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An Atomic-Level Perspective of HMG-Coa-Reductase

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An Atomic-Level Perspective of HMG-Coa-Reductase molecules Review Review AnAn Atomic-LevelAtomic-Level PerspectivePerspective ofof HMG-CoA- HMG-CoA-Reductase:Reductase: The Target Enzyme The Target to Treat Enzyme to TreatHypercholesterolemia Hypercholesterolemia Diana S. Gesto 1, Carlos, Carlos M. M. S. S.Pereira Pereira 2, Nuno2, Nuno M. M.F. S. F. S.Cerqueira Cerqueira 2 and2 and Sérgio Sérgio F. Sousa F. Sousa 2,* 2,* 1 1 UCIBIO,UCIBIO, Departamento Departamento de de Química, Química, Faculdade Faculdade de de Ci Ciênciasências e eTecnologia, Tecnologia, Universidade Nova de Lisboa, 2829-516Universidade Caparica, Nova Portugal de Lisboa,; [email protected] 2829-516 Caparica, Portugal; [email protected] 2 UCIBIO/REQUIMTE, BioSIM, Departamento de Biomedicina, 2 UCIBIO/REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; [email protected] (C.M.S.P.); 4200-319 Porto, Portugal; [email protected] (C.M.S.P.); [email protected] (N.M.F.S.C.) [email protected] (N.M.F.S.C.) * Correspondence: [email protected] * Correspondence: [email protected] Academic Editor: Pierluigi Plastina Academic Editor: Pierluigi Plastina Received: 31 July 2020; Accepted: 24 24 Augu Augustst 2020; Published: 26 26 August August 2020 2020 Abstract: This review provides an an updated updated atomic atomic-level-level perspective perspective regarding regarding the the enzyme enzyme 3- 3-hydroxy-3-methylglutarylhydroxy-3-methylglutaryl coenzyme coenzyme A Areductase reductase (HMG-CoAR), (HMG-CoAR), linking linking the the more more recent recent data data on onthis this enzyme enzyme with with a structure/function a structure/function interpre interpretation.tation. This This enzyme enzyme catalyzes catalyzes one one of of the most important stepssteps in in cholesterol cholesterol biosynthesis biosynthesis and and is regarded is regarded as one as of one the mostof the important most important drug targets drug in thetargets treatment in the oftreatment hypercholesterolemia. of hypercholesterolemia. Taking this intoTaking consideration, this into consideration, we review in thewe presentreview articlein the severalpresent aspectsarticle several of this enzyme,aspects of including this enzyme, its structure including and its biochemistry, structure and its biochemistry, catalytic mechanism its catalytic and differentmechanism reported and different and proposed reported approaches and proposed for inhibiting approaches this for enzyme, inhibiting including this enzyme, the commercially including availablethe commercially statins or available the possibility statins of or using the possibility dimerization of using inhibitors. dimerization inhibitors. Keywords: HMG-CoAR; structure; biochemistry; regulation;regulation; statins; dimerization inhibitors.inhibitors. 1. Introduction 1. Introduction Cholesterol (Figure 1) is a molecule of vital importance to most life forms and an essential Cholesterol (Figure1) is a molecule of vital importance to most life forms and an essential structural structural component of eukaryotic cells. Nevertheless, this compound is commonly associated with component of eukaryotic cells. Nevertheless, this compound is commonly associated with several several heart conditions, which leads to a public perception of cholesterol as an “evil” molecule. heart conditions, which leads to a public perception of cholesterol as an “evil” molecule. (a) (b) Figure 1. ((a)) 2D; and ( b) 3D structures of the cholesterol molecule. The chemicalchemical structure of thisthis sterol,sterol, withwith thethe formalformal namename cholest-5-en-3cholest-5-en-3ββ-ol, waswas firstlyfirstly determined in in 1932 by WindausWindaus [[11].]. ThisThis molecule,molecule, alongalong withwith otherother sterols,sterols, containscontains a corecore Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 3891; doi:10.3390/molecules25173891 www.mdpi.com/journal/molecules Molecules 2020, 25, 3891 2 of 21 cyclopentanoperhydrophenanthrene ring system (i.e., four fused rings, three of which are six-carbon rings and oneMolecules with 2020 five, 25 carbons), x and is planar, rigid and water insoluble, due its large hydrophobic hydrocarbon2 of 23 body. Cholesterol is also an amphiphilic molecule due to its hydrophilic head, which includes the cyclopentanoperhydrophenanthrene ring system (i.e., four fused rings, three of which are six-carbon hydroxyl group [2,3]. These properties allow this compound to be the major sterol present in animal rings and one with five carbons) and is planar, rigid and water insoluble, due its large hydrophobic tissueshydrocarbon and to play body. a vitalCholesterol role in is thealso properan