title: A mathematical model gives insights into the effects of vitamin B-6 deficiency on 1-carbon and glutathione metabolism.
abstract: We experimented with a mathematical model for 1-carbon metabolism and glutathione (GSH) synthesis to investigate the effects of vitamin B-6 deficiency on the reaction velocities and metabolite concentrations in this metabolic network. The mathematical model enabled us to independently alter the activities of each of the 5 vitamin B-6-dependent enzymes and thus determine which inhibitions were responsible for the experimentally observed consequences of a vitamin B-6 deficiency. The effect of vitamin B-6 deficiency on serine and glycine concentrations in tissues and plasma was almost entirely due to its effects on the activity of glycine decarboxylase. The effect of vitamin B-6 restriction on GSH concentrations appeared to be indirect, arising from the fact that vitamin B-6 restriction increases oxidative stress, which, in turn, affects several enzymes in 1-carbon metabolism as well as the GSH transporter. Vitamin B-6 restriction causes an abnormally high and prolonged homocysteine response to a methionine load test. This effect appeared to be mediated solely by its effects on cystathionine beta-synthase. Reduction of the enzymatic activity of serine hydroxymethyltransferase (SHMT) had negligible effects on most metabolite concentrations and reaction velocities. Reduction or total elimination of cytoplasmic SHMT had a surprisingly moderate effect on metabolite concentrations and reaction velocities. This corresponds to the experimental findings that a reduction in the enzymatic activity of SHMT has little effect on 1-carbon metabolism. Our simulations showed that the primary function of SHMT was to increase the rate by which the glycine-serine balance was reequilibrated after a perturbation.
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA. hfn@duke.edu
authors.forename: H Frederik
authors.initials: HF
authors.lastname: Nijhout
authors.forename: Jesse F
authors.initials: JF
authors.lastname: Gregory
authors.forename: Courtney
authors.initials: C
authors.lastname: Fitzpatrick
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cho
authors.forename: K Yvonne
authors.initials: KY
authors.lastname: Lamers
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Michael C
authors.initials: MC
authors.lastname: Reed
mesh_terms: D015415:Biomarkers; D002244:Carbon / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D012694:Serine / Q000378:metabolism; D026681:Vitamin B 6 Deficiency / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012694:Serine; D002244:Carbon; D012696:Glycine Hydroxymethyltransferase; D005978:Glutathione; D005998:Glycine