The Serpintine Solution
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& Experim l e ca n i t in a l l C C f a Journal of Clinical & Experimental o r d l i a o n l o r g u Lucas et al., J Clin Exp Cardiolog 2017, 8:1 y o J Cardiology ISSN: 2155-9880 DOI: 10.4172/2155-9880.1000e150 Editorial Open Access The Serpintine Solution Alexandra Lucas, MD, FRCP(C)1,2,*, Sriram Ambadapadi, PhD1, Brian Mahon, PhD3, Kasinath Viswanathan, PhD4, Hao Chen, MD, PhD5, Liying Liu, MD6, Erbin Dai, MD6, Ganesh Munuswami-Ramanujam, PhD7, Jacek M. Kwiecien, DVM, MSc, PhD8, Jordan R Yaron, PhD1, Purushottam Shivaji Narute, BVSc & AH, MVSc, PhD1,9, Robert McKenna, PhD10, Shahar Keinan, PhD11, Westley Reeves, MD, PhD12, Mark Brantly, MD, PhD13, Carl Pepine, MD, FACC14 and Grant McFadden, PhD1 1Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe AZ, USA 2Saint Josephs Hospital, Dignity Health Phoenix, Phoenix, AZ, USA 3NIH/ NIDDK, Bethesda MD, USA 4Zydus Research Centre, Ahmedabad, India 5Department of tumor surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu, P.R.China 6Beth Israel Deaconess Medical Center, Harvard, Boston, MA, USA 7Interdisciplinary Institute of Indian system of Medicine (IIISM), SRM University, Chennai, Tamil Nadu, India 8MacMaster University, Hamilton, ON, Canada 9Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda MD, USA 10Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA 11Cloud Pharmaceuticals, Durham, North Carolina, USA 12Division of Rheumatology, University of Florida, Gainesville, FL, USA 13Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA 14Division of Cardiovascular Medicine, University of Florida, Gainesville, FL, USA *Corresponding author: Alexandra Lucas, MD FRCP(C), Director Cardiovascular Fellowship Research, Saint Josephs Hospital, Dignity Health Phoenix, Professor , Biodesign Institute / Arizona State University, Center for Personalized Diagnostics, Room A220D, Tempe, AZ, 727 E Tyler St, 85287, Tel: 352-672-2301; E-mail: [email protected] Received date: January 16, 2017; Accepted date: January 17, 2017; Published date: January 20, 2017 Copyright: © 2017 Lucas A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Editorial dinosaur to man and virus to horseshoe crab, representing up to 2-10% of circulating proteins in man. And yet the role of serpins is often Subtle war overlooked; overlooked as remarkable control mechanisms for crucial Circling round pathways in clotting and immune systems, overlooked as biomarkers of diseases such as unstable plaque or even cancers, and overlooked as Infinite core potential therapeutics in disease. A serpin, as for the ‘Seven Percent Sublime door Solution’ in the Sherlock Holmes mysteries, is both an unexpected mystery and a potential source for new therapeutics. With this editorial Resolution we will, in brief, review what is known about the molecular mechanism Eternally bound of serpin-mediated protease inhibition, the natural physiological functions of serpins, the role of serpins in genetic disorders, termed Extreme creation serpinopathies, and finally the potential for serpins as therapeutics. Absolute Solution Serpin inhibition is a form of suicide inhibition. In the thrombotic One on one and thrombolytic protease cascades, serpin-mediated regulation ensures a balancing of opposing regulatory steps thus blocking excess Without a sound protease activation in either direction, as for either excess clot or excess The game begun bleeding, herein termed the serpintine solution [1]. This serpintine solution represents an evolutionary adaptation that has proven highly The battle won effective. Serpins have proven so effective that many species have Fatal bite developed or borrowed serpin functions or even sequences and adapted these to their own uses. Thus organisms from viruses to Serpent bound bacteria, plants and dinosaurs to horseshoe crabs, and finally Life and light mammals, have evolved pathways dependent upon serpin regulation [2]. In fact, serpin-like molecules in horseshoe crabs have been So bright developed as a diagnostic tool for identifying clotting responses in the Alexandra Lucas 2017 blood [3]. Serpins are serine proteinase inhibitors that regulate central Serpins have wondrously complex machinery, a truly fascinating pathways throughout the human body. Many serpin-regulated mechanism of action. The molecular mechanism of serpin inhibition pathways are essential processes in normal physiological functions. was discovered through elegant analyses of the crystal structures of The serpins are a class of ancient proteins, preserved in time from serpins and serpin protease suicide