Combined use of selective inhibitors and fluorogenic substrates to study the specificity of somatic wild-type angiotensin-converting enzyme

The FEBS Journal
Nicolas D JullienVincent Dive

Abstract

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. Studies on the selectivity of these ACE domains towards either substrates or inhibitors have mostly relied on the use of mutants or isolated domains of ACE. To determine directly the selectivity properties of each ACE domain, working with wild-type enzyme, we developed an approach based on the combined use of N-domain-selective and C-domain-selective ACE inhibitors and fluorogenic substrates. With this approach, marked differences in substrate selectivity were revealed between rat, mouse and human somatic ACE. In particular, the fluorogenic substrate Mca-Ala-Ser-Asp-Lys-DpaOH was shown to be a strict N-domain-selective substrate of mouse ACE, whereas with rat ACE it displayed marked C-domain selectivity. Similar differences in selectivity between these ACE species were also observed with a new fluorogenic substrate of ACE, Mca-Arg-Pro-Pro-Gly-Phe-Ser-Pro-DpaOH. In support of these results, changes in amino-acid composition in the binding site of these three ACE species were pinpointed. Together these data demonstrate that the substrate selectivity of the N-domain and C-domain depends on the ACE species. These resu...Continue Reading

References

Mar 14, 1978·Biochimica Et Biophysica Acta·A Cornish-Bowden, R Eisenthal
Sep 21, 1978·Journal of Theoretical Biology·A Cornish-BowdenW F Trager
Dec 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·F SoubrierP Corvol
Jun 1, 1974·The Biochemical Journal·R Eisenthal, A Cornish-Bowden
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Apr 14, 1999·Proceedings of the National Academy of Sciences of the United States of America·V DiveP Corvol
Oct 3, 1999·The Journal of Biological Chemistry·E G NovikovaL D Fricker
Feb 13, 2001·Biophysical Journal·T H Thanka Christlet, K Veluraja
Oct 31, 2002·Nature Reviews. Drug Discovery·Mohammad Amin ZamanDavid A Calhoun
Jan 24, 2003·Nature·Ramanathan NateshK Ravi Acharya
Dec 12, 2003·Nature Reviews. Drug Discovery·K Ravi AcharyaMario R W Ehlers
Nov 13, 2004·The Journal of Biological Chemistry·Santiago CalCarlos López-Otín
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus

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Citations

Dec 25, 2009·Biological Chemistry·Xiaoou SunWolf-Eberhard Siems
Feb 25, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Paolo DentiNeil H Davies

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