Identification of Protein Fold Topology Shared between Different Folds Inhibited by Natural Products

Natural products have withstood the test of time as therapeutics, but new lead‐generation strategies have focussed away from natural products. A new approach that uses natural‐product recognition to drive an understanding of biological space might provide an impetus for renewed focus on natural‐product starting points. Protein fold topology (PFT) has been shown to be an underlying factor for natural‐product recognition. An investigation of natural product inhibitors of the Zincin‐like fold has demonstrated their capacity also to inhibit targets of different fold types. Analysis of crystal structure complexes for natural products cocrystallised within different fold types has shown similarity at the PFT level. Two new PFTT (where subscript T denotes PFT shared between therapeutic targets) relationships have been established: the Zincin‐like– metallohydrolase/oxidoreductase PFTT and the Zincin‐like–phosphorylase/hydrolase PFTT. The PFT relationship between a natural product's biosynthetic enzyme and therapeutic target, and now between different fold targets of the same natural product, suggests that PFT is the simplest descriptor of biological space. This fundamental factor for recognition could facilitate a rational approach to drug development guided by natural products.

[1]  S. Swaminathan,et al.  Crystallographic evidence for doxorubicin binding to the receptor-binding site in Clostridium botulinum neurotoxin B. , 2001, Acta crystallographica. Section D, Biological crystallography.

[2]  N. Hooper,et al.  Families of zinc metalloproteases , 1994, FEBS letters.

[3]  B. Matthews,et al.  A crystallographic study of the complex of phosphoramidon with thermolysin. A model for the presumed catalytic transition state and for the binding of extended substances. , 1977, Journal of molecular biology.

[4]  Magali Mathieu,et al.  The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: a platform for the structure-based design of antibacterial agents. , 2002, Journal of molecular biology.

[5]  B. Roques,et al.  Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Matthews,et al.  Comparison of the structures of carboxypeptidase A and thermolysin. , 1977, The Journal of biological chemistry.

[7]  Chi‐Huey Wong,et al.  Crystal structures of leukotriene A4 hydrolase in complex with captopril and two competitive tight‐binding inhibitors , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  S. Charleson,et al.  Enkephalinase: selective peptide inhibitors. , 1981, Life sciences.

[9]  T. Aoyagi,et al.  Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. , 1976, The Journal of antibiotics.

[10]  James M. Gavin,et al.  Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. , 2002, Journal of the American Chemical Society.

[11]  U. Abel,et al.  Modern methods to produce natural-product libraries. , 2002, Current opinion in chemical biology.

[12]  A. M. Boldi,et al.  Libraries from natural product-like scaffolds. , 2004, Current opinion in chemical biology.

[13]  F. Winkler,et al.  Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon. , 2000, Journal of molecular biology.

[14]  Ook Joon Yoo,et al.  Crystal structure of Drosophila angiotensin I‐converting enzyme bound to captopril and lisinopril 1 , 2003, FEBS letters.

[15]  A. Taylor,et al.  Inhibition of bovine lens leucine aminopeptidase by bestatin: number of binding sites and slow binding of this inhibitor. , 1993, Biochemistry.

[16]  D W Cushman,et al.  Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. , 1977, Biochemistry.

[17]  J. Widom,et al.  Structure of human methionine aminopeptidase-2 complexed with fumagillin. , 1998, Science.

[18]  B. Mikami,et al.  Crystal structure of peptide deformylase from Staphylococcus aureus in complex with actinonin, a naturally occurring antibacterial agent , 2004, Proteins.

[19]  D J Newman,et al.  Natural products in drug discovery and development. , 1997, Journal of natural products.

[20]  G. Schneider,et al.  Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. , 2001, Journal of combinatorial chemistry.

[21]  P Bork,et al.  Homology-based fold predictions for Mycoplasma genitalium proteins. , 1998, Journal of molecular biology.

[22]  T. Aoyagi,et al.  A THERMOLYSIN INHIBITOR PRODUCED BY ACTINOMYCETES: PHOSPHORAMIDON , 1973 .

[23]  Herbert Waldmann,et al.  From protein domains to drug candidates – natural products as guiding principles in , 2002 .

[24]  D. Schomburg,et al.  BRENDA: a resource for enzyme data and metabolic information. , 2002, Trends in biochemical sciences.

