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PDBsum entry 1w3y

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Lyase PDB id
1w3y
Jmol
Contents
Protein chain
721 a.a. *
Ligands
PVC
XYL ×2
SO4 ×5
Waters ×564
* Residue conservation analysis
PDB id:
1w3y
Name: Lyase
Title: Crystal structure of s. Pneumoniae hyaluronate lyase in complex with palmitoyl-vitamin c
Structure: Hyaluronate lyase. Chain: a. Synonym: hyaluronidase, hyase. Engineered: yes
Source: Streptococcus pneumoniae. Organism_taxid: 1313. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.65Å     R-factor:   0.192     R-free:   0.210
Authors: D.J.Rigden,M.J.Jedrzejas
Key ref:
A.Botzki et al. (2004). L-Ascorbic acid 6-hexadecanoate, a potent hyaluronidase inhibitor. X-ray structure and molecular modeling of enzyme-inhibitor complexes. J Biol Chem, 279, 45990-45997. PubMed id: 15322107 DOI: 10.1074/jbc.M406146200
Date:
21-Jul-04     Release date:   26-Aug-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q54873  (HYSA_STRPN) -  Hyaluronate lyase
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1066 a.a.
721 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 8 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.4.2.2.1  - Hyaluronate lyase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hyaluronate = N 3-(4-deoxy-beta-D-gluc-4-enuronosyl)-N-acetyl-D- glucosamine

= N
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     carbohydrate metabolic process   1 term 
  Biochemical function     catalytic activity     4 terms  

 

 
    Added reference    
 
 
DOI no: 10.1074/jbc.M406146200 J Biol Chem 279:45990-45997 (2004)
PubMed id: 15322107  
 
 
L-Ascorbic acid 6-hexadecanoate, a potent hyaluronidase inhibitor. X-ray structure and molecular modeling of enzyme-inhibitor complexes.
A.Botzki, D.J.Rigden, S.Braun, M.Nukui, S.Salmen, J.Hoechstetter, G.Bernhardt, S.Dove, M.J.Jedrzejas, A.Buschauer.
 
