The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
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 sympto...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Diagnostics |
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| Online Access: | https://www.mdpi.com/2075-4418/9/3/82 |
| _version_ | 1817989366680649728 |
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| author | Alex A. Kashi Ronald W. Davis Robert D. Phair |
| author_facet | Alex A. Kashi Ronald W. Davis Robert D. Phair |
| author_sort | Alex A. Kashi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T00:46:05Z |
| format | Article |
| id | doaj.art-5ed06f4781d44c099386f9590c5e3aaa |
| institution | Directory Open Access Journal |
| issn | 2075-4418 |
| language | English |
| last_indexed | 2024-04-14T00:46:05Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Diagnostics |
| spelling | doaj.art-5ed06f4781d44c099386f9590c5e3aaa2022-12-22T02:22:00ZengMDPI AGDiagnostics2075-44182019-07-01938210.3390/diagnostics9030082diagnostics9030082The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFSAlex A. Kashi0Ronald W. Davis1Robert D. Phair2Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USAStanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USAIntegrative Bioinformatics Inc., Mountain View, CA 94041, USAMyalgic 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.https://www.mdpi.com/2075-4418/9/3/82tryptophan metabolismindoleamine-2,3-dioxygenasebistabilitykynurenine pathwaysubstrate inhibitionmyalgic encephalomyelitischronic fatigue syndromemathematical modelcritical point |
| spellingShingle | Alex A. Kashi Ronald W. Davis Robert D. Phair The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS Diagnostics tryptophan metabolism indoleamine-2,3-dioxygenase bistability kynurenine pathway substrate inhibition myalgic encephalomyelitis chronic fatigue syndrome mathematical model critical point |
| title | The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS |
| title_full | The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS |
| title_fullStr | The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS |
| title_full_unstemmed | The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS |
| title_short | The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS |
| title_sort | ido metabolic trap hypothesis for the etiology of me cfs |
| topic | tryptophan metabolism indoleamine-2,3-dioxygenase bistability kynurenine pathway substrate inhibition myalgic encephalomyelitis chronic fatigue syndrome mathematical model critical point |
| url | https://www.mdpi.com/2075-4418/9/3/82 |
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