[25]  J. Kobayashi,et al.  Nakijiquinones C and D, new sesquiterpenoid quinones with a hydroxy amino acid residue from a marine sponge inhibiting c-erbB-2 kinase , 1995 .

[26]  Philip E. Bourne,et al.  A database and tools for 3-D protein structure comparison and alignment using the Combinatorial Extension (CE) algorithm , 2001, Nucleic Acids Res..

[27]  L. Hersh,et al.  Human kidney "enkephalinase", a neutral metalloendopeptidase that cleaves active peptides. , 1983, Biochemistry.

[28]  L. Lohmander,et al.  The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. , 1993, Arthritis and rheumatism.

[29]  H. R. Evans,et al.  Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. , 2004, Biochemistry.

[30]  Gianfranco Amicosante,et al.  The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril* , 2003, Journal of Biological Chemistry.

[31]  W. Lipscomb,et al.  X-ray crystallographic determination of the structure of bovine lens leucine aminopeptidase complexed with amastatin: formulation of a catalytic mechanism featuring a gem-diolate transition state. , 1993, Biochemistry.

[32]  Herbert Waldmann,et al.  Protein structure similarity clustering and natural product structure as guiding principles in drug discovery. , 2005, Drug discovery today.

[33]  P E Bourne,et al.  Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. , 1998, Protein engineering.

[34]  P. Weber,et al.  Binding affinities and geometries of various metal ligands in peptide deformylase inhibitors. , 2002, Biophysical chemistry.

[35]  W. Lipscomb,et al.  Structure determination and refinement of bovine lens leucine aminopeptidase and its complex with bestatin. , 1992, Journal of molecular biology.

[36]  Cheryl A. Janson,et al.  Identification of a Series of Tricyclic Natural Products as Potent Broad-Spectrum Inhibitors of Metallo-β-Lactamases , 2002, Antimicrobial Agents and Chemotherapy.

[37]  Lei Wei,et al.  The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. , 1992, The Journal of biological chemistry.

[38]  Matthias Keil,et al.  Identifification of Substrate Channels and Protein Cavities , 1998 .

[39]  A. Serero,et al.  Distinctive features of the two classes of eukaryotic peptide deformylases. , 2001, Journal of molecular biology.

[40]  A G Murzin,et al.  SCOP: a structural classification of proteins database for the investigation of sequences and structures. , 1995, Journal of molecular biology.

[41]  Herbert Waldmann,et al.  Compound library development guided by protein structure similarity clustering and natural product structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Rich,et al.  Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes. , 1984, Journal of medicinal chemistry.

[43]  C Sander,et al.  Mapping the Protein Universe , 1996, Science.

[44]  L. Binderup,et al.  Inhibition of collagenase by aranciamycin and aranciamycin derivatives. , 1992, Journal of medicinal chemistry.

[45]  J. Frère,et al.  Three-dimensional structure of FEZ-1, a monomeric subclass B3 metallo-beta-lactamase from Fluoribacter gormanii, in native form and in complex with D-captopril. , 2003, Journal of molecular biology.

[46]  B. Roques,et al.  Relationship between the inhibitory potencies of thiorphan and retrothiorphan enantiomers on thermolysin and neutral endopeptidase 24.11 and their interactions with the thermolysin active site by computer modelling. , 1987, Biochemical and biophysical research communications.

[47]  B. Matthews,et al.  Thiorphan and retro-thiorphan display equivalent interactions when bound to crystalline thermolysin. , 1989, Biochemistry.

[48]  W. Bornmann,et al.  The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Ronald J Quinn,et al.  A common protein fold topology shared by flavonoid biosynthetic enzymes and therapeutic targets. , 2006, Journal of natural products.

[50]  Jesper Z. Haeggström,et al.  Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation , 2001, Nature Structural Biology.

[51]  K. Tanzawa,et al.  Purification and characterization of endothelin-converting enzyme from rat lung. , 1993, The Journal of biological chemistry.

[52]  J. M. Prescott,et al.  The slow, tight binding of bestatin and amastatin to aminopeptidases. , 1985, The Journal of biological chemistry.

[53]  Z. Ni,et al.  Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. , 2000, Biochemistry.

[54]  Herbert Waldmann,et al.  Protein structure similarity clustering (PSSC) and natural product structure as inspiration sources for drug development and chemical genomics. , 2005, Current opinion in chemical biology.

[55]  Herbert Waldmann,et al.  From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. , 2002, Angewandte Chemie.

