Angiotensin converting enzyme, ACE (EC number 3. 4. 15. 1), is a zinc dependent
dipeptidyl carboxypeptidase that has an essential role in mammalian blood pressure
regulation as part of the renin-angiotensin aldosterone system. ACE acts to increase
blood pressure through its actions on two peptides: angiotensin I and bradykinin. In light
of this role ACE is a key target in the treatment of hypertension and ACE inhibitors
have been widely used since the 1980s. Although these are effective drugs, a number of
side effects are commonly associated with their use. These occur as a result of the
inhibition of the roles of ACE in other physiological processes.
Somatic ACE consists of two homologous domains, each with a functional peptidase
active site. Only one of these domains, the C-domain, is required for blood pressure
homeostasis. There is a great deal of interest in developing a new generation of ACE
inhibitors to selectively target the C-domain, whilst leaving the N-domain active and
able to fulfil the other biological functions of ACE.
In the work presented here, AnCE, an ACE homologue from Drosophila melanogaster,
has been used as a model to study the structural basis of ACE inhibition by a number of
different inhibitory peptides. This has highlighted how interactions with active site
residues could be exploited in the development of new, domain selective, inhibitors.
ACE homologues in insects are thought to have a conserved role in reproduction. The
ACE-like enzymes from Anopheles gambiae are of particular interest due to the role of
this organism in the transmission of malaria. In the work presented here the recombinant
expression of an ACE homologue from Anopheles gambiae is reported for the first time.
This is an important step towards the structural and biochemical characterisation of
|Date of Award||11 Feb 2016|
|Supervisor||Ravi Acharya (Supervisor)|