Binding of SARS-CoV-2 to ACE2 does not affect ACE2 enzymatic function

The Biochemical Society posted a recording of a fascinating webinar titled ACE2: Friend or Foe. I have indexed the third portion, a talk by Prof Michael Bader on the non-enzymatic functions of ACE2. I hope to index the other portions soon.

Highlights:

 - ACE2 enzymatic function is not affected by SARS-CoV-2 binding. Dr Roger Seheult, a pulmonologist, and others have proposed what I thought to be a quite plausible hypothesis that loss of ACE2 function due to SARS-CoV-2 binding results in high levels of oxidative stress which in turn causes hypercoagulability and attendant pathologies. Loss of ACE2 activity may be occurring due to reduced ACE2 transcription, however [see previous post on this].

- Vascular pericytes are potential targets of infection (very interesting, IMHO)

- AT2 pneumocytes are targets of infection in lung tissue

- loss of ACE2 results in reduced tryptophan uptake due to loss of amino acid transport function > reduction in serotonin production > loss of exercise-induced neurogenesis

- Prof Bader notes that collectrin cannot bind to SARS-CoV-2 and therefore concludes that it does not play a role in the disease process; he also states that collectrin 'has no real activity' but I have read otherwise (it is involved in insulin release, salt-sensitive hypertension, trafficking of Na/K ATPase). Perhaps Prof Bader only refers to enzymatic activity. While collectrin does not serve as a receptor for the virus, I don't believe that that necessarily precludes collectrin from participating in the disease process.

Index:

32:27 Prof. Michael Bader, Non-Enzymatic Functions of ACE2

33:30 B0AT1 - Sodium-dependent neutral amino acid transporter , encoded by the SLC6A19 gene

34:10 collectrin has the same function in the kidney

35:12 no B0AT1 in the intestine of ACE2 knockouts

35:32 in collectrin KO, no B0AT1 in kidney

35:44 Amino acid levels in ACE2 deficient mice; due to redundancy in intestinal a.a. transporters there's not much difference except modest reduction in glycine and marked reduction in tryptophan

36:48 reduced tryptophan uptake results in reduced serotonin levels

37:04 reduction in serotonin results in loss of adult neurogenesis in hippocampus in response to exercise; ACE2 is needed for serotonin production and exercise-dependent neurogenesis

37:37 Summary and Conclusions part I

38:20 ACE2 as SARS receptor

40:41 TMPRSS2 not only cuts the spike protein it also cuts ACE2 and this is needed for viral entry into the cell

41:33 TMPRSS2 inhibitors may prevent infection; Camostat and Nafamostat are in clinical trials

42:59 ACE2 forms a dimer

43:05 speculation on viral entry mechanism

43:36 Expression of ACE2 in human cells and tissues

43:48 in lungs, ACE2 and TMPRSS2 are expressed by AT2 pneumocytes

44:17 Tissue expression of ACE2 in monkeys, most expressing site is ileum

44:45 ACE2 expressed by sustentatcular cells in olfactory epithelium

45:33 ACE2 is an interferon inducible gene, IFN alpha 2, IFN gamma

46:15 Summary and Conclusions, part II

46:26 ACE2 expressing cells are targets of the virus - AT2 pneumocytes, sustentacular cells, enterocytes and VASCULAR PERICYTES

47:57 Question & Answer (not all are indexed)

54:18 To what extent does binding of SARS-CoV-2 to ACE2 block ACE2 activity and ang 1to 7 formation? { paraphrased } SARS-CoV1 showing that the binding of the virus does not affect the enzymatic function. If you block the enzymatic function with MLN4760 the virus can bind, so this is completely independent. We have proven that that ACE2 is still active in the presence of the SARS-CoV2 virus (not yet published), the same as CoV1.

50:13 Is there any inhibitor of collectrin that is being investigated for ACE2 in the context of COVID? { paraphrased } not that I know of, there are no known inhibitors because it has no real activity it just binds to amino acid transporters, ther is not B0AT1 in the lungs so it is not relevant for the virus.