Low efficiency <scp>IDO</scp>2 enzymes are conserved in lower vertebrates, whereas higher efficiency <scp>IDO</scp>1 enzymes are dispensable

Yuasa, Hajime; Mizuno, Keiko; Ball, Helen J.

doi:10.1111/febs.13316

Cited by 45 publications

(49 citation statements)

References 49 publications

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“…In this study, together with previously reported distal‐Ser , distal‐Tyr was also detected as crucial for high affinity for l ‐Trp. The two amino acid substitutions (distal‐Thr/Ser and distal‐His/Tyr) bestowed high affinity for l ‐Trp on ancestral IDO2 and chicken IDO2.…”

Section: Resultssupporting

confidence: 85%

“…2C) had a much higher K m (3230 lM) than those of the above-mentioned IDO1s. This value is comparable to those of chicken IDO2 (1840 lM) and frog IDO2 (7310 lM) [3]. A rather high K m value (low affinity for L-Trp) is a common feature among vertebrate IDO2.…”

Section: Resultssupporting

confidence: 68%

“…In a previous report, the distal‐Ser (corresponding to Ser167 of human IDO1) was suggested to be crucial for the high l ‐Trp affinity . However, the distal‐Ser to Thr variants of mammalian IDO1 had K m values < 100 μ m , whereas K m of chicken IDO2 Thr171Ser was 469 μ m , which was the smallest K m among the distal‐Thr to Ser variants.…”

Section: Introductionmentioning

confidence: 83%

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High l‐Trp affinity of indoleamine 2,3‐dioxygenase 1 is attributed to two residues located in the distal heme pocket

Yuasa¹

2016

The FEBS Journal

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Indoleamine 2, 3-dioxygenase (IDO) catalyzes the oxidative cleavage of the pyrrole ring of l-Trp to generate N-formyl-kynurenine. Two IDO genes, IDO1 and IDO2, are found in vertebrates. Mammalian IDO1s are high-affinity, l-Trp-degrading enzymes, whereas IDO2s generally have a relatively low affinity. It has been suggested that the distal-Ser (corresponding to Ser167 of human IDO1) was crucial for improvement in the affinity for l-Trp but this idea was insufficient to explain the high affinity shown by mammalian IDO1. In this study, the amino acid sequences of vertebrate ancestral IDO1 and ancestral IDO2 were inferred, and bacterially expressed ancestral IDOs were characterized. Although the amino acid sequences of the enzymes shared high identity (86%) with each other, they showed distinct enzymatic properties. In analyses of a series of ancestral IDO1/IDO2 chimeric enzymes and their variants, the distal-Tyr (corresponding to Tyr126 of human IDO1) was detected as another and was probably the most crucial residue for high l-Trp affinity. The two amino acid substitutions (distal-Ser to Thr and distal-Tyr to His) drastically decreased the l-Trp affinity and catalytic efficiency of IDO1s. Conversely, two substitutions (distal-Thr to Ser and distal-His to Tyr) were sufficient to bestow IDO1-like high affinity on ancestral and chicken IDO2.

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Section: Resultssupporting

confidence: 85%

Section: Resultssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 83%

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High l‐Trp affinity of indoleamine 2,3‐dioxygenase 1 is attributed to two residues located in the distal heme pocket

Yuasa¹

2016

The FEBS Journal

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“…It is now known that at least three enzymes can do this: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase-1 (IDO1) and indoleamine 2,3-dioxygenase-2 (IDO2) [47]. Studies have demonstrated that some fish species have genes for all three of these enzymes though efficiency for the conversion of tryptophan by the fish IDO2 enzyme is very low compared with mammals while IDO1 has moderate efficiency compared to mammals [48, 49]. In mammals, tryptophan 2,3-dioxygenase is found predominantly in the liver, while IDO1 and two are also found in the kidney and testes and less in the liver [47, 50].…”

