title: Mathematical modeling of the methionine cycle and transsulfuration pathway in individuals with autism spectrum disorder.
abstract: Previous research has shown a connection between metabolic abnormalities in the methionine cycle and transsulfuration pathway and autism spectrum disorder. Using clinical data from a case-control study investigating measurements of transmethylation and transsulfuration metabolites, a steady-state model of these metabolites in liver cells was developed and participant-specific parameters were identified. Comparison of mean parameter values and parameter distributions between neurotypical study participants and those on the autism spectrum revealed significant differences for four model parameters. Sensitivity analysis identified the parameter describing the rate of glutamylcysteine synthesis, the rate-limiting step in glutathione production, to be particularly important in determining steady-state metabolite concentrations. These results may provide insight into key reactions to target for potential intervention strategies relating to autism spectrum disorder.
authors.affiliation: Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Vargason
authors.affiliation: Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Howsmon
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
authors.affiliation: Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA. Electronic address: hahnj@rpi.edu.
authors.forename: Juergen
authors.initials: J
authors.lastname: Hahn
mesh_terms: D000067877:Autism Spectrum Disorder / Q000378:metabolism*; D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000378:metabolism*; D008962:Models, Theoretical; D013455:Sulfur / Q000378:metabolism*
chemical_list: D013455:Sulfur; D008715:Methionine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Parameter estimation; Personalized model; Sensitivity analysis; Steady-state analysis; Transmethylation