7th BWs: Cu enzyme and trace metals in medicine

Abstract

Introduction to the 7th international Biometals webinarsWelcome to the 7th international Biometals webinars series For those who don't already know, these webinars have been set up by the international Biometals society and the journal Biometals with the help of Cassyni platform. The aim is to promote research in the field of metal interactions in biology and to encourage the interdisciplinary exchange of information at international level. Copper and trace metals are in the spotlight today- Firstly, copper, an essential metal that can play a role in redox chemistry, for electron transfer, as in plastocyanin... with an exposed saturated metal binding site... the first structurally characterised blue copper protein; or for catalysis, with the well-known copper superoxide dismutase working so fast, just limited by diffusion (kcat/KM (an approximation of catalytic efficiency) ( 7 x 109 M-1s-1)).But today, Karrera Djoko, our first speaker, is going to tell us about a copper nitrate reductase which, if I'm not mistaken, contains copper transfer and catalysis sites for nitrite reduction. Karrera, who has worked in Australia for a long time, is a young associate professor at Durham University in the UK who is interested in metals in microbes and antimicrobial resistance.- Our second speaker will be talking about metals in medicine. From a physiological point of view, several metal ions are essential in large quantities or only in trace amounts, unknown for a long time..... Others are not essential but could be of interest in pharmacology (I'm thinking of lithium, platinum)... Metals in medicine are therefore a vast area of interest.But I'm sure that today we'll be concentrating on the metal ions of vanadium. Indeed, everyone knows that our second speaker, Debbie Crans, will always be associated with vanadium stories. But Debbie also likes to point out, quite rightly, the importance of speciation in metal homeostasis and reactivity. How do Cu-dependent nitrite reductases acquire Cu? (We still have no idea.)Cu-dependent nitrite reductases (CuNiR or NirK) catalyse the reduction of nitrite to nitric oxide and allow many microorganisms to respire when O2 is limiting. The best characterised CuNiRs are functional homotrimers. Each monomer contains a type-1 Cu centre, which is the site of electron input from cellular electron donors, and a type-2 Cu centre, which is the site of nitrite reduction. Decades of literature have described the structure and activity of holo-CuNiR in great molecular details. What does apo-CuNiR look like and how does it acquire Cu? This talk will outline our group’s progress so far and describe the major ongoing challenges in addressing this question. Our ultimate goal is to exploit the knowledge to block CuNiR enzyme assembly as a way to combat serious bacterial infections, including those caused by pathogenic Neisseria species. Diverse activities of metal ions in medicine by essential and nonessential trace metalsOf the nine first row transition metal ions five are essential elements for human beings, three are known to impact biological processes, and one is relatively innocuous. Considering the prevalence of metals the biological activities of these elements are important. Indeed, some of them can be used with great success for therapeutic uses against illnesses such as cancer, diabetes, tuberculosis, and neurodegenerative diseases. We illustrate that not only the fundamental roles of essential elements but also their speciation chemistry and the interaction of metal complexes with both protein, membrane, and nucleic acid targets can be very impactful. For example, a metal such as platinum can change the regulation of cellular metabolism and combat cancer. In this presentation, we will describe our studies with ions of nonessential elements such as found in vanadium complexes and the diverse modes of action that they have. Specifically, we will describe the proteins that naturally contain vanadium, vanadium haloperoxidases, and vanabins, as well as describe phosphatases for which vanadate is a potent transition state inhibitor. We will also describe the effects that vanadium compounds have on signal transduction as well as our recent work developing vanadium-containing potential drugs for intertumoral administration.