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Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
An N-terminal peptide containing residues 1-18 was found in the tryptic digest but with a 1-Da mass decrease compared with the theoretical mass calculated from the cDNA sequence. The MS/MS spectrum of this peptide showed that the modification occurs within the first three amino acid residues (Figure 2). By deducing the elemental composition corresponding to the m/z of the b3 ion, we proposed a possible chemical structure for this modification in which the N-terminal Glu was oxidatively deaminated to alpha-ketoglutaric acid. ESI-MS and MS/MS analyses also showed that Trp 94 was heavily oxidized. The unmodified Trp and its singly and doubly oxidized variants (hydroxytryptophan and N-formylkynurenine) were all found in the digest, with the singly oxidized form being the most abundant. In addition, both Asp and Asn were observed at position 49, suggesting that the asparagine residue has been partially deamidated. ECD experiments on a tryptic peptide containing Asp 49 confirmed this modification by detecting both aspartyl and isoaspartyl residues at this position. S-sulfonation at Cys 194 was observed in a tryptic peptide. We have observed S-sulfonation modification in other kappa light chains and transthyretin, and this PTM may play a role in making these proteins amyloidogenic. A peptide in the Lys-C digest was found containing two segments 191-207 and 208-214, but with a 30-Da mass increase, which agrees with the mass difference observed between the two major protein components at 23,170 and 23,200 Da in the reduced sample. This modification may come from the formation of a thiosulfonate linkage between an oxidized C-terminal Cys and a nearby Cys. Besides the b and y series, some fragment ions resulting from the linkage breakdown between two peptides (e*7+SO2, e*7+O2-H, e*7-SH2) were also observed, which support the thiosulfonate linkage between the two cysteine
Tyk2 is a tumor suppressor in colorectal cancer
Published in OncoImmunology, 2022
Stefan Moritsch, Bernadette Mödl, Irene Scharf, Lukas Janker, Daniela Zwolanek, Gerald Timelthaler, Emilio Casanova, Maria Sibilia, Thomas Mohr, Lukas Kenner, Dietmar Herndler-Brandstetter, Christopher Gerner, Mathias Müller, Birgit Strobl, Robert Eferl
Ido1 is the rate-limiting enzyme of the kynurenine pathway. It catalyzes oxidation of tryptophan to N-formylkynurenine, which is further converted to kynurenine and several kynurenine metabolites.55 High Ido1 activity leads to tryptophan depletion and a corresponding increase of kynurenine metabolites. Tryptophan depletion negatively affects proliferation of effector T cells, while kynurenine promotes Treg differentiation via the aryl hydrocarbon receptor.56,57 Consequently, Ido1 creates an immunosuppressive microenvironment with reduced CD8+ T cell count and expansion of Tregs.58–60 Ido1 is frequently overexpressed in human CRC, which is associated with reduced levels of serum tryptophan and increased levels of kynurenine metabolites.61–63 In tumors, Ido1 is expressed by infiltrating myeloid cells and neoplastic epithelial cells.42,43,64 We have shown that the neoplastic epithelium of CRC is an important source of kynurenine.28 Similarly, Ido1-expressing neoplastic epithelial cells of pancreatic ductal adenocarcinomas (PDACs) were critically involved in immune escape.65 We have not performed metabolomics of mouse Tyk2-deficient CRCs. Ido1 expression was reduced in stromal immune cells but not in neoplastic cells of Tyk2Δ/Δ tumors. In contrast, Ido1 expression was unaffected in stromal immune cells but increased in neoplastic cells of Tyk2ΔIEC tumors. Therefore, metabolomics of Tyk2Δ/Δ and Tyk2ΔIEC would help to identify the main source of kynurenine metabolites in CRC.
δEPCD: the electrophysiologic coefficient of depressiveness
Published in Biomarkers, 2021
Rami Bou Khalil, Rhéa El Khoury
From another perspective, a sufficient amount of evidence links the metabolism of tryptophan to the occurrence of depressive symptoms via disturbances in the serotonin synthesis pathway. However, the vast majority of metabolised tryptophan is converted by the two heme-containing enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) into N-formylkynurenine. The activation of IDO by stressful life events, among other factors, is considered to be responsible for the production of neuroprotective substances such as Kynurenic acid (KYNA) as well as neurotoxic substances such quinolinic acid (QUIN) (Savitz et al. 2015a, 2015b). Recent studies have shown that this kynurenine pathway plays an important role in depression as well as in other psychiatric diseases, such as schizophrenia and bipolar disorder. However, the neurobiological effects found in the kynurenine pathway seem to be different in these diseases and depression. While a pathologic shift towards KYNA and away from QUIN production has been found in schizophrenia and bipolar disorder patients, the contrary has been established in the depression model in which KYNA is neuroprotective and QUIN is neurotoxic (Réus et al. 2015).
Changes in kynurenine pathway metabolites after acute psychosocial stress in healthy males: a single-arm pilot study
Published in Stress, 2021
Danique La Torre, Boushra Dalile, Henriette de Loor, Lukas Van Oudenhove, Kristin Verbeke
Increased levels of cortisol and inflammation influence the conversion of the essential amino acid tryptophan (TRP). TRP is catabolized into either kynurenine (KYN; ∼90%), or serotonin (5-HT; ∼3%; Figure 1). TRP is converted by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) into N’-formylkynurenine, which is further hydrolyzed to KYN by N’-formylkynurenine foramidase (Badawy, 2017). KYN can be further metabolized along different pathways, into either kynurenic acid (KYNA) or quinolinic acid (QUINO) and ultimately into oxidized nicotinamide-adenine-dinucleotide+ (Schwarcz et al., 2012), which induce opposite effects. As a highly selective N-methyl-D-aspartate receptor (NMDAR) agonist, QUINO can induce excitotoxicity, whereas KYNA is an NMDAR and α7 nicotinic acetylcholine receptor antagonist and induces neuroprotective effects by inhibiting glutamate signaling (Schwarcz et al., 2012).