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Conjoined NO-sensitive guanylyl cyclases
BMC Pharmacology volume 11, Article number: P6 (2011)
NO-sensitive guanylyl cyclases (NO-GC’s) that catalyze the reaction of GTP to the second messenger molecule cGMP are heterodimeric enzymes consisting of an α and a β1 subunit. The two prevalent isoforms in humans (α1/β1, α2/β1) are time-tested targets for drugs that release nitric oxide (NO) and new compounds that either sensitize the enzyme for activation by NO or activate the enzyme independently of NO. Homologous NO-GC subunits consist of an amino-terminal HNOX domain followed by a PAS- and a coiled coil domain and the carboxy-terminal catalytic domain.
Measurement of FRET between fluorescent proteins tagged to the amino- and carboxy-terminus of the subunits indicated close proximity between the amino-terminal HNOX domains and the carboxy-terminal catalytic domains of the enzyme. On the basis of these results we constructed conjoined NO-GC’s by fusion of the α amino-terminus to the β1 carboxy-terminus leading to a monomeric enzyme complex. Surprisingly but in accordance with the FRET results these conjoined NO-GC’s (β1α1, β1α2) showed specific enzyme activity and stimulation by NO and various modulators of GC activity.
These obligate enzyme variants faithfully reproduced the pharmacological properties of the heterodimeric enzymes including an isoform specific differential activation of the NO-independent drug cinaciguat. Novel applications of conjoined NO-GC’s including adenoviral gene transfer will be discussed.
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Behrends, S., Busker, M., Haase, N. et al. Conjoined NO-sensitive guanylyl cyclases. BMC Pharmacol 11, P6 (2011) doi:10.1186/1471-2210-11-S1-P6
- Nitric Oxide
- Gene Transfer
- Fluorescent Protein
- Pharmacological Property
- Enzyme Complex