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PDBsum entry 1m54

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protein ligands Protein-protein interface(s) links
Lyase PDB id
1m54
Jmol
Contents
Protein chains
(+ 0 more) 352 a.a. *
Ligands
PLP ×6
HEM ×6
Waters ×104
* Residue conservation analysis
PDB id:
1m54
Name: Lyase
Title: Cystathionine-beta synthase: reduced vicinal thiols
Structure: Cystathionine beta-synthase. Chain: a, b, c, d, e, f. Fragment: residues 44-406. Synonym: serine sulfhydrase, beta-thionase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Gene: cbs. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PQS)
Resolution:
2.90Å     R-factor:   0.271     R-free:   0.365
Authors: S.Taoka,B.W.Lepore,O.Kabil,S.Ojha,D.Ringe,R.Banerjee
Key ref:
S.Taoka et al. (2002). Human cystathionine beta-synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the CXXC motif seen in the crystal structure of the truncated enzyme. Biochemistry, 41, 10454-10461. PubMed id: 12173932 DOI: 10.1021/bi026052d
Date:
08-Jul-02     Release date:   14-Aug-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P35520  (CBS_HUMAN) -  Cystathionine beta-synthase
Seq:
Struc:
 
Seq:
Struc:
551 a.a.
352 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.22  - Cystathionine beta-synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-serine + L-homocysteine = L-cystathionine + H2O
L-serine
+ L-homocysteine
= L-cystathionine
+ H(2)O
      Cofactor: Pyridoxal 5'-phosphate
Pyridoxal 5'-phosphate
Bound ligand (Het Group name = PLP) matches with 93.75% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     cysteine biosynthetic process from serine   2 terms 
  Biochemical function     cystathionine beta-synthase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1021/bi026052d Biochemistry 41:10454-10461 (2002)
PubMed id: 12173932  
 
 
Human cystathionine beta-synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the CXXC motif seen in the crystal structure of the truncated enzyme.
S.Taoka, B.W.Lepore, O.Kabil, S.Ojha, D.Ringe, R.Banerjee.
 
