Fatty Acid-Mediated Inhibition of Metal Binding to the Multi-Metal Site on Serum Albumin: Implications for Cardiovascular Disease

Abstract

(2016) Fatty acid-mediated inhibition of metal binding to the multi-metal site on serum albumin : implications for cardiovascular disease. Current Trends in Medicinal Chemistry, 16. Permanent WRAP URL:http://wrap.warwick.ac.uk/78963 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work by researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-for-profit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.Publisher's statement: © Bentham Science Publishers. http://dx.doi.org/10.2174/1568026616666160216155927 A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP URL' above for details on accessing the published version and note that access may require a subscription. Abstract: Human serum albumin (HSA) is the major protein in blood plasma and is responsible for circulatory transport of a range of small molecules including fatty acids, metal ions and drugs. We previously identified the major plasma Zn 2+ transport site on HSA and revealed that fatty-acid binding (at a distinct site called the FA2 site) and Zn 2+ binding are interdependent via an allosteric mechanism. Since binding affinities of long-chain fatty acids exceed those of plasma Zn 2+ , this means that under certain circumstances the binding of fatty acid molecules to HSA is likely to diminish HSA Zn 2+ -binding, and hence affects the control of circulatory and cellular Zn 2+ dynamics. This relationship between circulatory fatty acid and Zn 2+ dynamics is likely to have important physiological and pathological implications, especially since it has been recognised that Zn 2+ acts as a signalling agent in many cell types. Fatty acid levels in the blood are dynamic, but most importantly, chronic elevation of plasma fatty acid levels is associated with some metabolic disorders and disease states -including myocardial infarction and other cardiovascular diseases. In this article, we briefly review the metalbinding properties of albumin and highlight the importance of their interplay with fatty acid binding. We also consider the impact of this dynamic link upon levels and speciation of plasma Zn 2+ , its effect upon cellular Zn 2+ homeostasis and its relevance to cardiovascular and circulatory processes in health and disease.

Native electrospray mass spectrometry approaches to probe the interaction between zinc and an anti-angiogenic peptide from histidine-rich glycoprotein

“…In this way, the recruitment of platelets to sites of injury such as tumours and wounds, followed by their activation, generates a Zn 2+ -rich microenvironment 92 . This has implications for angiogenesis 15 in malignant tumours 93 and physiological haemostasis 29 , 30 , 94 , 95 . In both processes, Zn 2+ binding to HRG, or some of its histidine-rich derivatives, increases the affinity to poly-anionic biomolecules, specifically heparin and cell surface-bound heparan sulfate.…”

“…Haemostasis, the first step in wound healing, is dynamically regulated by Zn 2+ 29 , again with platelets as central players. Several lines of evidence indicate that HRG is a central part of this dynamic regulation 30 , 94 , 95 . Zinc-mediated HRG-heparin interactions promote blood clotting, as they decrease anti-coagulatory heparin/anti-thrombin complex formation 29 .…”

Novel Invasive and Noninvasive Cardiac-Specific Biomarkers in Obesity and Cardiovascular Diseases

“…178 Thus, FFA binding alters conformational changes and inhibits the metal ion binding to albumin. 179,180 Chronic diseases associated with ''glycated/ oxidized'' albumin, oxidative stress generates ''irreversible'' oxidation-modified albumin secondary to oxidation adducts on albumin. 176 Henceforth, the use of both standard ACB assay and ELISA tests for determining IMA levels is ideal.…”

A metalloproteomic analysis of interactions between plasma proteins and zinc: elevated fatty acid levels affect zinc distribution

“…37,49 studied in depth using X-ray crystallography, 37,42,43 molecular modelling, NMR spectroscopy, 44 and isothermal titration calorimetry, 41,45 and is now well-understood in chemical model systems. 46 Interdependence of Zn 2+ and FFA binding is due to the proximal location of the primary Zn 2+ binding site (site A) and one (out of three; 47 Fig. 1b) high affinity fatty acid binding site (FA2), both situated at the interface of domains I and II of albumin.…”

“…47 As a result of this finding, it has been suggested that fluctuations in the levels of FFAs in the blood may impact zinc speciation, with several downstream effects predicted. 14,46,48 Although cellular zinc uptake and compartmentalisation is largely governed by membrane-bound transporters of the ZIP and ZnT families, 50,51 it is conceivable that plasma speciation could impact the uptake of Zn 2+ by endothelial cells and blood cells, including leukocytes involved in immune function. 13 In this regard, the effects of zinc on immune cells are of high relevance, since zinc is required for both innate and adaptive immune response, modulating cytokine secretion, 52 and playing roles in T cell maturation 53 and B cell response to vaccination.…”