A functional missense variant inlinks methionine salvage to reduced type 2 diabetes risk
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Summary Type 2 diabetes (T2D) pathogenesis is shaped by both risk and protective genetic variants, but mechanisms underlying disease protection remain understudied. Previously, in a population isolate with high T2D prevalence, we unexpectedly identified a relatively frequent protective missense variant (Arg149Cys, rs551664067 C/T) in the methionine salvage gene, never reported for T2D. MRI1 is expressed in human pancreatic islets and insulin-responsive tissues, with islet expression correlating with insulin expression. Using MRI1’s resolved crystal structure, we show Arg149Cys substitution compacts the ligand-binding pocket by >53%, and enzyme kinetics confirm enhanced substrate engagement and 18.6% improved catalytic flux, boosting methionine salvage for downstream pathway enzymes. Circulating methionine levels inversely correlated with insulin sensitivity, consistent with enhanced MRI1 activity channeling methionine into salvage rather than pathological accumulation. Together, MRI1 is identified as a metabolic regulator that links enzyme biophysics to efficient methionine recycling and T2D protection, showcasing quantitative NMR as a genetics-to-mechanism bridge. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.webp undfig1 anchor portrait graphical abs00151 Highlights • MRI1 Arg149Cys protective gain-of-function variant delays T2D onset by 5 years u0010 • MRI1 Cys149 shows stability-activity trade-off with enhanced catalytic kinetics u0015 • Arg14
Abstract
Summary Type 2 diabetes (T2D) pathogenesis is shaped by both risk and protective genetic variants, but mechanisms underlying disease protection remain understudied. Previously, in a population isolate with high T2D prevalence, we unexpectedly identified a relatively frequent protective missense variant (Arg149Cys, rs551664067 C/T) in the methionine salvage gene, never reported for T2D. MRI1 is expressed in human pancreatic islets and insulin-responsive tissues, with islet expression correlating with insulin expression. Using MRI1’s resolved crystal structure, we show Arg149Cys substitution compacts the ligand-binding pocket by >53%, and enzyme kinetics confirm enhanced substrate engagement and 18.6% improved catalytic flux, boosting methionine salvage for downstream pathway enzymes. Circulating methionine levels inversely correlated with insulin sensitivity, consistent with enhanced MRI1 activity channeling methionine into salvage rather than pathological accumulation. Together, MRI1 is identified as a metabolic regulator that links enzyme biophysics to efficient methionine recycling and T2D protection, showcasing quantitative NMR as a genetics-to-mechanism bridge. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.webp undfig1 anchor portrait graphical abs00151 Highlights • MRI1 Arg149Cys protective gain-of-function variant delays T2D onset by 5 years u0010 • MRI1 Cys149 shows stability-activity trade-off with enhanced catalytic kinetics u0015 • Arg149Cys enables efficient methionine salvage conferring T2D protection u0020 • High-resolutionH-NMR spectra of 3 key methionine salvage intermediates provided u0025 simple ulist0010 author-highlights abs0015 Spectroscopy; Molecular biology; Data analysis in structural biology teaser abs0020