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PDBsum entry 2fmz

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protein ligands metals links
Lyase PDB id
2fmz
Jmol
Contents
Protein chain
257 a.a. *
Ligands
DPN
Metals
_ZN
_HG
Waters ×161
* Residue conservation analysis
PDB id:
2fmz
Name: Lyase
Title: Carbonic anhydrase activators. Activation of isoforms i, ii, iv, va, vii and xiv with l- and d- phenylalanine, structure with d-phenylalanine.
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, ca-ii, carbonic anhydrasE C. Ec: 4.2.1.1
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
1.60Å     R-factor:   0.218     R-free:   0.237
Authors: C.Temperini,A.Scozzafava,D.Vullo,C.T.Supuran
Key ref: C.Temperini et al. (2006). Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with L- and D-phenylalanine and crystallographic analysis of their adducts with isozyme II: stereospecific recognition within the active site of an enzyme and its consequences for the drug design. J Med Chem, 49, 3019-3027. PubMed id: 16686544 DOI: 10.1021/jm0603320
Date:
10-Jan-06     Release date:   23-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
Seq:
Struc:
260 a.a.
257 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.1  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
H(2)CO(3)
= CO(2)
+ H(2)O
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   11 terms 
  Biological process     angiotensin-mediated signaling pathway   21 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/jm0603320 J Med Chem 49:3019-3027 (2006)
PubMed id: 16686544  
 
 
Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with L- and D-phenylalanine and crystallographic analysis of their adducts with isozyme II: stereospecific recognition within the active site of an enzyme and its consequences for the drug design.
C.Temperini, A.Scozzafava, D.Vullo, C.T.Supuran.
 
  ABSTRACT  
 
Activation of six human brain carbonic anhydrases (hCAs, EC 4.2.1.1), hCA I, II, IV, VA, VII, and XIV, with l-/d-phenylalanine was investigated kinetically and by X-ray crystallography. l-Phe was a potent activator of isozymes I, II, and XIV (K(A)s of 13-240 nM), a weaker activator of hCA VA and VII (K(A)s of 9.8-10.9 microM), and a quite inefficient hCA IV activator (K(A) of 52 microM). d-Phe showed good hCA II activatory properties (K(A) of 35 nM), being a moderate hCA VA, VII, and XIV (K(A)s of 4.6-9.7 microM) and a weak hCA I and IV activator (K(A)s of 63-86 microM). X-ray crystallography of the hCA II-l-Phe/d-Phe adducts showed the activators to be anchored at the entrance of the active site, participating in numerous bonds and hydrophobic interactions with amino acid residues His64, Thr200, Trp5, and Pro201. This is the first study showing different binding modes of stereoisomeric activators within the hCA II active site, with consequences for overall proton transfer processes (rate-determining for the catalytic cycle). It also points out differences of activation efficiency between various isozymes with structurally related activators, exploitable for designing alternative proton transfer pathways. CA activators may lead to the design of pharmacologically useful derivatives for the enhancement of synaptic efficacy, which may represent a conceptually new approach for the treatment of Alzheimer's disease, aging, and other conditions in which spatial learning and memory therapy must be enhanced. As the blood and brain concentrations of l-Phe are quite variable (30-73 microM), activity of some brain CAs may strongly be influenced by the level of activator(s) present in such tissues.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21369613 K.Dave, A.Scozzafava, D.Vullo, C.T.Supuran, and M.A.Ilies (2011).
Pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms I, II and VII.
  Org Biomol Chem, 9, 2790-2800.  
21036610 K.Dave, M.A.Ilies, A.Scozzafava, C.Temperini, D.Vullo, and C.T.Supuran (2011).
An inhibitor-like binding mode of a carbonic anhydrase activator within the active site of isoform II.
  Bioorg Med Chem Lett, 21, 2764-2768.  
20945495 B.Kanbar, and E.Ozdemir (2010).
Thermal stability of carbonic anhydrase immobilized within polyurethane foam.
  Biotechnol Prog, 26, 1474-1480.  
18167490 C.T.Supuran (2008).
Carbonic anhydrases: novel therapeutic applications for inhibitors and activators.
  Nat Rev Drug Discov, 7, 168-181.  
18224701 J.Yang, S.Singh, and J.Shen (2008).
13C saturation transfer effect of carbon dioxide-bicarbonate exchange catalyzed by carbonic anhydrase in vivo.
  Magn Reson Med, 59, 492-498.  
18335973 V.M.Krishnamurthy, G.K.Kaufman, A.R.Urbach, I.Gitlin, K.L.Gudiksen, D.B.Weibel, and G.M.Whitesides (2008).
Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.
  Chem Rev, 108, 946.  
17071654 D.Bhatt, S.Z.Fisher, C.Tu, R.McKenna, and D.N.Silverman (2007).
Location of binding sites in small molecule rescue of human carbonic anhydrase II.
  Biophys J, 92, 562-570.
PDB codes: 2fnk 2fnm 2fnn
17499996 I.Nishimori, S.Onishi, D.Vullo, A.Innocenti, A.Scozzafava, and C.T.Supuran (2007).
Carbonic anhydrase activators: the first activation study of the human secretory isoform VI with amino acids and amines.
  Bioorg Med Chem, 15, 5351-5357.  
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.