  ABSTRACT  
 
Hyaluronidases are enzymes that degrade hyaluronan, an important component of the extracellular matrix. The mammalian hyaluronidases are considered to be involved in many (patho)physiological processes like fertilization, tumor growth, and metastasis. Bacterial hyaluronidases, also termed hyaluronate lyases, contribute to the spreading of microorganisms in tissues. Such roles for hyaluronidases suggest that inhibitors could be useful pharmacological tools. Potent and selective inhibitors are not known to date, although L-ascorbic acid has been reported to be a weak inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL). The x-ray structure of SpnHL complexed with L-ascorbic acid has been elucidated suggesting that additional hydrophobic interactions might increase inhibitory activity. Here we show that L-ascorbic acid 6-hexadecanoate (Vcpal) is a potent inhibitor of both streptococcal and bovine testicular hyaluronidase (BTH). Vcpal showed strong inhibition of Streptococcus agalactiae hyaluronate lyase with an IC(50) of 4 microM and weaker inhibition of SpnHL and BTH with IC(50) values of 100 and 56 microM, respectively. To date, Vcpal has proved to be one of the most potent inhibitors of hyaluronidase. We also determined the x-ray structure of the SpnHL-Vcpal complex and confirmed the hypothesis that additional hydrophobic interactions with Phe-343, His-399, and Thr-400 in the active site led to increased inhibition. A homology structural model of BTH was also generated to suggest binding modes of Vcpal to this hyaluronidase. The long alkyl chain seemed to interact with an extended, hydrophobic channel formed by mostly conserved amino acids Ala-84, Leu-91, Tyr-93, Tyr-220, and Leu-344 in BTH.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Chemical structures of L-ascorbic acid and L-ascorbic acid 6-hexadecanoate.
Figure 3.
FIG. 3. A, the SpnHL binding site for L-ascorbic acid 6-hexadecanoate. Hydrogen bonds are represented as dotted lines. Shown is the final sigmaA-weighted omit map electron density calculated to a resolution of 1.65 Å when the inhibitor was excluded from the model and contoured at 2.0 . B, schematic diagram of interactions of L-ascorbic acid 6-hexadecanoate with SpnHL. Hydrogen bonds are represented as dotted lines. Other residues shown form hydrophobic interactions with the inhibitor. The figure was made with LIGPLOT (35). C, binding mode of hexasaccharide substrate. The coordinates of the hexasaccharide substrate originate from its complex with SpnHL (Protein Data Bank code 1loh [PDB] (54)). D, binding mode of L-ascorbic acid 6-hexadecanoate. The cryoprotectant xylitol molecule close to the inhibitor (see text) is also shown (bottom right corner).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 45990-45997) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20534434 J.A.Sloane, C.Batt, Y.Ma, Z.M.Harris, B.Trapp, and T.Vartanian (2010).
Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2.
  Proc Natl Acad Sci U S A, 107, 11555-11560.  
19479740 J.H.Baek, T.H.Woo, C.B.Kim, J.H.Park, H.Kim, S.Lee, and S.H.Lee (2009).
Differential gene expression profiles in the venom gland/sac of Orancistrocerus drewseni (Hymenoptera: Eumenidae).
  Arch Insect Biochem Physiol, 71, 205-222.  
19201751 L.Zhang, A.G.Bharadwaj, A.Casper, J.Barkley, J.J.Barycki, and M.A.Simpson (2009).
Hyaluronidase activity of human Hyal1 requires active site acidic and tyrosine residues.
  J Biol Chem, 284, 9433-9442.  
19438710 P.Mishra, R.Prem Kumar, A.S.Ethayathulla, N.Singh, S.Sharma, M.Perbandt, C.Betzel, P.Kaur, A.Srinivasan, V.Bhakuni, and T.P.Singh (2009).
Polysaccharide binding sites in hyaluronate lyase--crystal structures of native phage-encoded hyaluronate lyase and its complexes with ascorbic acid and lactose.
  FEBS J, 276, 3392-3402.
PDB codes: 2yw0 3eka
19876387 Y.Hirayama, M.Yoshimura, Y.Ozeki, I.Sugawara, T.Udagawa, S.Mizuno, N.Itano, K.Kimata, A.Tamaru, H.Ogura, K.Kobayashi, and S.Matsumoto (2009).
Mycobacteria exploit host hyaluronan for efficient extracellular replication.
  PLoS Pathog, 5, e1000643.  
18207690 A.Senff-Ribeiro, P.Henrique da Silva, O.M.Chaim, L.H.Gremski, K.S.Paludo, R.Bertoni da Silveira, W.Gremski, O.C.Mangili, and S.S.Veiga (2008).
Biotechnological applications of brown spider (Loxosceles genus) venom toxins.
  Biotechnol Adv, 26, 210-218.  
18598174 E.Bralley, P.Greenspan, J.L.Hargrove, and D.K.Hartle (2008).
Inhibition of hyaluronidase activity by select sorghum brans.
  J Med Food, 11, 307-312.  
18508614 M.A.Simpson, and V.B.Lokeshwar (2008).
Hyaluronan and hyaluronidase in genitourinary tumors.
  Front Biosci, 13, 5664-5680.  
18448355 V.B.Lokeshwar, and M.G.Selzer (2008).
Hyalurondiase: both a tumor promoter and suppressor.
  Semin Cancer Biol, 18, 281-287.  
17720239 J.K.Kutty, E.Cho, J.Soo Lee, N.R.Vyavahare, and K.Webb (2007).
The effect of hyaluronic acid incorporation on fibroblast spreading and proliferation within PEG-diacrylate based semi-interpenetrating networks.
  Biomaterials, 28, 4928-4938.  
17415544 M.Nieuwdorp, F.Holleman, E.de Groot, H.Vink, J.Gort, A.Kontush, M.J.Chapman, B.A.Hutten, C.B.Brouwer, J.B.Hoekstra, J.J.Kastelein, and E.S.Stroes (2007).
Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis.
  Diabetologia, 50, 1288-1293.  
17986205 S.Olgen, A.Kaessler, D.Nebio─člu, and J.Jose (2007).
New potent indole derivatives as hyaluronidase inhibitors.
  Chem Biol Drug Des, 70, 547-551.  
16402398 G.Das, and S.Matile (2006).
Substrate-independent transduction of chromophore-free organic and biomolecular transformations into color.
  Chemistry, 12, 2936-2944.  
16632110 J.P.Gaut, A.Belaaouaj, J.Byun, L.J.Roberts, N.Maeda, B.Frei, and J.W.Heinecke (2006).
Vitamin C fails to protect amino acids and lipids from oxidation during acute inflammation.
  Free Radic Biol Med, 40, 1494-1501.  
16522010 R.Stern, and M.J.Jedrzejas (2006).
Hyaluronidases: their genomics, structures, and mechanisms of action.
  Chem Rev, 106, 818-839.  
16718670 W.Hertel, G.Peschel, J.H.Ozegowski, and P.J.Müller (2006).
Inhibitory effects of triterpenes and flavonoids on the enzymatic activity of hyaluronic acid-splitting enzymes.
  Arch Pharm (Weinheim), 339, 313-318.  
16104017 M.J.Jedrzejas, and R.Stern (2005).
Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysis.
  Proteins, 61, 227-238.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.