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Human Cystathionine gamma lyase

PDB entry: 2NMP

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Cystathionine-γ-lyase (EC 4.4.1.1, CTH, cystathionase) is a pyridoxal-phosphate (PLP) dependent enzyme that catalyses the conversion of L-cystathionine to L-cysteine in the transulfuration pathway. Deficiency of CTH causes the autosomal recessive disease cystathioninemia. CTH can also convert L-cysteine to H2S. This gas transmitter is highly interesting from a medical perspective since it functions as a neuromodulator in the central nervous system and as a smooth muscle relaxant in the vascular system. It has also been suggested to be linked to several cardiovascular diseases, to (anti-) inflammatory responses and to gastric injury caused by non-steroidal anti-inflammatory drugs. H2S is produced in the liver, kidney, vascular system and gut by CTH and in the brain by cystathionine beta-synthetase (CBS). Overexpression of CTH inhibits cell proliferation, induces cell death and is linked to inflammation. Here we present the crystal-structure of CTH at 2.6Å resolution. The enzyme is crystallized as a tetramer with PLP observed covalently bound to Lys212 forming a Schiff base in three out of four active sites. Both monomers in the subunit interfaces contribute to the active site pocket.

References

  1. Fiorucci et al (2006). The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterolgy 131, 259-271.
  2. Li et al (2006). Hydrogen sulphide-a novel mediator of inflammation. Curr. Opin. Pharmacol. 6, 125-129 Yang et al (2004). Cystathionine gamma-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK1/2 phosphorylation and p21Cip/WAK-1. J. Biol. Chem. 279, 49199-49205