The structures of KDM A revealed a Cys His Zn

The structures of KDM4A revealed a Cys-His Zn(II) binding site that is close to the substrate binding spot, which bioinformatic analyses indicated was not present in any other histone demethylase subfamily. Therefore, an alternative method to inhibit the KDM4 family (95) would be to use compounds that chelate Zn(II) ions. One derivative of disulfiram is a potent KDM4A inhibitor; it changes the methyl lysine–binding site by the chelation of Zn(II) ions (95). This strategy may have potential for the development of selective inhibitors for those Jumonji protein subtypes containing a structural Zn(II) ion (KDM4) (96). Different chelants that may be involved in KDM4 inhibition are 8-hydroxyquinoline and its derivatives; 8-hydroxyquinoline chelates the Fe(II) ion with a bidentate structure and executes its inhibitory action via a carboxylic s7694 motif positioned toward the active site (97). Interestingly, there is a new compound that performs its inhibitory action by similarly chelating the Fe(II) ion and binding to the cosubstrate cleft (107). This compound consists of a peptide and an α-ketoglutarate analogue that are connected by a disulfide bridge. Although studies have revealed potent and partially high selectivity of this compound, its peptide nature may be an obstacle to the further development of these compounds into potential drugs due to cell permeability, intracellular stability, and other pharmacokinetic parameters (105).
Conclusions and final remarks Another challenge is designing a drug that is selective for a subset of demethylases. This selectivity could potentially be achieved by linking the drug to at least three protein domains; however, the designed drug would be too large to penetrate the cellular membrane. In addition, an allosteric inhibitor that changes the conformation of the catalytic site of the enzyme without binding to this site could be designed. A recent computational screen identified putative allosteric sites that could be used for this purpose (108). However, more research is required to further experimentally identify and characterize these sites.
Acknowledgments This work was supported by the Consejo Nacional de Ciencia y Tecnología (grant number 83959 and 182997) and the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica, Universidad Nacional Autónoma de México (grant number IN213311). L. Guerra-Calderas was supported by an undergraduate fellowship from Básica SEP-CONACyT (19071).
Introduction The development and progression of atherosclerotic lesions is a complex process that includes endothelial cell dysfunction [1], inflammation, fibrous cap and necrotic core formation as well as plaque destabilization and rupture [2]. Given the multifactorial phenotype of atherosclerosis, novel diagnostic and therapeutic approaches should be based on the study of multiple molecular features simultaneously [3]. High-throughput omics strategies including genomics, transcriptomics, proteomics, lipidomics and metabolomics have been applied in atherosclerosis studies [4]. Among these omics approaches, proteomics produces a stable readout directly linked to cell function and phenotype. In addition, proteins can be pharmacologically addressed, and may serve as biomarkers of disease [5]. Previous proteomics or metabolomics-based efforts to delineate molecular mechanisms of early atherosclerosis, included among others, proteome and metabolome characterization of atherosclerotic rabbit models with subsequent investigation of translatability of the findings into human disease using plasma or urine samples [6,7] as well as studies of comprehensive analysis of the proteomic architecture of human early atherosclerotic arterial tissues [8]. Nevertheless many mechanisms still remain elusive. Well established animal models of atherosclerosis have shown to be important tools for the elucidation of the molecular mechanisms that govern atherosclerosis [9]. Among those, we and others have shown that low density lipoprotein receptor deficient (Ldlr−/−) and apolipoprotein E deficient (ApoE−/−) mice on high cholesterol diet mimic major characteristics of human dyslipidemia [9] and metabolic changes [10], supporting their frequent use as preclinical models of atherosclerotic disease. In brief, in a previous study, we employed five different models of cardiovascular disease (CVD) including the atherosclerotic Ldlr−/− and ApoE−/− animal models, the klotho-hypomorphic mice (kl/kl) and the stroke-prone spontaneously hypertensive (SHRSP) rats with or without salt feeding [10]. Comparison of the blood metabolite signature of these animals with the 26 metabolite- signature from patients with CVD (represented as carotid intima media thickness (cIMT)), identified eleven and ten metabolites in the Ldlr−/− and the ApoE−/− animals respectively having the same statistical significant regulation trend with humans [10]. Among the common blood metabolites were several phospholipids and acylcarnitines. The lower coverage that was observed when comparing the other animal models with the human metabolite signature further suggested that the Ldlr−/− and ApoE−/− models better recapitulate the human cIMT signature [10]. Even more, diabetes-accelerated atherosclerosis, characterized currently by increased prevalence and limited therapeutic options [11] can be mimicked in ApoE−/− and Ldlr−/− models by artificial induction of diabetes using streptozotocin (STZ) [12]. As these models (ApoE−/− and Ldlr−/−) are characterized by different types of lipoproteins, the atherogenic mechanisms should ideally be investigated in both genetic backgrounds [13].