Family 11: Amino Acid and Neurotransmitter Metabolism
Family overview. Amino acid catabolism provides structural proteins and metabolic intermediates, including neurotransmitter precursors and NAD⁺. Disruption of these pathways simultaneously alters neurotransmitter availability, energy metabolism, and immune regulation.
Concrete mechanisms and ME/CFS evidence:
Tryptophan/IDO/kynurenine pathway dysregulation. IDO1 and IDO2 divert tryptophan from serotonin synthesis toward kynurenine catabolism under immune activation. In ME/CFS: elevated 3-hydroxykynurenine (3HK) and 3-hydroxyanthranilic acid (3HAA), with implications for neuroimmune regulation and cytotoxic T cell function (Kavyani et al. 2022).
IDO metabolic trap (bistable system). Phair’s mathematical model proposes that dysfunctional IDO2, combined with IDO1 substrate inhibition at high tryptophan concentrations and kinetic asymmetry of the LAT1 transporter, creates a bistable system with two stable steady states: a physiological state and a pathological “locked” state where tryptophan metabolism is dysregulated. This formal model predicts discrete disease-onset events and treatment targets (Phair, Davis, and Kashi 2019).
Serotonin depletion. Elevated tryptophan/serotonin (Trp/5-HT) ratio indicates reduced serotonin synthesis; consistent with IDO-mediated rerouting. Contributes to non-restorative sleep, affective symptoms, and gut motility disruption.
NAD⁺ biosynthesis impairment. The kynurenine pathway is the primary endogenous route to NAD⁺; its disruption reduces NAD⁺ availability and further impairs mitochondrial OXPHOS and DNA repair capacity (linking back to Families 1 and 12).
Global amino acid depletion. Plasma amino acid profiles show depletion at baseline; limited precursor substrate for energy metabolism, neurotransmitter synthesis, and immune cell proliferation during exertion (Naviaux et al. 2016).
Glutamate/GABA imbalance (indirect). Glutamate is an amino acid metabolite; E/I imbalance (Family 10) partly reflects altered glutamate synthesis and reuptake; kynurenic acid (a kynurenine metabolite) is an NMDA receptor antagonist — its reduction may contribute to glutamate excitotoxicity.
Full discussion: Energy Metabolism and Mitochondrial Function and Neurological and Neurocognitive Dysfunction.
Evidence status: Probable (tryptophan metabolomics replicated; IDO trap is a formal mathematical hypothesis with experimental support; NAD⁺ and amino acid depletion mechanistically coherent).