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

1
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
2
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
3
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
*
Author to whom correspondence should be addressed.
Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Received: 24 May 2019 / Revised: 22 July 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)
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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. View Full-Text
Keywords: tryptophan metabolism; indoleamine-2,3-dioxygenase; bistability; kynurenine pathway; substrate inhibition; myalgic encephalomyelitis; chronic fatigue syndrome; mathematical model; critical point tryptophan metabolism; indoleamine-2,3-dioxygenase; bistability; kynurenine pathway; substrate inhibition; myalgic encephalomyelitis; chronic fatigue syndrome; mathematical model; critical point
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Kashi, A.A.; Davis, R.W.; Phair, R.D. The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. Diagnostics 2019, 9, 82.

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