Angiotensin converting enzyme: implications from molecular biology for its physiological functions

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• Human angiotensin converting enzyme (ACE) exists as two isozymes: endothelial and testicular.
• The endothelial isozyme features two catalytic domains, while the testicular isozyme possesses a single domain, representing an ancestral gene form.
• Both isozymes are membrane-anchored and glycosylated, with soluble forms arising from post-translational modifications.

Purpose of the Study:

• To detail the structural and functional characteristics of human ACE isozymes.
• To elucidate the evolutionary relationship between the two ACE isozymes.
• To understand the substrate specificity and inhibition of ACE.

Main Methods:

• Gene cloning and sequencing of human ACE isozymes.
• Analysis of protein structure, including catalytic sites and membrane anchoring.
• Investigation of glycosylation patterns (N- and O-linked).
• Characterization of substrate specificity and inhibitor interactions.

Main Results:

• The endothelial ACE isozyme has two catalytic domains, while the testicular isozyme has one, resembling the ancestral form.
• Both isozymes are N-glycosylated and membrane-bound; the testicular form may also be O-glycosylated.
• Soluble ACE is derived from the membrane-bound endothelial form via post-translational modification.
• ACE exhibits complex substrate specificity beyond dipeptidyl peptidase activity.
• ACE is highly conserved across species, highlighting its physiological importance.

Conclusions:

• The two human ACE isozymes share conserved structural features and are vital for physiological processes like blood pressure regulation.
• Understanding ACE isozyme structure and function is crucial for developing targeted therapeutics.
• Inhibitor side effects may stem from interactions with other metalloenzymes, necessitating careful drug design.