12551-12557.

69.       He, X. Reeve, A., Kellogg, G. E., Desai, U., and Reynolds, K. A.,1,2-Dithiole-3-ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH),Antimicro. Agents Chemother., 48, 2004, 3093-3102.

70.       Kim, B. S., Sherman, D. H., andReynolds, K. A., An efficient method for creation and functional analysis of libraries of hybrid type I polyketide synthases, Protein Engin. Design and Selection, 17, 2004, 277-284. 

71.       Kim, B. S., Sherman, D. H., andReynolds, K. A.: An efficient method for creation and functional analysis of libraries of hybrid type I polyketide synthases, ProteinEngin. Des. Sel., 17, 277-284, 2004   

72.       Li, C. Florova, G., Akopiants, K andReynolds, K. A.:  Crotonyl coenzyme A reductase provides methylmalonyl CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in anoil-based extended fermentation, Microbiology, 150, 3463-3472, 2004.

73.       Mo, S. J., Kim, B. S. and Reynolds, K. A. : Production of novel alkylprodiginines in Streptomyces coelicolor by replacement of the 3-ketoacyl ACP synthase IIIinitiation enzyme (RedP), Chem. Biol., 12 , 191-200, 2005.

74.       Musayev, F, Sachdeva, S., Scarsdale, J.N., Reynolds, K. A. and Wright, H. T  Crystal Structure of a Substrate Complex of Mycobacterium Tuberculosis3-Ketoacyl-Acyl Carrier Protein Synthase III (FabH) with Lauroyl-Coenzyme-A. J. Mol. Biol., 346, 1313-21, 2005.

75.       Li, Y, Florova, G and Reynolds, K. A.  Alteration of the fatty acid profile of Streptomyces coelicolor by replacement of the initiation enzyme 3-ketoacyl ACP synthase III(FabH), J. Bacteriol, 187, 3795-9, 2005.

76.       Akopiants, K., Florova, G., Li, C., and Reynolds, K. A.   Multiple pathways for acetate assimilation in Streptomyces cinnamonensis.  J. Indus. Microbiol. Biotechnol., in press, 2005.

77.       Li, C., Akopiants, K. and Reynolds, K. A.  Identification and Disruptional Analysis of the Streptomyces cinnamonensis msdA gene, Encoding Methylmalonic Acid Semialdehyde Dehydrogenase, J. Indus. Microbiol. Biotechnol., in press, 2005.

78.       Das Choudhuri, S., Ayers, S., Soine, W. H., and Reynolds, K. A.  A pH-stability study of phoslactomycin B and analysis of the acid and base degradation products. J. Antibiotics, in press 2005.

79.       Ghatge, M., and Reynolds, K. A. The plmS₂ –encoded cytochrome P450 monooxygenase mediates hydroxylation of phoslactomycin B in Streptomyces sp. HK803, J. Bacteriol., in press 2005.