amphiphi functioninglic molecule of our due cells.to its Besideshydrophilic being head, an which important structuralincludes lipid the thathydroxyl can be group found [2,3]. in theThese cellular properti membranees allow this of most compound eukaryotic to be cells,the major cholesterol sterol also workspresent as a precursorin animal tissues to several and to steroid play a hormones vital role in [ 3the,4]. proper functioning of our cells. Besides being anMembranes, important structural at a cellular lipid level, that can are responsiblebe found in the for cellular the separation membrane of theof most cytosol eukaryotic from the cells, external medium.cholesterol They also comprise works very as a diprecursorfferent components,to several steroid although hormones in a simplistic[3,4]. way they can be represented as a doubleMembranes, layer of phospholipids.at a cellular level, These are responsible complex fo systemsr the separation also allow of the the cytosol transference from the of external compounds throughmedium. them They and carrycomprise out very other different important components functions., although in a simplistic way they can be represented as a double layer of phospholipids. These complex systems also allow the transference The importance of cholesterol in cellular membranes can be estimated by comparing the fluidity of compounds through them and carry out other important functions. of membranes with their cholesterol content. As cholesterol is a somewhat rigid molecule, membranes The importance of cholesterol in cellular membranes can be estimated by comparing the fluidity withof a highermembranes cholesterol with their composition cholesterol tend content. to be more As cholesterol rigid and packed,is a somewhat and those rigid with molecule, less tend to be moremembranes fluid [2]. Thewith fluiditya higher cholestero of membranesl composition is diminished tend to be not more only rigid due and to packed, the rigidity and those of cholesterol, with but canless tend also to be be influenced more fluid [2]. by Th thee fluidity interaction of membranes of this molecule is diminished with not the only di ffdueerent to the membrane rigidity of lipids (e.g.,cholesterol, the creation but can of cholesterol–sphingolipidalso be influenced by the interaction rafts makes of this molecule membranes with the slightly different thicker membrane and more ordered)lipids [(e.g.,3,5]. the Additionally, creation of cholesterol–sphingolipid this membrane lipid rafts also makes aidsthe membranes cell in other slightly homeostasis thicker and more processes, suchordered) as endocytosis [3,5]. Additionally, [3]. this membrane lipid also aids the cell in other homeostasis processes, suchAs mentioned as endocytosis above, [3]. cholesterol is also a precursor of natural steroid hormones produced in our As mentioned above, cholesterol is also a precursor of natural steroid hormones produced in body, providing them with their core ring system, such as the hormones produced in the adrenal gland our body, providing them with their core ring system, such as the hormones produced in the adrenal and the sex hormones (Figure2). gland and the sex hormones (Figure 2). Figure 2. a b c Figure 2D2. 2D structures structures of: of: (a)) cholesterol; cholesterol; and and some some of its of precursors: its precursors: (b) aldosterone; ( ) aldosterone; (c) cortisol; ( ) (d cortisol;) (d) testosterone;testosterone; ( (ee)) progesterone; progesterone; and and (f) (vitamin-D3.f) vitamin-D3. TheThe adrenal adrenal gland gland is locatedis located just just above above the the kidneys kidneys andand itsits mainmain role is to produce produce and and release release two classestwo of classes hormones: of hormones: corticosteroids corticosteroids and catecholamines. and catecholamines. Only Only corticosteroid corticosteroid hormones hormones are are derived from cholesterol, and these can be further divided into two different classes: mineralocorticoids Molecules 2020, 25, 3891 3 of 21 and glucocorticoids. Mineralocorticoids (e.g., aldosterone (Figure2b)) are hormones related to the reabsorption of ions such as Cl-, Na+ and HCO3- by the kidney. On the other hand, glucocorticoids (e.g., cortisol (Figure2c)) are a centerpiece for the metabolism of carbohydrates in the body, being responsible for the regulation of the levels of glucose. Both male and female sex glands also produce molecules that can be derived from cholesterol. These can be divided into androgens, such as testosterone (Figure2d), which are responsible for the development of male characteristics, and estrogens and progestogens (Figure2e), which are responsible for the development of female characteristics. Additionally, cholesterol
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