Eileen Jaffe

Summary

Affiliation: Fox Chase Cancer Center
Country: USA

Publications

  1. pmc Impact of quaternary structure dynamics on allosteric drug discovery
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Curr Top Med Chem 13:55-63. 2013
  2. pmc A new model for allosteric regulation of phenylalanine hydroxylase: Implications for disease and therapeutics
    Eileen K Jaffe
    Developmental Therapeutics, Institute for Cancer Research, Fox Chase Cancer Center, Temple Health, 333 Cottman Ave, Philadelphia, PA 19111, USA Electronic address
    Arch Biochem Biophys 530:73-82. 2013
  3. pmc Allostery and the dynamic oligomerization of porphobilinogen synthase
    Eileen K Jaffe
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
    Arch Biochem Biophys 519:144-53. 2012
  4. pmc Rhodobacter capsulatus porphobilinogen synthase, a high activity metal ion independent hexamer
    David W Bollivar
    Department of Biology, Illinois Wesleyan University, P, O, Box 2900, Bloomington, IL 61702 2900, USA
    BMC Biochem 5:17. 2004
  5. ncbi request reprint Morpheeins--a new structural paradigm for allosteric regulation
    Eileen K Jaffe
    BioMolecular Structure and Function Group, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
    Trends Biochem Sci 30:490-7. 2005
  6. pmc Crystal structure of Toxoplasma gondii porphobilinogen synthase: insights on octameric structure and porphobilinogen formation
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 286:15298-307. 2011
  7. pmc The morpheein model of allostery: evaluating proteins as potential morpheeins
    Eileen K Jaffe
    Fox Chase Cancer Center, Philadelphia, PA, USA
    Methods Mol Biol 796:217-31. 2012
  8. pmc ALAD porphyria is a conformational disease
    Eileen K Jaffe
    Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Am J Hum Genet 80:329-37. 2007
  9. ncbi request reprint Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase
    Sabine Breinig
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 2497, USA
    Nat Struct Biol 10:757-63. 2003
  10. pmc Plastid-associated porphobilinogen synthase from Toxoplasma gondii: kinetic and structural properties validate therapeutic potential
    Dhanasekaran Shanmugam
    Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:22122-31. 2010

Research Grants

  1. Hexameric PBGS as a Bioterrorism Defense
    Eileen Jaffe; Fiscal Year: 2006
  2. Human PBGS Quaternary Structure Dynamics, Drugs, and Half-of-the-sites Reactivity
    Eileen K Jaffe; Fiscal Year: 2010
  3. PORPHOBILINOGEN SYNTHASE FAMILY
    Eileen Jaffe; Fiscal Year: 2002
  4. PORPHOBILINOGEN SYNTHASE, PROBES OF THE ACTIVE SITE
    Eileen Jaffe; Fiscal Year: 1993
  5. The Porphobilinogen Synthase Family
    Eileen K Jaffe; Fiscal Year: 2010