Section: Discussionmentioning

confidence: 99%

Sea lampreys elicit strong transcriptomic responses in the lake trout liver during parasitism

et al. 2016

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BackgroundThe sea lamprey (Petromyzon marinus) is a jawless vertebrate that parasitizes fish as an adult and, with overfishing, was responsible for the decline in lake trout (Salvelinus namaycush) populations in the Great Lakes. While laboratory studies have looked at the rates of wounding on various fish hosts, there have been few investigations on the physiological effects of lamprey wounding on the host. In the current study, two morphotypes of lake trout, leans and siscowets, were parasitized in the laboratory by sea lampreys and the liver transcriptomes of parasitized and nonparasitized fish were analyzed by RNA-seq (DESeq2 and edgeR) to determine which genes and gene pathways (Ingenuity Pathway Analysis) were altered by lamprey parasitism.ResultsOverall, genes encoding molecules involved in catalytic (e.g., enzymatic) and binding activities (factors and regulators) predominated the regulated gene lists. In siscowets, the top upregulated gene was growth arrest and DNA-damage-inducible protein and for leans it was interleukin-18-binding protein. In leans, the most significantly downregulated gene was UDP-glucuronosyltransferase 2A2 - DESeq2 or phosphotriesterase related - edgeR. For siscowets, the top downregulated gene was C-C motif chemokine 19 - DESeq2 or GTP-binding protein Rhes - edgeR. Gene pathways associated with inflammatory-related responses or factors (cytokines, chemokines, oxidative stress, apoptosis) were regulated following parasitism in both morphotypes. However, pathways related to energy metabolism (glycolysis, gluconeogenesis, lipolysis, lipogenesis) were also regulated. These pathways or the intensity or direction (up/downregulation) of regulation were different between leans and siscowets. Finally, one of the most significantly downregulated pathways in both leans and siscowets was the kynurenine (tryptophan degradation) pathway.ConclusionsThe results indicate a strong transcriptional response in the lake trout to lamprey parasitism that entails genes involved in the regulation of inflammation and cellular damage. Responses to energy utilization as well as hydromineral balance also occurred indicating an adjustment in the host to energy demands and osmotic imbalances during parasitism. Given the role of the kynurenine pathway in promoting immunotolerance in mammals, the downregulation observed in this pathway during parasitism may signify an attempt by the host to inhibit any feedback suppression of the immune response to the lamprey.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2959-9) contains supplementary material, which is available to authorized users.

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“…These two enzymes resulted from an ancient gene duplication of an ancestral IDO with relatively low tryptophan catalytic activity (1). The immunoregulatory properties of IDO were first revealed in pharmacological studies of an IDO pathway inhibitor which suggested a critical role in maintaining maternal-fetal tolerance through a T cell-dependent mechanism (2).…”

Section: Introductionmentioning

confidence: 99%

IDO2 Modulates T Cell–Dependent Autoimmune Responses through a B Cell–Intrinsic Mechanism

Merlo

DuHadaway

Grabler

et al. 2016

The Journal of Immunology

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Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self antigens, however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, antigen-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, where IDO2-expresing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2 deficient B cells lacked the ability to upregulate the co-stimulatory marker CD40, suggesting IDO2 acts at the T:B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross-talk between autoreactive T and B cells.

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Low efficiency IDO2 enzymes are conserved in lower vertebrates, whereas higher efficiency IDO1 enzymes are dispensable

Cited by 45 publications

References 49 publications

High l‐Trp affinity of indoleamine 2,3‐dioxygenase 1 is attributed to two residues located in the distal heme pocket

High l‐Trp affinity of indoleamine 2,3‐dioxygenase 1 is attributed to two residues located in the distal heme pocket

Sea lampreys elicit strong transcriptomic responses in the lake trout liver during parasitism

IDO2 Modulates T Cell–Dependent Autoimmune Responses through a B Cell–Intrinsic Mechanism

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