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Contact details

Georgios A. Spyroulias, PhD.
Department of Pharmacy
University of Patras
GR-26504 Patras, GREECE
Tel:    +30.2610.969950 (office)
+30.2610.969951 (terra silico)
+30.2610.969952 (terra vitro)
Fax:    +30.2610.969950
Email:  G.A.Spyroulias@upatras.gr

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Now is: 2017-09-20 07:31
Heme & Copper proteins

target5Metalloenzymes with Iron (Fe) or Copper (Cu) metal ions as prosthetic groups, usually control enzymatic activity by changing the coordination and electronic properties of their metal centers. These metal sites are usually the centers where catalysis, chemical or electronic reactions, takes place. The enzymatic action involves the inter-conversion of inactive and active states of the enzymes and these changes can be frequently tuned by altering the coordination number of the metal site. Changes in the coordination properties of  a metal ion is usually coupled by changes in the electronic properties of the metal (redox transitions, spin state changes etc.) and in many cases are associated with local or extended conformational and dynamical changes change. These processes are clearly illustrated in heme proteins, like like soluble guanylyl cyclase  (sGC) or cytochromes, and copper proteins involved in copper transfer and translocation into the cells.

Soluble Guanylyl Cyclase
Nitric oxide (NO) has a prominent role in biological process and may acts as a critical cytotoxic agent and as an essential signaling molecule. The first registered evidence, empirical though, of the NO impact in cardiovascular disease is coming from the factory of Alfred Nobel in late 1860s {Ignarro LJ PNAS, 99, 7816-7817, (2002)}. Since then, the toxicity of the diatomic gas has long been accepted; however, it was not known to be a signaling molecule until it was identified as the endothelium-derived relaxing factor (EDRF). Many of the cellular responses that NO modulates are mediated by the heme protein soluble guanylate cyclase (sGC). Specifically, sGC is a hemeprotein that acts as a nitric oxide (NO) sensor in mammals. When NO binds to the sGC Protoporphyrin-IX-Fe(III) prosthetic group, its GTP cyclase activity markedly increases, thus generating cyclic GMP, which serves to regulate several cell signaling functions. However, other diatomic gases, like O2 or CO, either do not bind (dioxygen), or do not significantly activate (carbon monoxide) sGC. This provides selectivity and efficiency for NO even in an aerobic environment, which is critical due to the high reactivity of NO. Several biochemical studies have focused on elucidating the mechanism of NO activation and O2 discrimination.
The crystal structure of a member of a recently discovered family of prokaryotic sGC homologues has provided important insights into structure-function relationships within the sGC family and has been used as a template in the homology modeling of human sGC. This homology model has been used for the prediction of the binding modes of various sGC heme-dependent or heme-independent regulators of sGC and SAR studies.

Completed Projects : Copper chaperons/transporters and cytochromes