Rate-Limiting Enzymes in Cardiometabolic Health and Aging in Humans

Abstract

Introduction. Rate-limiting enzymes (RLEs) are innate slow points in metabolic pathways, and many function in bioprocesses related to nutrient sensing. Many RLEs carry causal mutations relevant to inherited metabolic disorders. Because the activity of RLEs in cardiovascular health is poorly characterized, our objective was to assess their involvement in cardiometabolic health and disease, and where altered biophysical and biochemical functions can promote disease. Methods. A dataset of 380 human RLEs was compared to protein and gene datasets for factors likely to contribute to cardiometabolic disease, including proteins showing significant age-related altered expression in blood, and genetic loci with variants that associate with common cardiometabolic phenotypes. The biochemical reactions catalyzed by RLEs were evaluated for metabolites enriched in RLE subsets associating with various cardiometabolic phenotypes. Most significance tests were based on Z-score enrichment converted to P values with a normal distribution function. Results. Of 380 RLEs analyzed, 112 function in mitochondria, and 53 are assigned to inherited metabolic disorders. There was a depletion of RLE proteins known as aging biomarkers. At the gene level, RLEs were assessed for common genetic variants that associated with important cardiometabolic traits of LDL-cholesterol or any of the five outcomes pertinent to metabolic syndrome. This revealed several RLEs with links to cardiometabolic traits, from a minimum of 26 for HDL-cholesterol to a maximum of 45 for plasma glucose. Analysis of these GWAS-linked RLEs for enrichment of the molecular constituents of the catalyzed reactions disclosed a number of significant phenotype-metabolite links. These included blood pressure with acetate (P = 2.2x10-4) and NADP+ (P = 0.0091), plasma HDL-cholesterol and triglyceride with diacylglycerol (P = 2.6x10-5, 6.4x10-5, respectively) and diolein (P = 2.2x10-6, 5.9x10-6), and waist circumference with D-glucosamine 6-phosphate (P = 1.8x10-4). Conclusion. In the context of cardiometabolic health, aging and disease, these results highlight key diet-derived metabolites that are central to specific rate-limited processes that are linked to cardiometabolic health. These metabolites include acetate and diacylglycerol, pertinent to blood pressure and triglycerides, respectively, as well as diacylglycerol and HDL-cholesterol.

Metabolic Insights into Neuropsychiatric Illnesses and Ketogenic Therapies: A Transcriptomic View

“…A notable observation was the pronounced perturbation of gene(s) encoding the rate-limiting enzyme in each pathway across all disease profiles. Rate-limiting enzymes are pivotal as they represent inherent bottlenecks, dictating the overall flux through those pathways [68]. Thus, perturbations in the expression of genes encoding rate-limiting enzymes may profoundly influence the activity of the entire pathway, contributing to the metabolic dysfunction observed in disease states and offering targets for therapeutic intervention.…”