The active site specificity of angiotensin II converting enzyme 2 investigated through single and multiple residue changes and β-amino acid substrate analogs.
Angiotensin converting enzyme 2 (ACE2) is a recently discovered zinc carboxypeptidase involved in the renin angiotensin system (RAS). This enzyme inactivates the potent vasopressive peptide angiotensin II (AngII) by removing the C-terminal phenylalanine residue. ACE2 is also found to be upregulated in the heart in human and animal models of cardiovascular disease and specifically in the human fibrotic liver. Given the role of ACE2 in the RAS and its suspected involvement in other organ systems, a stable and specific inhibitor of low toxicity would be useful in further elucidating the precise role that ACE2 plays in the pathology of heart and liver disease and as a possible therapeutic for the hypotension associated with chronic liver failure.
Approach & Methods
Several approaches were taken to identify leads for a high affinity ACE2 inhibitor: 1) single and multiple residue substitutions were made to the peptide encompassing the four C-terminal residues (IHPF) of AngII...
KeywordsConverting Enzyme Renin Angiotensin System Chronic Liver Failure Fibrotic Liver Amino Acid Analog
The support of the Australian Research Council is gratefully acknowledged, and many thanks to Dr. Rebecca Lew for discussions on ACE2 QFS assay analysis.