Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme by dipeptides identified in dry-cured ham

Abstract

High cholesterolemia is a key risk factor for the development of cardiovascular diseases, which are the main cause of mortality in developed countries. Most therapies are focused on the modulation of its biosynthesis through 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) inhibitors. In this sense, food-derived bioactive peptides might act as promising health alternatives through their ability to interact with crucial enzymes involved in metabolic pathways, avoiding the adverse effects of synthetic drugs. Dry-cured ham has been widely described as an important source of naturally-generated bioactive peptides exerting ACEI-inhibitory activity, antioxidant activity, and anti-inflammatory activity between others. Based on these findings, the aim of this work was to assess, for the first time, the in vitro inhibitory activity of HMG-CoAR exerted by dipeptides generated during the manufacturing of dry-cured ham, previously described with relevant roles on other bioactivities.The in vitro inhibitory activity of the dipeptides was assessed by measuring the substrate consumption rate of the 3-hydroxy-3-methylglutaryl CoA reductase in their presence, with the following pertinent calculations.Further research was carried out to estimate the possible interactions of the most bioactive dipeptides with the enzyme by performing in silico analysis consisting of molecular docking approaches.Main findings showed DA, DD, EE, ES, and LL dipeptides as main HMG-CoAR inhibitors. Additionally, computational analysis indicated statin-like interactions of the dipeptides with HMG-CoAR.This study reveals, for the first time, the hypocholesterolemic potential of dry-cured ham-derived dipeptides and, at the same time, converges in the same vein as many reports that experimentally argue the cardiovascular benefits of dry-cured ham consumption due to its bioactive peptide content.

Identification and Quantitation of Bioactive and Taste-Related Dipeptides in Low-Salt Dry-Cured Ham

“…The dipeptide DA has also been reported to reduce the activity of DPP-III in vitro, whereas the dipeptide EE was shown to act as a stimulating vasoactive substance release in human aortic endothelial cells. More recently, dipeptides EE, ES, and DA have been tested for their anticholesterolemic activity, obtaining values of 47.2, 45.5, and 49.6% of HMG-CoA inhibitory activity, respectively, at 1 mM [ 23 ]. In this work, the multifunctional properties of the dipeptides were assessed by testing their inhibitory capacity for key enzymes related to cardiovascular and chronic inflammatory pathologies.…”

Bioactive and Sensory Di- and Tripeptides Generated during Dry-Curing of Pork Meat

“…Curiously, hydrophilic dipeptides KA and VK, probably generated in dry-cured ham [ 91 ], were identified in soy protein hydrolysate and reported to decrease triglyceride synthesis in cultured hepatocytes [ 86 ]. Moreover, dry-cured ham-derived dipeptides DA, DD, EE, ES, and LL have been characterized as potential hypocholesterolemic agents through in vitro and in silico HMG-CoAR inhibition [ 87 , 146 ].…”

“…LL has been described as Immunomodulator, hypoglycemic, antihypercholesterolemic, and bitter [ 91 , 142 , 143 ]. In addition, the umami peptides EL, EV, RL, EEL, and ESV, identified in Jinhua dry-cured ham, have been reported to exert moderate in vitro ACE-I inhibitory activity [ 14 , 86 ], while dipeptides DA, DD, EE, and ES exerted in vitro HMG-CoAR inhibition [ 86 , 91 , 101 , 146 ].…”

Characterization of Umami Dry-Cured Ham-Derived Dipeptide Interaction with Metabotropic Glutamate Receptor (mGluR) by Molecular Docking Simulation

“…More recently, dipeptides EE, ES, and DA have been tested for their anticholesterolemic activity obtaining values of 47.2, 45.5, and 49.6% of HMG-CoA inhibitory activity, respectively, at 1 mM [72].…”