Zhang et al. Plos One manuscript data

Cobalamin and thiol metabolite data are provided for the specified Figures

Cobalamin-related redox metabolic pathways in neuronal cells.

<p>Endocytosis brings TC-bound Cbl species to lysosomes where axial ligands are removed by MMACHC and MeCbl or AdoCbl are subsequently formed by SAM and ATP-dependent pathways, respectively. MeCbl is a required cofactor for methionine synthase, whose activity supports a large number of methylation reactions, including DNA methylation, as well as dopamine-stimulated phospholipid methylation, carried out by the D4 dopamine receptor (D4R). AdoCbl supports MMACoA mutase in mitochondria. Cysteine, which is rate-limiting for GSH synthesis, can be provided either by cellular uptake via the cysteine/glutamate transporter EAAT3 (excitatory amino acid transporter 3) or by transsulfuration of HCY via cystathionine. The latter pathway is restricted in human brain, increasing the importance of growth factor-dependent cysteine uptake by EAAT3.</p

Redox and methylation metabolites in aging and autism.

<p>(a) Redox and methylation pathway metabolites in control subjects of 0–20 yrs (n = 12) compared to subjects of 61–80 yrs (n = 10). (b) GSH/GSSG ratio (left) and SAM/SAH ratio (right) in aging. (c) Redox and methylation pathway metabolites in frontal cortex of autistic subjects (n = 9) compared to age-matched controls (n = 9). (d) GSH/GSSG ratio (left) and SAM/SAH ratio (right) in autism. * Indicates a significant difference from 0–20 yrs group (panels a and b) or control group (panels c and d) (* p < 0.05, ** p < 0.01, *** p < 0.001).</p

Redox and methylation metabolite and cobalamin status in GCLM KO mice.

<p>(a) Redox and methylation metabolite levels in frontal cortex of GCLM KO mice at P40 and P90 (n = 7). Results are expressed as a percentage of the WT level of each metabolite. (b) Levels of five individual Cbl species in frontal cortex of GLCM KO and WT mice at P40 and P90. Inset indicates total Cbl levels. * Indicates a significant difference from control group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p

Methionine synthase activity in autism.

<p>Methionine synthase activity in frontal cortex of autistic and age-matched control subjects measured either with only endogenous Cbl or with the addition of OHCbl. * Indicates a significant difference from control group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p

Cobalamin status in human frontal cortex.

<p>(a) The general structure of Cbl species in which “X” represents various ligands linked to the cobalt atom, giving rise to the five different Cbl species measured in postmortem frontal cortex. (b) Total Cbl levels in frontal cortex of control subjects divided into four age groups: 0–20 yrs (n = 12), 21–40 yrs (n = 5), 41–60 yrs (n = 10) and 61–80 yrs (n = 12). (c) Levels of five individual Cbl species of control subjects in four age groups. (d) Age-dependent decrease of MeCbl in human frontal cortex (n = 43). Inset: Age trends of serum Cbl, frontal cortex total Cbl and MeCbl. Serum Cbl data is from Ref. 30. (e) Total Cbl levels in placenta (n = 6), frontal cortex of fetal (n = 4) and control (0–20 yrs) subjects (n = 12). (f) Levels of five individual Cbl species in placenta (n = 6), frontal cortex of fetal (n = 4) and control (0–20 yrs) subjects (n = 12). * Indicates a significant difference from 0–20 yrs group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p