  ABSTRACT  
 
Elevated levels of homocysteine, a sulfur-containing amino acid, are correlated with increased risk for cardiovascular diseases and Alzheimers disease and with neural tube defects. The only route for the catabolic removal of homocysteine in mammals begins with the pyridoxal phosphate- (PLP-) dependent beta-replacement reaction catalyzed by cystathionine beta-synthase. The enzyme has a b-type heme with unusual spectroscopic properties but as yet unknown function. The human enzyme has a modular organization and can be cleaved into an N-terminal catalytic core, which retains both the heme and PLP-binding sites and is highly active, and a C-terminal regulatory domain, where the allosteric activator S-adenosylmethionine is presumed to bind. Studies with the isolated recombinant enzyme and in transformed human liver cells indicate that the enzyme is approximately 2-fold more active under oxidizing conditions. In addition to heme, the enzyme contains a CXXC oxidoreductase motif that could, in principle, be involved in redox sensing. In this study, we have examined the role of heme versus the vicinal thiols in modulating the redox responsiveness of the enzyme. Deletion of the heme domain leads to loss of redox sensitivity. In contrast, substitution of either cysteine with a non-redox-active amino acid does not affect the responsiveness of the enzyme to reductants. We also report the crystal structure of the catalytic core of the enzyme in which the vicinal cysteines are reduced without any discernible differences in the remainder of the protein. The structure of the catalytic core is compared to those of other members of the fold II family of PLP-dependent enzymes and provides insights into active site residues that may be important in interacting with the substrates and intermediates.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21036862 Q.Xu, and R.L.Dunbrack (2011).
The protein common interface database (ProtCID)--a comprehensive database of interactions of homologous proteins in multiple crystal forms.
  Nucleic Acids Res, 39, D761-D770.  
21308989 S.H.Mudd (2011).
Hypermethioninemias of genetic and non-genetic origin: A review.
  Am J Med Genet C Semin Med Genet, 157, 3.  
21081698 M.Koutmos, O.Kabil, J.L.Smith, and R.Banerjee (2010).
Structural basis for substrate activation and regulation by cystathionine beta-synthase (CBS) domains in cystathionine {beta}-synthase.
  Proc Natl Acad Sci U S A, 107, 20958-20963.
PDB codes: 3pc2 3pc3 3pc4
20155941 V.Karunakaran, A.Benabbas, Y.Sun, Z.Zhang, S.Singh, R.Banerjee, and P.M.Champion (2010).
Investigations of low-frequency vibrational dynamics and ligand binding kinetics of cystathionine beta-synthase.
  J Phys Chem B, 114, 3294-3306.  
19722721 C.L.Weeks, S.Singh, P.Madzelan, R.Banerjee, and T.G.Spiro (2009).
Heme regulation of human cystathionine beta-synthase activity: insights from fluorescence and Raman spectroscopy.
  J Am Chem Soc, 131, 12809-12816.  
19733148 L.Celano, M.Gil, S.Carballal, R.Durán, A.Denicola, R.Banerjee, and B.Alvarez (2009).
Inactivation of cystathionine beta-synthase with peroxynitrite.
  Arch Biochem Biophys, 491, 96.  
19448746 P.H.Lodha, H.Shadnia, C.M.Woodhouse, J.S.Wright, and S.M.Aitken (2009).
Investigation of residues Lys112, Glu136, His138, Gly247, Tyr248, and Asp249 in the active site of yeast cystathionine beta-synthase.
  Biochem Cell Biol, 87, 531-540.  
19232736 S.Singh, P.Madzelan, J.Stasser, C.L.Weeks, D.Becker, T.G.Spiro, J.Penner-Hahn, and R.Banerjee (2009).
Modulation of the heme electronic structure and cystathionine beta-synthase activity by second coordination sphere ligands: The role of heme ligand switching in redox regulation.
  J Inorg Biochem, 103, 689-697.  
18849566 T.Majtan, L.R.Singh, L.Wang, W.D.Kruger, and J.P.Kraus (2008).
Active cystathionine beta-synthase can be expressed in heme-free systems in the presence of metal-substituted porphyrins or a chemical chaperone.
  J Biol Chem, 283, 34588-34595.  
17534535 S.Singh, P.Madzelan, and R.Banerjee (2007).
Properties of an unusual heme cofactor in PLP-dependent cystathionine beta-synthase.
  Nat Prod Rep, 24, 631-639.  
16505479 M.Puranik, C.L.Weeks, D.Lahaye, O.Kabil, S.Taoka, S.B.Nielsen, J.T.Groves, R.Banerjee, and T.G.Spiro (2006).
Dynamics of carbon monoxide binding to cystathionine beta-synthase.
  J Biol Chem, 281, 13433-13438.  
16831608 S.Fiorucci, E.Distrutti, G.Cirino, and J.L.Wallace (2006).
The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver.
  Gastroenterology, 131, 259-271.  
15890000 C.G.Zou, and R.Banerjee (2005).
Homocysteine and redox signaling.
  Antioxid Redox Signal, 7, 547-559.  
15890029 K.H.Jhee, and W.D.Kruger (2005).
The role of cystathionine beta-synthase in homocysteine metabolism.
  Antioxid Redox Signal, 7, 813-822.  
15087459 E.W.Miles, and J.P.Kraus (2004).
Cystathionine beta-synthase: structure, function, regulation, and location of homocystinuria-causing mutations.
  J Biol Chem, 279, 29871-29874.  
15189131 M.H.Stipanuk (2004).
Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine.
  Annu Rev Nutr, 24, 539-577.  
15552268 W.Herrmann, U.Hübner, I.Koch, R.Obeid, U.Retzke, and J.Geisel (2004).
Alteration of homocysteine catabolism in pre-eclampsia, HELLP syndrome and placental insufficiency.
  Clin Chem Lab Med, 42, 1109-1116.  
12615917 C.G.Zou, and R.Banerjee (2003).
Tumor necrosis factor-alpha-induced targeted proteolysis of cystathionine beta-synthase modulates redox homeostasis.
  J Biol Chem, 278, 16802-16808.  
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.