Collaborators

Detail Information

Publications22

  1. pmc Impact of quaternary structure dynamics on allosteric drug discovery
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Curr Top Med Chem 13:55-63. 2013
    ..Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics...
  2. pmc A new model for allosteric regulation of phenylalanine hydroxylase: Implications for disease and therapeutics
    Eileen K Jaffe
    Developmental Therapeutics, Institute for Cancer Research, Fox Chase Cancer Center, Temple Health, 333 Cottman Ave, Philadelphia, PA 19111, USA Electronic address
    Arch Biochem Biophys 530:73-82. 2013
    ..Pharmacological chaperones that stabilize the ACT:ACT interface can potentially provide PKU patients with a novel small molecule therapeutic...
  3. pmc Allostery and the dynamic oligomerization of porphobilinogen synthase
    Eileen K Jaffe
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
    Arch Biochem Biophys 519:144-53. 2012
    ..Some of these inhibitors are drugs in clinical use leading to the hypothesis that extrinsic allosteric inhibition of human PBGS could be a mechanism for drug side effects...
  4. pmc Rhodobacter capsulatus porphobilinogen synthase, a high activity metal ion independent hexamer
    David W Bollivar
    Department of Biology, Illinois Wesleyan University, P, O, Box 2900, Bloomington, IL 61702 2900, USA
    BMC Biochem 5:17. 2004
    ..This paper reports new information on the metal ion independence and quaternary structure of PBGS from the photosynthetic bacterium Rhodobacter capsulatus...
  5. ncbi request reprint Morpheeins--a new structural paradigm for allosteric regulation
    Eileen K Jaffe
    BioMolecular Structure and Function Group, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
    Trends Biochem Sci 30:490-7. 2005
    ..It is proposed here that the behavior of some other allosteric enzymes reflect dynamic morpheein equilibrium systems and six candidate proteins are enumerated...
  6. pmc Crystal structure of Toxoplasma gondii porphobilinogen synthase: insights on octameric structure and porphobilinogen formation
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 286:15298-307. 2011
    ..The TgPBGS structure suggests strategies for the development of parasite-selective PBGS inhibitors...
  7. pmc The morpheein model of allostery: evaluating proteins as potential morpheeins
    Eileen K Jaffe
    Fox Chase Cancer Center, Philadelphia, PA, USA
    Methods Mol Biol 796:217-31. 2012
    ..The other is a two-dimensional native gel electrophoresis method to monitor ligand-induced changes in an equilibrium of alternate multimeric assemblies...
  8. pmc ALAD porphyria is a conformational disease
    Eileen K Jaffe
    Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Am J Hum Genet 80:329-37. 2007
    ..We propose that the disequilibrium of morpheein assemblies broadens the definition of conformational diseases beyond the prion disorders and that ALAD porphyria is the first example of a morpheein-based conformational disease...
  9. ncbi request reprint Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase
    Sabine Breinig
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 2497, USA
    Nat Struct Biol 10:757-63. 2003
    ....
  10. pmc Plastid-associated porphobilinogen synthase from Toxoplasma gondii: kinetic and structural properties validate therapeutic potential
    Dhanasekaran Shanmugam
    Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:22122-31. 2010
    ..The distinct phylogenetic, enzymatic, and structural features of apicomplexan PBGS offer scope for developing selective inhibitors of the parasite enzyme based on its quaternary structure characteristics...
  11. pmc Allosteric inhibition of human porphobilinogen synthase
    Sarah H Lawrence
    Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 284:35807-17. 2009
    ..Data support the hypothesis that human PBGS hexamer stabilization may explain these side effects. The current work identifies allosteric ligands of human PBGS and, thus, identifies human PBGS as a medically relevant allosteric enzyme...
  12. ncbi request reprint Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 277:19792-9. 2002
    ..A comparison of these with other PBGS structures identifies highly conserved active site water molecules, which are isolated from bulk solvent and implicated as proton acceptors in the PBGS-catalyzed reaction...
  13. ncbi request reprint The porphobilinogen synthase catalyzed reaction mechanism
    Eileen K Jaffe
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
    Bioorg Chem 32:316-25. 2004
    ..The reaction appears to stall at a covalently bound almost-product intermediate that is poised for breakdown to product upon binding of a substrate molecule to an adjacent active site and a subsequent conformational change...
  14. ncbi request reprint Investigations on the metal switch region of human porphobilinogen synthase
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA
    J Biol Inorg Chem 8:176-84. 2003
    ..The R221K mutation was inserted into wild type and chimeric human PBGS and found to further reduce the activity of both, illustrating the subtle nature of the role of this residue...
  15. ncbi request reprint An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase
    Eileen K Jaffe
    Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA
    Chem Biol 10:25-34. 2003
    ..The phylogenetic distribution of PBGS metal ion utilization suggests that the primordial PBGS required zinc and supports a hypothesis that the loss of the zinc site was concurrent with the advent of oxygenic photosynthesis...
  16. ncbi request reprint Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth
    Jonathan D Cheng
    Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 2497, USA
    Mol Cancer Ther 4:351-60. 2005
    ....
  17. ncbi request reprint Single amino acid mutations alter the distribution of human porphobilinogen synthase quaternary structure isoforms (morpheeins)
    Lei Tang
    Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 281:6682-90. 2006
    ..The metastable nature of the R240A hexamer supports the hypothesis that octameric and hexameric morpheeins of PBGS are very close in energy. W19A assembles into a mixture of dimers, which appear to be stable...
  18. doi request reprint Kinetics and thermodynamics of the interchange of the morpheein forms of human porphobilinogen synthase
    Trevor Selwood
    Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA
    Biochemistry 47:3245-57. 2008
    ....
  19. ncbi request reprint Substrate-induced interconversion of protein quaternary structure isoforms
    Lei Tang
    Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    J Biol Chem 280:15786-93. 2005
    ..This observation illustrates that the assembly and disassembly of oligomeric proteins can be facilitated by the protein motions that accompany enzymatic catalysis...
  20. ncbi request reprint A structural basis for half-of-the-sites metal binding revealed in Drosophila melanogaster porphobilinogen synthase
    Lenka Kundrat
    Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 2497, USA
    J Biol Chem 278:31325-30. 2003
    ..5/subunit. This result reveals a structural basis for half-of-the-sites metal binding that is consistent with a reciprocating motion model for function of oligomeric PBGS...
  21. pmc Shape shifting leads to small-molecule allosteric drug discovery
    Sarah H Lawrence
    Fox Chase Cancer Center, Philadelphia, PA 19111, USA
    Chem Biol 15:586-96. 2008
    ..We propose that this strategy for inhibitor discovery can be applied to other proteins that use the morpheein model for allosteric regulation...
  22. ncbi request reprint delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations
    Reiko Akagi
    Department of Nutritional Science, Okayama Prefectural University, Soja, Japan
    Mol Genet Metab 87:329-36. 2006
    ..This case represents the molecular analysis of the ALAD gene defects in the first case of ADP identified in North America, who is a compound heterozygote for two novel ALAD gene defects...

Research Grants20

  1. Hexameric PBGS as a Bioterrorism Defense
    Eileen Jaffe; Fiscal Year: 2006
    ..Success of the proposed studies will establish a much needed new target for species selective antibiotic development that can be applied to bio-defense against NIAID priority pathogens. ..
  2. Human PBGS Quaternary Structure Dynamics, Drugs, and Half-of-the-sites Reactivity
    Eileen K Jaffe; Fiscal Year: 2010
    ..Inactivation of human PBGS is involved in the human conditions of ALAD porphyria and lead poisoning, the latter of which remains a pervasive public health problem in the United States and around the world. ..
  3. PORPHOBILINOGEN SYNTHASE FAMILY
    Eileen Jaffe; Fiscal Year: 2002
    ....
  4. PORPHOBILINOGEN SYNTHASE, PROBES OF THE ACTIVE SITE
    Eileen Jaffe; Fiscal Year: 1993
    ..Complementary to our chemical modification studies, we will elucidate the amino acids present at the PBGS active site by purifying and sequencing the chemically modified peptides...
  5. The Porphobilinogen Synthase Family
    Eileen K Jaffe; Fiscal Year: 2010
    ..In support of these aims are collaborations to probe the structure and function of PBGS using X-ray crystallography, Raman spectroscopy, and analytical ultracentrifugation. ..