| Angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane zinc carboxypeptidase of the M2 peptidase family that functions as a counter-regulatory component of the renin–angiotensin system by cleaving a single C‑terminal residue from angiotensin peptides to generate products with vasodilatory and anti-proliferative properties. The ectodomain contains a globular metallopeptidase domain with the canonical HEMGH zinc-binding motif and a substrate-binding groove that accommodates angiotensin II and angiotensin I, while a short cytosolic tail with linear interaction motifs and a single transmembrane segment anchors ACE2 at the plasma membrane of endothelial and epithelial cells. Catalytic activity converts angiotensin II into angiotensin 1–7 and angiotensin I into angiotensin 1–9, thereby decreasing levels of the vasoconstrictor angiotensin II and increasing levels of peptides that signal through the Mas receptor and related pathways to promote vasodilation, natriuresis, antiproliferative signaling, and anti-fibrotic and anti-inflammatory actions in the cardiovascular and renal systems. Beyond angiotensin substrates, ACE2 hydrolyzes peptides including apelin-13, dynorphin A(1–13), and des-Arg⁹-bradykinin with high efficiency, linking this enzyme to additional vasoactive, opioid, and inflammatory peptide networks, although the full physiological impact of these activities varies by tissue context. Expression is prominent in vascular endothelial cells, renal tubular epithelium, cardiac myocytes, and testicular Leydig and Sertoli cells, and extends to respiratory and gastrointestinal epithelia, where ACE2 modulates local renin–angiotensin system balance and contributes to regulation of blood pressure, cardiac function, kidney homeostasis, and aspects of male fertility. The extracellular ectodomain is subject to shedding by metalloproteases such as ADAM17, releasing a soluble catalytically active form into the circulation and interstitial fluids, while the membrane-retained fragment participates in signaling crosstalk, so that proteolytic processing dynamically tunes ACE2 surface abundance and systemic versus local peptide processing. ACE2 serves as the entry receptor for severe acute respiratory syndrome coronaviruses SARS‑CoV and SARS‑CoV‑2, as well as human coronavirus NL63, through high-affinity binding of the viral spike protein to the ACE2 ectodomain, an interaction that promotes clathrin-dependent endocytosis of virus–receptor complexes and concurrent internalization and downregulation of ACE2 from the cell surface. Loss or reduced activity of membrane ACE2 in cardiovascular tissues enhances angiotensin II signaling through AT1 receptors, increases activation of ERK and NF‑κB pathways, and favors vasoconstriction, hypertrophy, oxidative stress, and inflammation, whereas preserved or augmented ACE2 expression shifts signaling toward angiotensin 1–7–Mas pathways that support endothelial function and cardioprotection. |
