The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients' standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.

Keywords: bistability; chronic fatigue syndrome; critical point; indoleamine-2,3-dioxygenase; kynurenine pathway; mathematical model; myalgic encephalomyelitis; substrate inhibition; tryptophan metabolism.

Figure 1

Differences in IDO1 (red) and IDO2 (blue) enzyme kinetics as functions of Trp concentration. Total IDO flux (green) is the sum of the IDO1 and IDO2 fluxes. (a) Wild type situation with IDO1 and IDO2 having comparable V_max values; (b) Fluxes when IDO2 flux is 90% reduced, for example, by the homozygous common damaging mutation, R248W.

Figure 2

Diagram of the kinetic model of the IDO metabolic trap. Colored rectangles represent molecules in either extracellular space or serotonergic neuron cytosol. Arrows represent processes including transport and biochemical reactions. LAT1 = large neutral amino acid transporter (SLC7A5:SLC3A2), IDO = indoleamine-2,3-dioxygenase, AFMID = arylforamidase, TPH = tryptophan hydroxylase, AADC = aromatic amino acid decarboxylase.

Figure 3

Multiple steady-states in the simplest model of LAT1 tryptophan (Trp) transport and IDO1-mediated Trp oxidation. Horizontal axis: cytosolic Trp abundance. Vertical axis: Fluxes (molecules·min⁻¹·cell⁻¹) cellular Trp influx (blue) carried by the LAT1 membrane transporter, and Trp removal (red) catalyzed by IDO1. Three possible steady-states are defined by the three points (A, B, and C) where the two fluxes are equal. Numerical parameter values are: $k_{cat}^{IDO1}$ = 84 molecules·min⁻¹ IDO1·molecule⁻¹, $IDO{1}_{cyto}$ = 208 IDO1 molecules/cell, $K_M^{Trp}$ = 3.4 × 10⁷ molecules/cell, $K_i^{Trp}$ = 2.5 × 10⁸ molecules/cell, $V_{mf}$ = 1.2 × 10⁸ molecules·min⁻¹·cell⁻¹, $T_{ECF}$ = 1.5 × 10⁹ molecules/cell, $K_{eq}$ = 3.43, $K_s^{T_{ECF}}$ = 2.2 × 10¹⁰ molecules/cell, $K_s^{T_{cyto}}$ = 2 × 10⁹ molecules/cell, $A$ = 5 × 10⁶ molecules/cell, and $K_i^A$ = 4.3 × 10³ molecules/cell.