Tryptophan

Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.[Pubmed:25189339]

J Nucl Med. 2014 Oct;55(10):1605-10.

UNLABELLED: alpha-(11)C-methyl-L-Tryptophan (AMT) PET allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III-IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral Tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of Tryptophan metabolic abnormalities in the nontumoral hemisphere of glioma patients. METHODS: Standardized AMT uptake values (SUVs) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in nontumoral gray matter) were quantified in the frontal and temporal cortex and thalamus in the nontumoral hemisphere in 77 AMT PET scans of 66 patients (41 men, 25 women; mean age +/- SD, 55 +/- 15 y) with grade III-IV gliomas. These AMT values were determined before treatment in 35 and after treatment in 42 patients and were correlated with clinical variables and survival. RESULTS: AMT uptake in the thalamus showed a moderate age-related increase before treatment (SUV, r = 0.39, P = 0.02) but decrease after treatment (K, r = -0.33, P = 0.057). Women had higher thalamic SUVs before treatment (P = 0.037) and higher thalamic (P = 0.013) and frontal cortical K values (P = 0.023) after treatment. In the posttreatment glioma group, high thalamic SUVs and high thalamocortical SUV ratios were associated with short survival in Cox regression analysis. The thalamocortical ratio remained strongly prognostic (P < 0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy, were entered in the regression model. Long interval between radiotherapy and posttreatment AMT PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values. CONCLUSION: These observations provide evidence for altered Tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic Tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.

Differential tolerance of 'pseudo-pathogenic' tryptophan residues in calcium-binding EGF domains of short fibulin proteins.[Pubmed:25481286]

Exp Eye Res. 2015 Jan;130:66-72.

An Arg345Trp (R345W) mutation in the last canonical calcium-binding epidermal growth factor (cbEGF) domain of fibulin-3 (F3) causes the rare macular dystrophy, Malattia Leventinese (ML). In cell culture studies, this mutation leads to inefficient F3 secretion and higher intracellular steady state levels, likely due to F3 disulfide bonding and/or protein folding problems. However, how the R345W mutation actually causes ML is still largely unknown. Herein we tested whether the introduction of analogous, 'pseudo-pathogenic' Tryptophan mutations immediately after the bn cysteine (bn+1) in other cbEGF domains also caused protein folding/secretion challenges. We found that introduction of Tryptophan mutations into each of the four other F3 canonical cbEGF domains caused a significant reduction in protein secretion ranging from 2.7 to 56% of wild-type (WT) F3 levels. Surprisingly, an R185W mutation in the first canonical cbEGF domain of F3 yielded the highest amount of secretion among the F3 Tryptophan mutants, and its secretion defect could be rescued to near WT levels (95%) after growth temperature reduction. Interestingly, when similarly positioned Tryptophan mutations were introduced into any of the canonical cbEGF domains of the highly homologous protein, fibulin-5 (F5), there was no effect on secretion. In an attempt to make F3 tolerant of Tryptophan residues (like F5), we genetically engineered F3 to have a higher sequence homology with F5 by deleting three insert regions present in F3, but not F5. However, deletion of one or more of these regions did not have a beneficial effect on R345W F3 secretion. Overall, these results demonstrate that the introduction of Tryptophan residues at the bn+1 position does not universally disrupt cbEGF domain folding and secretion, but that their effect is context dependent, and in this case, uniquely disrupt the folding of canonical cbEGF domains of F3, but not F5.

Tryptophan-containing dipeptides are C-domain selective inhibitors of angiotensin converting enzyme.[Pubmed:25053098]

Food Chem. 2015 Jan 1;166:596-602.

Somatic angiotensin-converting enzyme (ACE) contains two active sites, the C- and N-domain, from which the C-domain is supposed to play a major role in blood pressure regulation and is therefore a promising pharmacological target to reduce blood pressure without side-effects. We report for the first time that Tryptophan-containing dipeptides such as Ile-Trp or Val-Trp, which were recently found in food protein hydrolysates, are selective and competitive inhibitors for the C-domain with a selectivity factor of 40 and 70, respectively. Structure-activity studies showed that an N-terminal aliphatic amino acid and a Tryptophan moiety in the P2' position are favourable structures for C-domain inhibition in dipeptides. In contrast, the lactotripeptides Ile-Pro-Pro and Val-Pro-Pro, which were widely used as ingredients for hypotensive food, showed a slight selectivity for the N-domain. Hence, Tryptophan containing dipeptides are interesting ingredients for functional foods as a natural prevention for hypertension with reduced side effects due to its selective inhibition of the C-domain.