https://www.ncbi.nlm.nih.gov/pubmed/32156572

Research News

March 19, 2020

https://www.nih.gov/health-information/coronavirus

https://www.thestar.com.my/lifestyle/health/2020/03/01/decoding-the-genes-of-the-covid-19-virus

https://link.springer.com/article/10.1007%2Fs10863-016-9681-9

Kinetic and mutational studies of the adenosine diphosphate ribose hydrolase from Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis represents one of the world’s most devastating infectious agents with one third of the world’s population infected and 1.5 million people dying each year from this deadly pathogen. As part of an effort to identify targets for therapeutic intervention, we carried out the kinetic characterization of the product of gene rv1700 of M. tuberculosis. Based on its sequence and its structure, the protein had been tentatively identified as a pyrophosphohydrolase specific for adenosine diphosphate ribose (ADPR), a compound involved in various pathways including oxidative stress response and tellurite resistance. In this work we carry out a kinetic, mutational and structural investigation of the enzyme, which provides a full characterization of this Mt-ADPRase. Optimal catalytic rates were achieved at alkaline pH (7.5–8.5) with either 0.5–1 mM Mg2+ or 0.02–1 mM Mn2+. K m and k cat values for hydrolysis of ADPR with Mg2+ ions are 200 ± 19 μM and 14.4 ± 0.4 s−1, and with Mn2+ ions are 554 ± 64 μM and 28.9 ± 1.4 s−1. Four residues proposed to be important in the catalytic mechanism of the enzyme were individually mutated and the kinetics of the mutant enzymes were characterized. In the four cases, the K m increased only slightly (2- to 3-fold) but the k cat decreased significantly (300- to 1900-fold), confirming the participation of these residues in catalysis. An analysis of the sequence and structure conservation patterns in Nudix ADPRases permits an unambiguous identification of members of the family and provides insight into residues involved in catalysis and their participation in substrate recognition in the Mt-ADPRase.

https://www.chinadaily.com.cn/a/202003/05/WS5e606fa4a31012821727c8f1.html

http://jpet.aspetjournals.org/content/371/2/231

https://doi.org/10.3390/v9070182

https://www.dailystar.com.lb/News/World/2020/Mar-03/502113-child-drowns-at-sea-off-greece-in-first-fatality-after-turkey-opens-border.ashx

Mikä ihmeen sopulivuosi syyrialaisilla. Miksi  mennään mereen hukkumaan ja hukkaamaan lapsia? Olisivat nyt edes Turkin puoella, jossa on vielä inhimillisiä olentoja.

 

https://hdl.handle.net/2077/39562

https://www.ncbi.nlm.nih.gov/pubmed/?term=Cardiac+implication+in+SARS

Abstract:

The implication of the renin-angiotensin system (RAS) in the regulation of the cardiovascular system has been well known for many years. Accordingly, many pharmaceutical inhibitors have been developed to treat several pathologies, like hypertension and heart failure, and angiotensin converting enzyme (ACE) became one of the major target in the treatment of these cardiovascular diseases. In the last decade however, it has become apparent that the classical view of the RAS was not quite accurate. For instance, ACE has been shown to work not only by generating angiotensin-II but also by interacting with receptors outside the renin-angiotensin system. (My comment: Kininogen- Kallikrein- Bradykinin/kallidin – receptors B1 and B2- signalling way ) Moreover, it has been shown that many local RAS are present in different tissues, such as the heart, brain, kidney and vasculature. However, in the past, it was impossible to determine the role of these local systems as they were pharmacologically indistinguishable from the systemic RAS. Hence, in recent years, the development of transgenic animals has allowed us to determine that these local systems are implicated in the roles that had been originally attributed exclusively to the systemic action of the RAS. However, with almost 30% of the medicated hypertensive patients harboring an uncontrolled blood pressure, a need for new drugs and new targets appears necessary. With the new century came the discovery of a new homolog of ACE, called ACE2, and early studies suggest that it may play a pivotal role in the RAS by controlling the balance between the vasoconstrictor effects of angiotensin- II and the vasodilatory properties of the angiotensin1-7 peptide. Like ACE, ACE2 appears to hydrolyze peptides not related with the RAS   and the enzyme has also been identified as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Although the tissue localization of ACE2 was originally though to be very restricted, new studies have emerged showing a more widespread distribution. Therefore, the whole dynamics of the RAS has to be re-evaluated in light of this new information. In this review, we will compare the structures, distributions and properties of ACE and its new homologue in the context of cardiovascular function, focusing on the autocrine/paracrine cardiac and brain renin-angiotensin systems and we will present recent data from the literature and our laboratory offering a new perspective on this potential target for the treatment of cardiovascular diseases. (My comment:  ACE and NEP hydrolyzes bradykinin and  kallidin ).

Keywords: ACE Polymorphism, membrane-bound ACE2 protein, Severe Acute Respiratory Syndrome, Heart failure, Hypertension

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