PMC:7408073 / 39383-43824 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7408073","sourcedb":"PMC","sourceid":"7408073","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7408073","text":"ACE2, as well as ACE, is a zinc metalloprotease that can be inhibited by zinc chelating EDTA and activated by high concentrations of chloride or fluoride anions and zinc cation [79,90]. Indeed, both enzymes have chloride- and zinc-binding sites [90]. It is conceivable that these sites are responsible for the anion and zinc activation effect in both homologous enzymes [90]. However, the presence of chloride ions increases Ang I cleavage by ACE and ACE2 (increasing both Ang II and Ang (1–9)) and decreases Ang II cleavage by ACE2, suggesting that chloride induces specific ACE2 conformational changes in its active site (see [44]). To this regard, in plasma samples of COVID–19 patients, chloride range is usually normal or slightly higher (99.6–107.0 mmol/L) than normal values (96.–106.0 mmol/L) [5]. Unfortunately, I was not able to find plasma zinc concentrations in COVID-19 patients. Zinc is involved in several cellular activities and its systemic concentration is tightly regulated by several factors. Of interest, the major transporter/reservoir of zinc in plasma is albumin [91], a protein that was detected at significantly low concentrations in SARS-CoV-2 as well as severe adult respiratory distress syndrome (ARDS, a COVID-19-like disease) (usually \u003c 3.5 g/dL, normal range 3.5–5.4) and inflammatory bowel disease (IBD, a disease with increased ACE2 activity) [6,8,66,92] Since most of zinc in plasma is sequestered by albumin, the total amount of plasma zinc mostly depends on albumin concentration and even small changes in albumin’s capacity for zinc binding may have significant consequences. To this regard, reduced concentrations of plasma albumin is believed to increase plasma levels of free zinc, while reducing the total plasma zinc concentrations [91], a condition that was observed in ARDS patients [93,94]. Indeed, albumin can potentially deplete free bioavailable forms of zinc; vice versa, hypoalbuminaemia may increase free zinc levels in plasma. Therefore, some ARDS patients with low levels of both total zinc and albumin might have rather higher than lower free zinc levels [93]. The free zinc concentration, which describes the fraction of zinc that is loosely bound and easily exchangeable, represents the highly bioavailable (and toxic) part of plasma zinc but it is not clinically detected. To that end, zinc/albumin ratio might be a surrogate marker of free zinc levels. Indeed, only recently it was described a fluorescence-based method for determining the free zinc concentration in human serum samples [95]. With this method it was shown that free zinc concentration in sera from females was significantly lower than in males [95]. Moreover, free zinc concentration did correlate neither with total serum concentrations of zinc (or other metal ions such as iron) nor with age [95]. Notably, increased plasma zinc bioavailability consequent to reduced albumin levels induces zinc import into cells and likely increases the cellular functions associated to cellular zinc concentrations such as ACE and ACE2. Indeed, enzymatic activity of both enzymes seems significantly upregulated in ARDS patients as detected by analysis of Ang peptide concentrations in plasma (see Box later in ARDS topic). In addition, serum albumin levels in COVID-19 were usually very low (in severe forms is usually \u003c 3.1 g/dL) [6,8], raising the possibility of a negative correlation between albumin concentration in plasma and increase of the RAS activity. In line with these hypotheses, both asthmatic/allergic disease patients and chronic kidney disease patients without a history of cardiovascular disease, which are protected from developing COVID-19, showed a significant decrease in both circulating zinc levels and ACE2 activity as compared to normal values [96,97,98,99]. Interestingly, chronic renal disease patients with low zinc levels had normal concentrations of albumin but higher urinary zinc excretion than healthy controls [97], suggesting that low ACE2 activity in chronic renal diseases (and protection from SARS) might derive from a higher free Zn2+ renal excretion. A similar mechanism mediated by a reduction of extracellular levels of free Zn2+ might be hypothesised for asthma patients, as well [98]. Unfortunately, I could not find information on plasma albumin concentrations for asthma patients; nevertheless, we might suppose that in these patients the albumin concentration is in normal 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