complexes performed by Huber at J Clin Exp Cardiolog, an open access journal Volume 8 • Issue 1 • 1000e150 ISSN:2155-9880 Citation: Lucas A, Ambadapadi S, Mahon B, Viswanathan K, Chen H, et al. (2017) The Serpintine Solution. J Clin Exp Cardiolog 8: e150. doi: 10.4172/2155-9880.1000e150 Page 2 of 6 the Max-Planck-Institut für Biochemie (Martinsried, Germany) who cancers [25,26] and in severe inflammatory disorders [24-27]. delineated the first serpin crystal structure, as well as Huntington and Regulation of serpin control of many of enzymatic activities in diverse Carroll at Cambridge University (Cambridge, UK), the statesmen of pathologies still needs to be properly addressed and studied. When serpinology in Cambridge, among others [4-7]. Serpins inhibit there are genetic deficiencies of serpins these can cause a profound proteases via a suicide inhibitory mechanism, acting as a bait for target dysfunction with extensive consequences, termed a serpinopathy. serine proteases, and in some cases also possessing cross-class inhibition of other proteases, such as the cysteine proteases [8,9]. Once One of the best known of the serpinopathies is caused by mutations the reactive center loop (RCL) is cleaved, the cleaved arm springs a in Alpha 1 anti-trypsin (AAT, SERPINA1), which leads to early and trap and drags the targeted protease to the opposite pole of the serpin severe emphysema, as well as liver dysfunction. There are reportedly leaving the peptide arm embedded in the A beta sheet, effectively up to 70 or more AAT mutations [28-31]. Other serpinopathies biting onto the protease enzyme (Figure 1). The RCL is often depicted include genetic deficiencies of neuroserpin (NSP, SERPIN I1) and anti- as a serpentine structure curved or bending up above the serpin thrombin (AT, SERPINC1) [7,32,33]. For NSP (SERPINI1) mutations protein and exposed as a protease target. The protease and serpin once this leads to epilepsy and sometimes dementia whereas AT or cleaved remain bound and inactive, forming a fixed inactive complex, a antiplasmin mutants have disorders in clotting [32-34]. Mutation in suicide complex [2,4-6]. Thus the cleaved serpin RCL acts as a trap, or the complement inhibitor causes angioedema, a form of excessive perhaps similar to a serpent coiled to strike, where the serpent kills its immune reaction [33]. In some cases it is reported that the RCL, even protease prey swiftly and effectively (Figure 1-the RCL is depicted as a in an uncleaved state, can insert into the beta sheet of an adjacent serpent). The serpin can, however, also be cleaved and rendered serpin molecule forming inactive protein aggregates [31-36]. These inactive, as when large snakes swallow predators such as crocodiles. aggregates then can accumulate in the endoplasmic reticulum and cause both serpin deficiency and cellular dysfunction [37-41]. This mechanism of suicide inhibition implies the use of available serpins in quantities that match the target proteases, which in Serpins, as noted, have many central regulatory roles in nature. pathologies may lead to the exhaustion of their supply and therefore a Serpins regulate the crucial thrombotic and thrombolytic cascades. need to increase their production to meet the increased demand and to With genetic deficiency of AT (SERPINC1) there is excess clotting. return to homeostasis. This means that for every protease inhibited by With malfunction or deficiency of AT (SERPINC1) or PAI-1 a serpin, there is a necessity for an equivalent number of serpins bound (SERPINE1) in sepsis and DIC there can be excess hemorrhaging or to the inactive complexes. It also becomes evident that in genetic thrombosis, testaments to the key roles of serpin modulation in natural mutations in serpins, there can be a dysfunction of the serpin RCL clotting pathways. With a separate serpin genetic deficit in neuroserpin whereby the RCL of one serpin can insert into the A beta sheet of an (SERPINI1) there is epilepsy and dementia. With genetic mutations in adjacent serpin molecule, leading to inactive serpin aggregates [7]. The anti-chymotrypsin (SERPINA2) Alzheimer’s can develop, and protein serpin aggregations form the basis for several known and severe aggregates have been identified in the plaques that form in the brain. congenital disorders such as alpha 1 anti-trypsin (AAT, SERPIN A1) With deficit in AAT (SERPINA1), as noted above, the connective tissue deficiency that causes emphysema, a severe lung disease. Recent work degrading protease neutrophil elastase is functionally in excess, leading has also suggested that larger domain swaps can occur between serpins