Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation.
Recent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon in vivo immune...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0053005&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850224551587217408 |
|---|---|
| author | Julian E Fuchs Roland G Huber Susanne von Grafenstein Hannes G Wallnoefer Gudrun M Spitzer Dietmar Fuchs Klaus R Liedl |
| author_facet | Julian E Fuchs Roland G Huber Susanne von Grafenstein Hannes G Wallnoefer Gudrun M Spitzer Dietmar Fuchs Klaus R Liedl |
| author_sort | Julian E Fuchs |
| collection | DOAJ |
| description | Recent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon in vivo immune activation. Though the structural damage of oxidative stress is expected to be comparably small, a structural rationale for this experimental finding was lacking. Hence, we investigated the impact of side chain oxidation at two vicinal cysteine residues on local conformational flexibility in the protein by comparative molecular dynamics simulations. Analysis of backbone dynamics revealed a highly flexible loop region (Tyr138-loop) in proximity to the active center of phenylalanine hydroxylase. We observed elevated loop dynamics in connection with a loop movement towards the active site in the oxidized state, thereby partially blocking access for the substrate phenylalanine. These findings were confirmed by extensive replica exchange molecular dynamics simulations and serve as a first structural explanation for decreased enzyme turnover in situations of oxidative stress. |
| format | Article |
| id | doaj-art-80c6d4828a3a411d9bdf3363f15e75a6 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-80c6d4828a3a411d9bdf3363f15e75a62025-08-20T02:05:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5300510.1371/journal.pone.0053005Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation.Julian E FuchsRoland G HuberSusanne von GrafensteinHannes G WallnoeferGudrun M SpitzerDietmar FuchsKlaus R LiedlRecent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon in vivo immune activation. Though the structural damage of oxidative stress is expected to be comparably small, a structural rationale for this experimental finding was lacking. Hence, we investigated the impact of side chain oxidation at two vicinal cysteine residues on local conformational flexibility in the protein by comparative molecular dynamics simulations. Analysis of backbone dynamics revealed a highly flexible loop region (Tyr138-loop) in proximity to the active center of phenylalanine hydroxylase. We observed elevated loop dynamics in connection with a loop movement towards the active site in the oxidized state, thereby partially blocking access for the substrate phenylalanine. These findings were confirmed by extensive replica exchange molecular dynamics simulations and serve as a first structural explanation for decreased enzyme turnover in situations of oxidative stress.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0053005&type=printable |
| spellingShingle | Julian E Fuchs Roland G Huber Susanne von Grafenstein Hannes G Wallnoefer Gudrun M Spitzer Dietmar Fuchs Klaus R Liedl Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. PLoS ONE |
| title | Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. |
| title_full | Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. |
| title_fullStr | Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. |
| title_full_unstemmed | Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. |
| title_short | Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. |
| title_sort | dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0053005&type=printable |
| work_keys_str_mv | AT julianefuchs dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT rolandghuber dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT susannevongrafenstein dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT hannesgwallnoefer dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT gudrunmspitzer dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT dietmarfuchs dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation AT klausrliedl dynamicregulationofphenylalaninehydroxylasebysimulatedredoxmanipulation |