[56]  Antje Chang,et al.  BRENDA, enzyme data and metabolic information , 2002, Nucleic Acids Res..

[57]  D. Rice,et al.  Antibiotic Activity and Characterization of BB-3497, a Novel Peptide Deformylase Inhibitor , 2001, Antimicrobial Agents and Chemotherapy.

[58]  K. Biemann,et al.  Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. , 1997, Chemistry & biology.

[59]  Pedro M. Abreu,et al.  Natural product-like combinatorial libraries , 2003 .

[60]  F. Fitzpatrick,et al.  Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. , 1991, The Journal of biological chemistry.

[61]  H. Waldmann,et al.  Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold. , 2003, Journal of medicinal chemistry.

[62]  G. Petsko,et al.  Spectroscopic and X-ray crystallographic characterization of bestatin bound to the aminopeptidase from Aeromonas (Vibrio) proteolytica. , 2004, Biochemistry.

[63]  T. Aoyagi,et al.  Synthesis and structure-activity relationships of bestatin analogues, inhibitors of aminopeptidase B. , 1977, Journal of medicinal chemistry.

[64]  H. Waldmann,et al.  Von Proteindomänen zu Wirkstoffkandidaten - Naturstoffe als Leitstrukturen für das Design und die Synthese von Substanzbibliotheken , 2002 .

[65]  M. Groll,et al.  Crystal structure of TET protease reveals complementary protein degradation pathways in prokaryotes. , 2005, Journal of molecular biology.

[66]  T. Matsumiya,et al.  The enhancing effects of amastatin, phosphoramidon and captopril on the potency of [Met5]-enkephalin in rat vas deferens. , 1986, Japanese journal of pharmacology.

[67]  A. Turner,et al.  Kidney neutral endopeptidase and the hydrolysis of enkephalin by synaptic membranes show similar sensitivity to inhibitors. , 1982, The Biochemical journal.

[68]  D. Schuster,et al.  Identification and properties of the cell membrane bound leucine aminopeptidase interacting with the potential immunostimulant and chemotherapeutic agent bestatin. , 1983, Biochemical pharmacology.

[69]  M. Shimamura,et al.  Enkephalin-degrading dipeptidyl carboxypeptidase in guinea pig serum: its properties and action on bioactive peptides. , 1985, Archives of biochemistry and biophysics.

[70]  Gunter Schneider,et al.  Crystal Structure of Aclacinomycin Methylesterase with Bound Product Analogues , 2003, Journal of Biological Chemistry.

[71]  M. Ondetti,et al.  Angiotensin‐converting enzyme inhibitors: Medicinal chemistry and biological actions , 1982, Medicinal research reviews.

[72]  Chris Sander,et al.  Dali/FSSP classification of three-dimensional protein folds , 1997, Nucleic Acids Res..

[73]  J. Gierse,et al.  Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. , 1991, The Journal of biological chemistry.

[74]  J. Schwartz,et al.  The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice , 1980, Nature.

[75]  M. L. Connolly.  Solvent-accessible surfaces of proteins and nucleic acids. , 1983, Science.

[76]  M. L. Connolly.  Analytical molecular surface calculation , 1983 .

[77]  S. Zucker,et al.  Localization of Tissue Inhibitor of Matrix Metalloproteinases in Alzheimer's Disease and Normal Brain , 1995, Journal of neuropathology and experimental neurology.

[78]  J. Powers,et al.  Pseudomonas aeruginosa elastase. Development of a new substrate, inhibitors, and an affinity ligand. , 1980, Journal of Biological Chemistry.

[79]  D E Tronrud,et al.  Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin. , 1989, European journal of biochemistry.

[80]  A. Jeng,et al.  The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. , 2001, Current medicinal chemistry.

[81]  L. Lohmander,et al.  Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis. , 1993, Arthritis and rheumatism.

[82]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases and metastasis , 1999, Cancer Chemotherapy and Pharmacology.

[83]  S J Remington,et al.  Peptide aldehyde complexes with wheat serine carboxypeptidase II: implications for the catalytic mechanism and substrate specificity. , 1996, Journal of molecular biology.

[84]  B. Matthews,et al.  The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[85]  A. Strauss,et al.  Purification of a membrane-bound metalloendopeptidase from porcine kidney that degrades peptide hormones. , 1981, Proceedings of the National Academy of Sciences of the United States of America.