title: Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase.
abstract: Mitochondrial sn-glycerol 3-phosphate dehydrogenase (mGPDH) is a ubiquinone-linked enzyme in the mitochondrial inner membrane best characterized as part of the glycerol phosphate shuttle that transfers reducing equivalents from cytosolic NADH into the mitochondrial electron transport chain. Despite the widespread expression of mGPDH and the availability of mGPDH-null mice, the physiological role of this enzyme remains poorly defined in many tissues, likely because of compensatory pathways for cytosolic regeneration of NAD⁺ and mechanisms for glycerol phosphate metabolism. Here we describe a novel class of cell-permeant small-molecule inhibitors of mGPDH (iGP) discovered through small-molecule screening. Structure-activity analysis identified a core benzimidazole-phenyl-succinamide structure as being essential to inhibition of mGPDH while modifications to the benzimidazole ring system modulated both potency and off-target effects. Live-cell imaging provided evidence that iGPs penetrate cellular membranes. Two compounds (iGP-1 and iGP-5) were characterized further to determine potency and selectivity and found to be mixed inhibitors with IC₅₀ and K(i) values between ∼1-15 µM. These novel mGPDH inhibitors are unique tools to investigate the role of glycerol 3-phosphate metabolism in both isolated and intact systems.
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Orr
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Ashok
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Sarantos
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ng
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Shi
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Akos A
authors.initials: AA
authors.lastname: Gerencser
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hughes
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Brand
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D005453:Fluorescence; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000166:cytology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D013386:Succinates; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+); C011116:succinamide